Dopamine and the regulation of cognition and...

Progress in Neurobiology 67 (2002) 53–83

Dopamine and the regulation of cognition and attention

André Nieoullon∗Neurobiology Unit at the CNRS, Université de La Méditerranée, 31 Chemin Joseph Aiguier, 13402 Marseille Cedex 20, France

Received 1 November 2001; received in revised form 13 March 2002; accepted 15 March 2002

Abstract

Dopamine (DA) acts as a key neurotransmitter in the brain. Numerous studies have shown its regulatory role for motor and limbicfunctions. However, in the early stages of Parkinson’s disease (PD), alterations of executive functions also suggest a role for DA in regulatingcognitive functions. Some other diseases, which can also involve DA dysfunction, such as schizophrenia or attention deficit hyperactivitydisorder (ADHD) in children, as shown from the ameliorative action of dopaminergic antagonists and agonists, respectively, also showalteration of cognitive functions. Experimental studies showed that selective lesions of the dopaminergic neurons in rats or primates canactually provide cognitive deficits, especially when the mesocorticolimbic component of the dopaminergic systems is altered. Data from theexperiments also showed significant alteration in attentional processes, thus raising the question of direct involvement of DA in regulatingattention. Since the dopaminergic influence is mainly exerted over the frontal lobe and basal ganglia, it has been suggested that cognitivedeficits express alteration in these subcortical brain structures closely linked to cortical areas, more than simple deficit in dopaminergictransmission. This point is still a matter of debate but, undoubtedly, DA acts as a powerful regulator of different aspects of cognitive brainfunctions. In this respect, normalizing DA transmission will contribute to improve the cognitive deficits not only related to neurologic orpsychiatric diseases, but also in normal aging. Ontogenic and phylogenetic analysis of dopaminergic systems can provide evidences for arole of DA in the development of cognitive general capacities. DA can have a trophic action during maturation, which may influence thelater cortical specification, particularly of pre-frontal cortical areas. Moreover, the characteristic extension of the dopaminergic corticalinnervation in the rostro-caudal direction during the last stages of evolution in mammals can also be related to the appearance of progressivelymore developed cognitive capacities. Such an extension of cortical DA innervation could be related to increased processing of corticalinformation through basal ganglia, either during the course of evolution or development. DA has thus to be considered as a key neuroregulatorwhich contributes to behavioral adaptation and to anticipatory processes necessary for preparing voluntary action consequent upon intention.All together, it can be suggested that a correlation exists between DA innervation and expression of cognitive capacities. Altering thedopaminergic transmission could, therefore, contribute to cognitive impairment. © 2002 Elsevier Science Ltd. All rights reserved.

Keywords:Dopamine; Cognition; Attention

Contents

1. Introduction: aims and scope of the review. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 542. Cognitive deficits in Parkinson’s disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 553. Schizophrenia, cognition and dopamine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 574. The attention deficit hyperactivity syndrome in children: further contribution of dopaminergic

dysfunction?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 575. Autism and dopamine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 586. Experimental evidence for the contribution of dopamine to cognitive processes. . . . . . . . . . . . . . . . . . . . . 58

6.1. Lessons from experimental neurology: behavioral consequences of lesioning the dopaminergicneurons or terminals. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 596.1.1. Behavioral consequences of lesioning the nigrostriatal dopaminergic system. . . . . . . . . . . . . 596.1.2. Behavioral consequences of lesioning the mesocorticolimbic dopaminergic system. . . . . . . 60

∗ Tel.: +33-4-91-16-4128; fax:+33-4-91-77-5083.E-mail address:[email protected] (A. Nieoullon).

0301-0082/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved.PII: S0301-0082(02)00011-4

54 A. Nieoullon / Progress in Neurobiology 67 (2002) 53–83

6.1.3. Cortical dopamine and the pre-pulse inhibition of acoustic startle as a model to furtherinvestigate the role of cortical dopaminergic innervation in the cognitive signs ofschizophrenia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

6.1.4. Behavioral consequences of lesioning the dopaminergic terminals at the level of thesubthalamicus nucleus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

6.2. Dopaminergic neurons and attentional processes: more general implications. . . . . . . . . . . . . . . . . . . 626.3. Further lessons from recording neuronal activity in behaving animals. . . . . . . . . . . . . . . . . . . . . . . . . 63

7. Mechanisms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 657.1. Complexity of the anatomo-functional organization of the dopaminergic systems. . . . . . . . . . . . . . . 657.2. The action of dopamine at the cellular level. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 667.3. What subtypes of dopaminergic receptors are likely to be involved in cognitive processes?. . . . . . 677.4. Further illustrations of dopaminergic modulation of brain function. . . . . . . . . . . . . . . . . . . . . . . . . . . . 677.5. Molecular changes associated with alterations in central dopaminergic function. . . . . . . . . . . . . . . . 687.6. Dopamine in the basal ganglia: the role of the basal ganglia in cognition. . . . . . . . . . . . . . . . . . . . . . 68

8. Are cognitive deficits sensitive to stimulation of dopaminergic transmission?. . . . . . . . . . . . . . . . . . . . . . . 708.1. l-DOPA and dopamine agonists in Parkinson’s disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 708.2. Schizophrenia and attentional deficits in children. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 718.3. Is the cognitive impairment of normal aging sensitive to stimulation of the dopaminergic

transmission?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 719. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

9.1. Dopamine as a common regulator of motor, limbic and cognitive aspects of behavior. . . . . . . . . . 719.2. Dopamine and cognition: is the development of the dopaminergic system parallel to

the development of cognitive functions in human?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 729.2.1. Phylogenetic evidence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 729.2.2. Ontogenetic evidence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

9.3. Final remarks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74

Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

1. Introduction: aims and scope of the review

Dopamine (DA) was identified as a brain neurotransmit-ter about 50 years ago and has since been the subject of anextraordinary number of publications. Due to the early dis-covery of a robust correlation between the amount of striatalDA depletion and motor deficits observed in Parkinson’sdisease (PD) (Bernheimer et al., 1965), the involvement ofDA in movement control has long been emphasized. Thediscovery of the role of DA in the motoric componentsof PD (Bernheimer et al., 1973) initiated a long series ofexperiments and clinical investigations, which are still inprogress, leading to the development ofl-DOPA therapyand then to other types of medications to improve thepatient’s symptoms.

At about this time, the characterization of “neuroleptics”as powerful and rather selective blockers of DA receptorsassociated with the observations that DA agonists exacer-bate psychosis led to the suggestion of the involvement ofdopaminergic transmission in schizophrenia (Swerdlow andKoob, 1987). Patients in the latter case could benefit fromefficient antipsychotic drug development. Neuroleptics werefound to induce severe side effects, particularly in terms ofextrapyramidal movement disorders. However, characteriza-tion of more selective compounds acting at the various DAreceptor subtypes contributed to better improvement of thepsychotic patients and reduction in the motor side effects.

The efficacy of DA antagonists in the treatment of psychosisled to the concept of hyperactive DA neurons in some formsof schizophrenia (Deutch, 1993; Gray, 1994), a concept fur-ther supported by the discovery of a dopaminergic innerva-tion at the cortical level (Thierry et al., 1973).

A third area in which a connection between DA and be-havior has been made is reinforcement processes and drugabuse. DA is thought to play a key role in motivation andto contribute to the “drive” of action. For example, numer-ous studies have suggested the involvement of DA as a keytransmitter in cocaine dependency. However,Wickelgren(1997) noted that DA is not a “pleasure juice” as it wasemphasized to be during the 1970s (Wise, 1996). In fact,the idea today is that DA contributes to control more inte-grative aspects of behavior rather than represents a majorcomponent of a reward system. In this respect it has beenshown that DA neuron activation correlates with the detec-tion of salient stimuli, as suggested bySchultz et al. (1997)in monkeys. The situation, however, is probably morecomplex still, since DA hyperactivity can conversely con-tribute to disrupt attentional processes to external stimuli,as shown, for example, in schizophrenic patients (Cohenand Servan-Schreiber, 1993). Finally, signs of abnormalDA transmission have also been found in Alzheimer’s dis-ease, Tourette’s disease, Huntington’s chorea, autism andbipolar disorders and a role of DA in the attention deficithyperactivity disorder (ADHD) syndrome in children is also

A. Nieoullon / Progress in Neurobiology 67 (2002) 53–83 55

suspected. Because all these disorders can express cognitivedysfunctions, DA is thought to be involved in the broadregulation of brain output and behavior.

The deficits of patients suffering PD in accomplishingexecutive functions first raised the suggestion of a contri-bution of DA in controlling non-motor aspects of behavior.Numerous clinical and experimental studies have now in-vestigated this question (Brown, 1994; Dubois et al., 1994;Lees and Smith, 1983; Owen et al., 1992; Owen et al.,1993), but it still remains difficult to answer the questionof what actual DA contribution is to cognitive functions.Thus, although numerous excellent review papers havefocused on different aspects of the contribution of DA tothe regulation of behavior (Iversen, 1977; Le Moal andSimon, 1991; Salamone, 1991; Blackburn et al., 1992), theaim of the present review is to collect information arisingfrom clinical reports and experimental studies to furtherdiscuss the putative contribution of DA to cognitive andattentional processes. By cognitive processes, we under-stand here non-motor, -limbic aspects of behavior primarilyrelated to planning aspects of voluntary action. Such pro-cesses suppose reference to memorized past events as wellas close “on-line” integration of the environmental contextof action, correct time estimation and anticipatory adaptiveprogramming involving executive functions and workingmemory processes. In this respect, the contribution of DA topre-frontal cortex (PFC) activity will be particularly empha-sized as well as investigations on the putative improvementof non-motor aspects of Parkinsonism by dopaminergicagonists in patients. Finally, we will explore whether thefunctioning and further development of the dopaminergicsystem during ontogenesis and phylogenesis provides a keyelement for the expression of cognitive capacities.

2. Cognitive deficits in Parkinson’s disease

Numerous studies have shown the occurrence of cognitivedeficits in PD, although there is not yet a complete consen-sus on this issue (Brown and Marsden, 1990). The complex-ity of the deficit measured in a series of neuropsychologicaltests and analyses regarding the severity of patients and anymedication they may be taking contribute to the difficulty ofevaluating the nature of such deficits. Impairment of differ-ent aspects of visuospatial function, for example, has beenstudied for a long time (Proctor et al., 1976; Bowen et al.,1972; Bowen, 1976), but the significance of such deficits isstill discussed in terms of the inability to plan motor tasks(Boller et al., 1984; Taylor et al., 1986; Brown and Marsden,1988). Severe deficits have been particularly shown in visu-ospatial tests when mental rotation was required (Ransmayret al., 1987; Lichter et al., 1988; Laverhne et al., 1989), butthe evaluation of these deficits remains uncertain due to as-sociated movement impairment. However, since such clini-cal signs are recognized to occur in the early stages of PDwhen the neurodegenerative process is rather limited to the

nigrostriatal dopaminergic system, it can be proposed thatthis striatal DA is involved in the control of functions relatedto frontal cortical areas (Malapani et al., 1994).

Patients with PD have profound difficulties in motor plan-ning that, perhaps, can be related to an ideomotor apraxia,thus resulting in a slowness in initiating motor action, also af-fecting the generation of ideas and plans. The sequential or-ganization of behavior is considered to be markedly impairedin such patients, since complex behavior is actually consider-ably more affected than simple motor tasks in PD (Berardelliet al., 1986; Goldenberg et al., 1986). Marsden (1982, 1984)indicated that Parkinsonian patients are impaired if theydo not have sufficient external information to establish astrategy for action. It has been shown that the ability to usenon-visual feedback is impaired during the execution of armmovements in patients (Klockgether and Dichgans, 1994), aswe have previously demonstrated under similar experimen-tal conditions in the monkey following lesions of the sub-stantia nigra (Viallet et al., 1987). Conversely, when explicitinformation is available, the patients show no deficit in per-forming even complex tasks. Recent evidence from our labo-ratory highlighted the role of advance information for motorpreparation in a reaction-time procedure in Parkinsonianpatients. Patients have no difficulty in identifying a stimulusand selecting the appropriate primed motor response (Gueyeet al., 1998). These data are consistent with those previouslyobtained byBrown et al. (1993)showing no impairment inreaction-time tasks with either response uncertainty or re-sponse compatibility in a two-choice situation. Moreover, asnoticed byGlickstein and Stein (1991), reflexive behavior isnot considered markedly altered, whereas voluntary actionis strongly impaired, particularly when the patient is askedto rapidly repeat internally generated movements (Stelmachet al., 1987), further suggesting that patients are able to cor-rectly perform externally guided tasks, in agreement withMarsden’s (1982, 1984)earlier proposal. In this context,however, the role of the dopaminergic neurons is not clear,but evidence has been obtained for a contribution of DAto the evaluation of the extrapersonal space (Crow, 1973).Moreover, experiments in rats and monkeys with nigrostri-atal dopaminergic lesions have emphasized the occurrence ofa neglect-like syndrome (Ljungberg and Ungerstedt, 1976;Feeney and Wier, 1979; Viallet et al., 1981). No impairmentof sensory stimulus discrimination was found, however,thus indicating no primary deficit in the sensory informationprocessing in these animals (Carli et al., 1985).

Another central alteration in PD concerns executive-typebehavior based on a continual updating of information. Sucha deficit can be considered as related to a working memorydeficit that contributes normally to reasoning by storing,for a short period of time, information used to take intoaccount rapid changes in the external context of the motorbehavior (Owen et al., 1996). Numerous examples havebeen provided in the literature showing marked deficits inexecutive functions in patients with PD. Such patients wereshown particularly impaired in the Wisconsin card sorting


test (Lees and Smith, 1983), Tower of London test (Owenet al., 1992) and Stroop test (Dubois et al., 1994), thussuggesting that besides planning deficits, they are likely toshow mental inflexibility and rigidity. The contribution ofcortical DA to the working memory processes altered inthe late stage of PD has been emphasized (Goldman-Rakic,1998; Luciana et al., 1998). Deficits in executive functionsare thus illustrative of a serious impairment in behavioralflexibility, such as a lack of adaptation to rapid changes inmotor or intellectual strategies. This deficit originates fromthe inability of the patients to use new information and/or toshift from one strategy to another more adapted to the newsituation, thus suggesting in some cases a greater deficitin cognitive shifting than in motor shifting (Owen et al.,1992). In that case, the inability to shift can contribute toperseverative actions particularly when the patient needs toadapt his behavior very rapidly. The difficulties in alternat-ing between two rules in successive trials could also reflectimpairments in the ability to maintain a mental set ratherthan true perseveration or increased distractibility (Flowersand Robertson, 1985). To further characterize the cognitivedeficits in PD,Owen and Robbins (1994)have comparedthe deficits in these patients with those shown by non-PDpatients suffering from frontal cortical lesions. At the earlystages of the disease, unmedicated Parkinsonian patientswere rather selectively impaired in an attentional set-shiftingtest, the impairment worsening with the development of thedisease. Indeed, at the early stages of the disease, neitherthe spatial working memory nor the planning strategy in theTower of London test were affected when compared with thedeficits observed in patients with frontal dysfunction. Sincethe cognitive impairment appeared to progress in parallelwith the motor deficit at the early stage of PD, the impair-ment in the attentional set-shifting test may reflect selectivepathophysiological mechanisms. However, the contributionof DA neurons in the expression of cognitive impairment isstill a matter of debate. In this respect, the impairment in vi-suospatial, executive and even verbal fluency tasks found inaccidentally 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced Parkinsonism in humans can be consid-ered as a pure DA deficiency (Stern and Langston, 1985;Stern et al., 1990).

Other tests in PD patients also demonstrate impairment indifferent aspects of memory processes. For example, the re-call for a list of words and the subsequent ordering of suchwords is deficient (Dubois et al., 1994). Although debated(Butters et al., 1994; White, 1997), an alteration in memoryprocesses is likely to concern the frontal circuits linking cor-tical areas to the basal ganglia. Memory impairment in PDmight involve mental strategies more than simple deficitsin short-term memory recall. Because such deficits occur inthe early stages of the disease the main difficulty may bein working memory processes (Owen et al., 1996) as men-tioned above. Indeed, explicit memory is usually not im-paired in PD, but the difficulty is obvious when the patientis asked to classify information, e.g. in relation to the main

semantic categories (Buytenhuijs et al., 1994; Pillon et al.,1998). Thus, memory tasks involving attentional processesrelated to a strategy of learning seem to be particularly defi-cient in Parkinsonian patients. Finally, it is noteworthy thatprocedural memory is not primarily altered in PD (Ferraroet al., 1993; Pascual-Leone et al., 1993) although implicituse of cognitive processes may show marked impairment(Soliveri et al., 1992).

Deficits in time estimation have been reported in patientssuffering from PD, particularly in relation to working mem-ory and short duration intervals of time (Artieda et al., 1992;Pastor et al., 1992). In those situations, the patients showeda tendency to underestimate time intervals. This deficit maybe related to difficulties the patients have in maintainingabstract mental representations and using further concepts,particularly in relation to the extrapersonal space. It hasbeen suggested that DA-related mechanisms at the level ofthe basal ganglia play a critical role in timing mechanisms(Meck, 1996; Ivry, 1996; Gibbon et al., 1997). Accordingly,we recently showed in the rat that bilateral lesions of thedopaminergic terminals at the striatal level disrupt the pre-diction of the unconditioned stimulus in a conditioned mo-tor task, possibly by inducing attentional deficits (Amalricet al., 1995; Baunez et al., 1995; seeSection 6.1). This isin agreement with data previously obtained byBrown andRobbins (1991). Various investigators have also pointed outpossible alterations of attentional processes that may actu-ally contribute to cognitive deficits in Parkinsonism. In thatcase, the perception of environmental stimuli is consideredto be strongly decreased as is general reactivity (Baunezand Robbins, 1999). Moreover, it has been reported that theParkinsonian patients have also some difficulties in ignor-ing non-significant stimuli. It has also been proposed thatsuch patients are unable to sustain attention in mental orbehavioral testing, particularly when an internal representa-tion of the environment is required. This would contributeto the alteration in motor planning mentioned above whenDA neurons are deficient (Clark et al., 1987).

Most of these clinical signs are generally considered tobe linked primarily to PFC alteration and the direct involve-ment of DA remains in question (Robbins and Brown, 1990).Alteration in attentional processes can be central in Parkin-sonism, since attentional deficits in such patients may oc-cur before motor impairment. Working memory processes,which are also central for language understanding and com-prehension and probably for intelligence and reasoning aswell, are commonly assumed to involve frontal lobe dys-function. However, the deficits found, for example, in pro-cedural memory tests also involve impairment of striatalfunctioning, particularly of the caudate nucleus. Moreover,the slowness of cognitive processes and attentional deficitscould also be due to cortical dysfunction. Thus, the cog-nitive deficits in PD appear to be independent of generalintellectual capacities, which have been found to be essen-tially unaffected (Lees and Smith, 1983). The most salientfeatures of the cognitive deficits are related to alterations of


visuospatial processes, difficulties in shifting conceptual setsand difficulties in maintaining mental sets. Patients can thusbe considered to exhibit a lack of mental flexibility as foundto a lesser extent in senescence, which illustrates marked al-teration of frontocortical processes probably involving thebasal ganglia and dopaminergic regulation.

3. Schizophrenia, cognition and dopamine

Although the nature of the contribution of DA toschizophrenia is still a matter of debate (Scatton and Sanger,2000) the model proposed byWeinberger (1987)and fur-ther developed by Gray (Gray et al., 1991; Gray, 1994)suggests a lack of interaction between limbic and motorsystems, which may contribute to explaining alteration ingoal-directed movements detected in some psychotic pa-tients. As noted above, schizophrenic patients can also showcognitive deficits (Gold and Weinberger, 1995). For exam-ple, they may show an inability to adjust their behavior tothe environmental context, presumably due to alteration inattentionality and/or mental representation of action. Thefocus on a role for DA in the pathogenesis of schizophre-nia resulted from the correlation of antipsychotic effects ofneuroleptics to their capacities to act as efficient blockersof dopaminergic receptors, as well as the observation ofmental confusion and exacerbation of psychosis inducedby amphetamine-like drugs in patients (Angrist and VanKammen, 1984; Deutch, 1992; Deutch, 1993). More re-cently, the proposal that hyperactivity of subcortical DAsystems underlies the positive symptoms of schizophreniahas been coupled with the hypothesis that hypoactivity ofthe cortical DA system underlies the negative symptoms.This putative hyperactivity of subcortical DA has beensuggested as the basis of the apparent hypofrontality insome patients evidenced using brain functional imaging(Silbersweig et al., 1995; Liddle et al., 1992).

A main concept in schizophrenia concerns a putativedeficit in evaluating action because of difficulties in usingstored information (Frith, 1987). Such a deficit is likelyto involve changes in cross-talk between sensorimotor andlimbic systems at the level of entorhinal cortex, hippocam-pus and nucleus accumbens, as emphasized byGray et al.(1991), thus leading to functional dissociation between theactivity of different cortical areas. In that situation, suchdifficulty in accessing past experience could explain the im-pairment in action evaluation. Deficits in evaluating actionscould result in permanent exploratory behavior and accountfor increased distractibility as mentioned byCrow (1980)for the positive form of the disease. Moreover, problems canalso occur in focusing attention onto non-significant stim-uli, which may be related to the perpetual exploration of theenvironment. Thus, cognitive dysfunction in schizophreniacould be associated with a tendency for perception to be-come less discriminative regarding the environmental con-text of the patient (McGhie and Chapman, 1961). As noted

by Sarter (1994), a hyperattention syndrome in schizophre-nia would thus correspond to a failure “to disattend irrele-vant stimuli including internally generated cues, impairmentin filtering irrelevant stimuli, deficit in divided attentionand inability to filter or to gate irrelevant information”. DAcould play a central role here, for example in contributingto the association between stimuli and responses in term ofbehavioral reinforcement.

Swerdlow and Koob (1987)also emphasized the idea thatschizophrenic patients could show some deficits in filteringand switching information, primarily at the limbic corticallevel. Indeed, a large majority of patients show difficultiesin movement initiation associated with hyperactivity andperseveration, which can contribute to cognitive deficits.Once again, perseveration could be viewed as a difficultyin switching attention and as a lack of mental flexibility. Inthat case, it should be specified whether this type of deficitis associated with positive or negative forms of schizophre-nia, which may reflect opposite changes in DA activity atthe cortical level. In the case of the negative symptoma-tology, the frontal hypoactivity has been suggested to becorrelated with DA decreases in medial pre-frontal corticalareas (Berman and Weinberger, 1990), thus leadingWillner(1997)to propose a therapeutic alternative with DA autore-ceptor antagonists to stimulate dopaminergic transmissionin these patients. Thus, if schizophrenia in general could berelated to a local alteration in cortical dopaminergic trans-mission, it is inferred that alterations in DA signaling couldaffect information processing. In these specific cases, itmight be expected that correcting such defects in DA trans-mission could help to improve cognitive deficits observedin schizophrenic patients.

4. The attention deficit hyperactivity syndromein children: further contribution of dopaminergicdysfunction?

The contribution of DA to the control of attentional pro-cesses can be further illustrated in the ADHD in children.This rather frequent pathology (1% of the childhood pop-ulation) is characterized by an excess of hyperactive, inat-tentive and impulsive behavior and has been considered tocombine executive attention and alerting deficits (Barkley,1998; Berger and Posner, 2000). Sustained attention is par-ticularly impaired, whereas orientating behavior is not andcognitive deficit can also be considered to result from “act-ing before thinking” due to uncontrolled impulsivity.

The involvement of dopaminergic dysfunction in thisdisease has long been suspected. However, its direct con-tribution to the pathology is not fully established. One ofthe major lines of treatment is related to the administra-tion of psychostimulants acting on dopaminergic trans-mission. Methylphenidate (Ritalin) andd-amphetamineare currently used to treat the patients, at least in US(Solanto, 1998) and their administration has been shown


to reduce impulsiveness and inattentiveness, thus pointingto a deficit in dopaminergic transmission. Brain imagingstudies showed that methylphenidate increased blood flowin hypoperfused striatal areas in young patients (Lou et al.,1989). Similarly, in functional magnetic resonance imag-ing (fMRI) studies methylphenidate also increased striatalactivation in patients, but in these studies it was shown todecrease striatal activation in controls, indicating abnormaldopaminergic regulation of striatal functioning in the dis-ease. Moreover, methylphenidate increased frontal cortexactivation in go/no-go behavioral protocols in patients withADHD, suggesting again decreased cortical activation inthe disease (Vaidya et al., 1998).

Recent evidence has pointed out the possible alterationin dopaminergic markers in ADHD further supporting thedopaminergic theory (Swanson et al., 2000). For instance,in linkage studies, the ADHD syndrome in children hasrecently been associated with allelic variations of genesencoding the DA transporter DAT1 (Cook et al., 1995;Gill et al., 1997) or possibly the D4 dopaminergic recep-tor (LaHoste et al., 1996; Smalley et al., 1998). Moreover,positron emission tomography (PET) studies using fluo-rodopa have shown abnormal accumulation of the markerin the midbrain of patients compared with control sub-jects, further indicating some possible alterations in DAmetabolism in ADHD children, although no difference wasdetected in the fluorodopa accumulation at striatal or corti-cal level (Ernst et al., 1999). Because the accumulation offluorodopa was higher in the right midbrain compared withthe left, the authors emphasized that such a lateralizationcould fit with the primary alteration of attentional processes,since the neuronal substrates of attention are proposed to berelated mainly to right-sided mechanisms correlating withthe preferential alteration of attention in the right side inpatients (Campbell et al., 1996).

5. Autism and dopamine

Although in autism there is some evidence of an ele-vation of serotonin, the clinical benefit obtained with D2receptor antagonists supports the concept of dysregula-tion of central dopaminergic transmission (Buitelaar andWillemsen-Swinkels, 2000). However, the alteration ofdopaminergic function in autism is probably more com-plex than simple hyperactivity (Goldberg et al., 1987). Lowdoses of DA antagonists, such as benzamides, for example,have been shown to produce a stimulant effect in patientswith autism, whereas DA agonists can have a sedative influ-ence. The hypothesis of a disorder in the maturation of thedopaminergic systems in infantile autism is thus still beinginvestigated, but recent data show no specific alteration inthe allelic frequency for genes encoding D2 or D3 dopamin-ergic receptors (Comings et al., 1991; Martineau et al.,1994). In fact, the most consistent change could be low me-dial pre-frontal dopaminergic activity (Ernst et al., 1997),

which is related to a deficit in anticipatory behavior andimpairment in shifting attention (Courchesne et al., 1994).

An interesting proposal is to consider some analogies be-tween behavioral symptoms in autism and Parkinsonism. Forexample, as evidenced in PD, autistic children show slow-ness in movement and a marked deficit in executive func-tions. Moreover, they show a deficit in initiating behavior,more likely at the psychomotor level. Finally, they showdifficulties in selecting the appropriate behavioral strategy.The analogies between autism and PD syndromes furtherappear when considering that the major change in behav-ioral control is due to a shift from a feedforward modeto a feedback mode, thus dramatically increasing the de-pendence of patients on sensory information. Indeed, asstated byLilensky et al. as early as 1981, “in many re-spects, the gait differences between the autistic and normalsubjects resembles differences between the gaits of Parkin-sonian patients and of normal adults.” Thus, the cognitivesigns in autism and Parkinsonism could be similarly re-lated to dysfunctioning of DA transmission occurring in thePFC.

6. Experimental evidence for the contribution ofdopamine to cognitive processes

Regarding the anatomo-functional organization of thedopaminergic systems in the brain, two series of experimentshave been conducted, primarily in the rat, but also, in somecases, in primates. The first set of experiments consisted oflesioning the dopaminergic neurons at mesencephalic level.In this case, the lesions differentially involved the nigrostri-atal and mesocorticolimbic neurons because of lesions oftenperformed at level of the medial forebrain bundle. Second,lesioning of the dopaminergic nerve terminals was con-ducted at the level of the striatum, nucleus accumbens, PFCand other terminal fields of DA neurons, thus allowing morespecifically the influence of DA in the denervated structureto be analyzed. Lesion protocols normally used the selectivetoxin 6-hydroxydopamine (6-OHDA) for catecholaminergicneurons, which can be infused locally at both the cell bodiesor nerve terminal level of the dopaminergic neurons. Theneurotoxin MPTP or its active derivative MPP+ was alsoused, since it has been shown to affect primarily these neu-rons even when injected systemically in primates or mice.Another method for investigating the role of DA systems isto use pharmacological treatments to either block or activatedopaminergic transmission with specific compounds admin-istered systemically or locally into the brain structures. Thismethod was shown to be useful to analyze the modulatoryeffects of DA transmission in intact or lesioned animalson spontaneous or conditioned behavior. Finally, althoughmore difficult, the possibility of correlating the neuronaldischarge of DA mesencephalic cells with behavior hasalso been used to specify their functional role, especially inprimates.


6.1. Lessons from experimental neurology: behavioralconsequences of lesioning the dopaminergic neuronsor terminals

6.1.1. Behavioral consequences of lesioning thenigrostriatal dopaminergic system

Numerous studies in the rat have long shown the motoreffects of lesions of DA mesencephalic neurons at the levelof the substantia nigra (Ungerstedt, 1971; Ungerstedt et al.,1974; Iversen, 1977). In brief, in the case of bilateral le-sions involving primarily the substantia nigra, a slowness ofmovement results, which is suggested to be highly correlatedwith bradykinetic symptoms observed in PD. This effect isevidenced by the lengthening of movement time observedin monkeys after 6-OHDA-induced lesion of the dopamin-ergic neurons (Viallet et al., 1984), but also in reaction-timein a conditioned motor task we developed in the rat (Baunezet al., 1995). Such a deficit is particularly apparent whenthe dopaminergic nerve terminals were destroyed after lo-cal 6-OHDA administration in the dorsolateral part of thestriatum recognized as the “motor part” of the structure inrodents (Amalric and Koob, 1987; Amalric et al., 1995). Itwas shown to be similar to that obtained following admin-istration of D2 dopaminergic receptor antagonists (Amalricet al., 1993; Marrow et al., 1993). Conversely, DA and DAagonists produced a decrease in reaction-time (Fowler et al.,1986; Amalric et al., 1995; Smith et al., 2000). Measuringreaction-time is indeed considered to give information onmotor programming and readiness in a voluntary motortask. As noted above, Parkinsonian patients have been gen-erally shown to have slower reaction-times than controls(Evarts et al., 1981; Jahanshahi et al., 1993), in agreementwith the results obtained in rodents following lesion of thenigrostriatal dopaminergic system. Experiments in primatesboth using 6-OHDA infusion in the substantia nigra orthe administration of the neurotoxin MPTP have similarlyshown increased reaction-times in conditioned motor tasks.Moreover, in such animals the blockade of dopaminergicreceptors induces similar effects (Weed and Gold, 1998),thus reinforcing the idea of a key role of the dopaminergicneurons in the early stages of motor control.

We also obtained evidence in the rat for a more complexinvolvement of nigrostriatal DA in behavioral regulation.More extensive bilateral lesions of the dopaminergic termi-nals involving the entire striatum and not the “motor part”of the structure not only increased reaction-time in the con-ditioned motor task but also induced a concomitant increasein the number of anticipated responses, shown as the pre-mature release of the lever the animals have to maintain de-pressed before the visual cue occurs (Amalric et al., 1995).Moreover, the lesion also resulted in an alteration of per-formance in terms of time estimation (Brown and Robbins,1991). Indeed, in our experimental conditioned motor task,the rats were trained to wait for different delays prior to theoccurrence of the unconditioned stimulus and, in the normalcondition, reaction-time was shown to decrease in parallel

Fig. 1. DA control of motor readiness in the rat. Animals were trained tohold a lever down until the occurrence of a light stimulus which occursafter an equiprobable and random period of 500, 750, 1000 and 1250 ms.At the time of the stimulus, the animals were required to release thelever within a reaction-time (RT) of 600 ms, in order to be reinforced. Ifrats release the lever before the light (premature responses), no rewardwas given, as well as if the release occurs after the imposed maximalRT (delayed responses). In intact animals, the longer the delay beforeoccurrence of the unconditioned stimulus, the shorter the RT, as illustratedon the lower part of the figure. Such a relationship can no longer bedetected following bilateral infusion of 6-OHDA in the striatum, thusillustrating the contribution of DA innervation to motor readiness andplanning of action (from M. Amalric, with permission).

with the delays (Fig. 1). In other words, in intact animals, thelonger the imposed delay ranging between 0.25 and 1 s, theshorter was the reaction-time (Baunez et al., 1995). Becausesuch a relationship was no longer detectable in animals sub-jected to lesion of the DA nerve terminals bilaterally at stri-atal level, we suggested the involvement of these neuronsin the prediction of the events and thus in time evaluation,further reinforcing the idea of a contribution of DA to mo-tor planning at the striatal level (Alhenius and Engel, 1972;Brown and Robbins, 1991).

Numerous studies in rodents have also shown otherdeficits in sensorimotor integration. For example, alter-ation of feeding or drinking behavior has been describedfor a long time (Salamone et al., 1990). Lesions of thedopaminergic nigrostriatal neurons have been shown toalter orientating behavior (Dunnett and Iversen, 1982)and visual spatial discrimination in a choice reaction-time


(Carli et al., 1985; Brown and Robbins, 1991). Moreover,skilled forepaw use in a reaching task was altered by similarlesions (Sabol et al., 1985; Motoya et al., 1990). A disrup-tion of active avoidance learning was shown after lesionof the DA terminals at the striatal level (Delacour et al.,1977), thus illustrating the contribution of the nigrostriataldopaminergic neurons to integrative aspects of behavior. Fi-nally, more recentlyBaunez and Robbins (1999)evidencedattentional deficits, since the animals subjected to the le-sion showed difficulties in switching from one situation toanother in the so-called “five-choice test”.

Altogether these data emphasize the contribution of ni-grostriatal dopaminergic neurons to both movement execu-tion and initiation of the voluntary movement. The situationresulting from the lesion is probably more complex thana simple alteration of motor preparation (Salamone, 1991)and could actually involve cognitive aspects of behavior. Inthis respect, although this point is still a matter of debate,simple reaction-time performance in Parkinsonian patientsis considered to be more affected than choice reaction-time(Brown and Robbins, 1991; Gueye et al., 1998), possiblybecause choice reaction-time is more dependent on the useof advance information and, perhaps, of cognitive processes.However, the question still remains open as to what extentthe deficit in reaction-time, particularly in the context of thesimple situation, is dopaminergic in nature or dependent onstriatal function.

6.1.2. Behavioral consequences of lesioning themesocorticolimbic dopaminergic system

The functional role of the mesocorticolimbic dopaminer-gic neurons was first extensively studied by lesions involvingthe ventral tegmental area (VTA) in the rat (Iversen, 1977).The involvement of these neurons in motivational processeswas more recently reviewed (Salamone, 1991; Le Moal andSimon, 1991). It was emphasized that these dopaminergicneurons do not have specific functions but could act as sen-sors of changes at environmental level or even at internallevel for adaptation of behavior. The lesioned animals wereshown to be hyperactive in a locomotor test and then un-able to focus on specific stimulus. They were particularlydeficient in the exploration of their environment and finallyshowed an inability to switch from one behavior to anotherwhen necessary. The same type of lesion also induced a se-vere and specific deficit in retention of delayed-alternationbehavior (Simon et al., 1980), as shown after lesioning ofthe pre-frontal cortical areas (Divac et al., 1975).

The lesioning of dopaminergic nerve terminals in the dif-ferent brain structures innervated by the mesocorticolimbicdopaminergic neurons showed more specific deficits regard-ing the nature of the brain area concerned with the infusionof the 6-OHDA, thus emphasizing the idea of a widespreadrole of DA in the regulation of the different aspects of be-havior. For example, lesions of the dopaminergic terminalsat septal level have been reported to result in impaired per-formances in different memory tests, such as in the maze

paradigm. In this scenario, the deficits were shown to be sim-ilar to those observed after lesioning the septal neurons, thusreinforcing the idea of a key role of DA in regulating the ac-tivity of the septohippocampal pathway (Simon et al., 1986;Taghzouti et al., 1986). Similar experiments have been con-ducted at the level of amygdala, hippocampus or habenula(Le Moal and Simon, 1991), leading to similar conclusionson the regulatory role of DA on the specific contribution ofthese structures to behavior.

Regarding the cognitive aspects of behavior, however,the most interesting data have been obtained after lesion ofthe dopaminergic terminals, either at the level of the nu-cleus accumbens or the PFC. Lesions of the dopaminergicterminals in the nucleus accumbens, which did not induceprimary motivational deficit nor disruption of the condi-tioned avoidance responses, induced spontaneous locomo-tor hypoactivity (Jones and Robbins, 1992), which contrastwith the effects induced by the lesion of VTA and alteredthe so-called “displacement behavior” (Robbins and Koob,1980; Koob et al., 1984). Cortical DA depletion causes loco-motor hyperactivity (Tassin et al., 1978; Jones and Robbins,1992) and a series of symptoms which can be consideredas very similar across species. The impairment of behaviorin this situation is expressed in terms of lack of motor in-hibition, temporal organization of the behavioral sequences,spatial orientation and even social interaction. Moreover,increases in novelty-induced locomotion were shown aftersystemic DA-agonist administration following DA PFC de-pletion, thus suggesting that the decrease in cortical DAtransmission is associated with reactive changes of the sub-cortical dopaminergic systems (Oades et al., 1986).

Consequently, the behavioral changes observed followingcortical DA depletion have to be considered not only as re-sulting directly from DA cortical depletion but also fromassociated changes in reactivity of dopaminergic transmis-sion at subcortical levels (Fig. 2). As locomotor and switch-ing responses are generally considered to depend on theventral striatum (Kelly, 1975), alterations in such behaviormay involve adaptive changes in DA transmission at the nu-cleus accumbens level. Accordingly, cortical DA depletionin the rat results in an increase in the spontaneous releaseof DA measured in the shell part of the nucleus accumbens,specifically. However, although the locomotor response topsychostimulant administration was shown not to be alteredafter DA depletion at the cortical level (Jones and Robbins,1992), recent data showed in contrast that such a responseto systemic amphetamine could be attenuated in that situ-ation (King et al., 1997). Since reactive decreases in loco-motor activity were also shown after non-specific lesions ofthe PFC, it can be suggested that inhibitory control is ex-erted at the subcortical level by the pre-frontal DA system(Costall et al., 1977).

We recently showed in our conditioned motor task thatselective ibotenic acid-induced lesions of the PFC in therat primarily induced premature responses (Risterucci et al.,submitted for publication), which can be markedly reduced


Fig. 2. Hypothetical model illustrating the presence of a functional link between cortical and subcortical dopaminergic activity. Alteration in cortical DAtransmission may contribute to a reactional process increasing striatal DA transmission. Such hyperactivity of subcortical DA transmission couldlikelycompensate for deficits related to cortical DA depletion and consequent frontal hypoactivity, but could also contribute to behavioral impairment.

by subsequent lesion of the dopaminergic nerve terminals inthe nucleus accumbens. Such data emphasize the idea thatthe ventral striatum contributes to the expression of someaspects of PFC activity and that DA is involved in the regu-lation of such activity at the subcortical level. Finally, it hasalso been shown that 6-OHDA lesion of the dopaminergicterminals in PFC could also influence dorsal striatum-relatedbehavior, since in the rat such a lesion was shown to increasereaction-time but not movement time in a conditioned mo-tor task (Hauber et al., 1994). However, the status and roleof cortical DA in the intact cortical areas still remains to beestablished (Robbins and Everitt, 1987).

Specific 6-OHDA-induced cortical denervation hasalso been performed in primates. In the PFC, this le-sion was shown to impair performance of monkeys indelayed-alternation spatial tasks (Brozowski et al., 1979).Lesioning the dopaminergic system, however, does not re-produce the effects of a cortical lesion. Indeed, the ability toexecute and generate sequences of responses in the commonmarmoset, which is not impaired by the local DA lesion, isaffected by the excitotoxic lesion of the PFC (Collins et al.,1998). Thus, DA can be considered to modulate certain, butnot all, aspects of cortical cognitive functions. In this re-spect, 6-OHDA lesions of the PFC in monkeys were shownto enhance performance on an analog of the Wisconsin cardsorting test (Roberts et al., 1994). In that situation, the au-thors propose that a reactive increase in the activity of thenigrostriatal dopaminergic system can actually contribute tothe improvement in attentional set-shifting ability. Conse-quently, the impairment in such attentional set-shifting abil-

ity in PD may result from primary alteration of the nigrostri-atal dopaminergic activity, which could likely contribute tosome aspects of the cognitive deficiency described earlier.

6.1.3. Cortical dopamine and the pre-pulse inhibitionof acoustic startle as a model to further investigatethe role of cortical dopaminergic innervation in thecognitive signs of schizophrenia

Numerous studies have shown decreased pre-pulse inhibi-tion of acoustic startle response in schizophrenia (Braff et al.,1978). Since this measure can be considered as a reliableindex of sensorimotor gating, an animal model of such a defi-ciency may provide useful information on the biological sub-strate of the disease (Swerdlow et al., 1992) and particularlyof the so-called “cognitive fragmentation” hypotheticallyrelated to deficient sensory gating (McGhie and Chapman,1961). Pre-pulse inhibition of the acoustic startle response isreduced in the rat after 6-OHDA infusion in the PFC (Bubserand Koch, 1994), suggesting that DA innervation of the PFCmodulates the sensory gating. Because overactivity of themesolimbic DA system in the nucleus accumbens showedsimilar disruption of the pre-pulse inhibition (Swerdlowet al., 1990), these two components of the dopaminergicsystems at both cortical and nucleus accumbens levels canact in apparently opposite ways regarding the modulation ofthe sensory gating and further cognitive cortical functions.

Dysfunction of these mesocorticolimbic dopaminergicneurons could contribute to schizophrenia in patients, butantipsychotic drugs would act differentially, depending onthe actual site of alteration in dopaminergic transmission.


In this respect, pre-pulse inhibition of the acoustic startleresponse has been shown to be reduced by treatments withdirect DA agonists acting at the D2, D3 and D4 receptorsubtypes, but not by the D1 agonists, suggesting a primarysubcortical action. Moreover, pharmacologically induceddisruption of pre-pulse inhibition was shown to be sensi-tive to classic neuroleptics (Caine et al., 1995; Johanssonet al., 1995). Because DA depletion in the medial PFCalso reduced other forms of hyperactivity (Sokolowski andSalamone, 1994), it may be considered that the pre-frontalDA cortical system is a part of the neuronal network in-volved in behavioral inhibition, which may be deficientin schizophrenic patients. However, in our hands, corticalDA depletion alone was insufficient to induce a prematureresponse in the conditioned motor task (Risterucci et al.,submitted for publication). We thus suggested that such DAdepletion at cortical level could act indirectly through areactive increase in subcortical DA transmission within thenucleus accumbens (Fig. 2).

In the ADHD syndrome in children and in animal modelsof the disease, a similar involvement of the mesocorticol-imbic dopaminergic system has been proposed primarily tooccur. It is thus conceivable that a lack in correct dopamin-ergic transmission in the cortical and limbic striatal areascan result from dysfunction of the forebrain network con-trolling behavioral inhibition. Consequently, a deficit inefficient dopaminergic control is likely to result in difficul-ties in selecting environmental stimuli and/or in an inabilityto select appropriate motor programs by inhibiting those incompetition (Russell et al., 1995; Sagvolden, 2000).

6.1.4. Behavioral consequences of lesioning thedopaminergic terminals at the level of the subthalamicusnucleus

In a recent series of experiments,Baunez and Robbins(1997)studied, in the rat, the effects of bilateral excitotoxiclesion of the subthalamic nucleus (STN) and subsequenteffects of selective deprivation from nigral dopaminergicinput. The STN was recently proposed to represent a keystructure in controlling basal ganglia functions (Levy et al.,1997) and to influence DA release and neuronal activity(Murer et al., 1995; Rosales et al., 1994). This structurereceives a dopaminergic input from the substantia nigra(Canteras et al., 1990; Parent and Lavoie, 1993), which hasbeen shown to be altered in PD. Moreover, DA modulatesthe activity of STN neurons (Kreiss et al., 1996; Mintzet al., 1986) and several lines of evidence have been ob-tained showing that the structure becomes hyperactive inParkinsonism (DeLong, 1990), thus representing a targetfor efficient surgical treatment of PD (Pollak et al., 1993;Benabid et al., 1994; Limousin et al., 1995; Krack et al.,1997).

We have shown in the rat that bilateral lesion of the STNin animals previously subjected to DA striatal depletion im-proves motor deficits in a way similar to that obtained inhumans. However, the STN lesion was also shown to induce

additional deficits (Baunez et al., 1995). The “five-choiceserial reaction-time” paradigm was chosen in the experi-ments byBaunez and Robbins (1999)to further approachthe functional role of this basal ganglia structure. Resultsshowed a large increase in perseverative responses as wellas an increase in the number of premature responses, indi-cating attentional as well as executive and motor sequencingdeficits. This behavioral deficit was similar to that found fol-lowing bilateral DA striatal depletion (Baunez and Robbins,1999), in that reducing the temporal predictability of the vi-sual event led to impaired performance, although prematureresponses were not increased.

Because subsequent striatal DA depletion in animals pre-viously subjected to STN lesions did not improve the at-tentional deficit, the effect of DA depletion locally in theSTN was investigated in the reaction-time procedure. Thebehavioral effects of lesioning the DA terminals in the nu-cleus were found to be similar to those induced by lesioningthe STN. These data suggest that the attentional and motordeficits result from the DA depletion, further emphasizingthe idea that DA has a potent modulatory role on the STN ac-tivity (Amalric and Baunez, 1999). Consequently, data alsosuggested that the attentional and motor deficits resultingfrom the inactivation of the STN may be related to its DAdepletion. Thus, changes in STN activity as a consequenceof DA depletion in Parkinsonism may contribute to cognitivedeficits by altering the preparation of action and time estima-tion, as well as inducing perseverative behavior, characteris-tic of difficulties in switching from one behavior to another,as shown, for example, following DA lesions of the PFC.

Chronic bilateral stimulation of the STN in PD patientshas been suggested to induce neuropsychological deficits(Saint Cyr et al., 2000), but these results are not in agreementwith previous observations in similar conditions showingno alteration in memory processes or executive functions(Ardouin et al., 1999) although a significant slowness inverbal fluency was detected. However, it is argued that thepatients in the latter case are younger than the population ofpatients studied bySaint Cyr et al. (2000)which could haveinfluenced neuropsychological test performances.

6.2. Dopaminergic neurons and attentional processes:more general implications

The lesion experiments focused on a putative role of DAin contributing to the regulation of attentional behavior.Lesioning the mesocorticolimbic dopaminergic neurons by6-OHDA caused a form of “disconnection syndrome” sim-ilar in many ways to that observed following destructionof the frontal lobe areas. More direct evidence has beenobtained for the involvement of dopaminergic neurons inthe regulation of attention. For example, lesioning the mes-encephalic dopaminergic neurons in the cat reduced theattentive component of behavior. Concomitantly, the typicalelectrocortical rhythms associated with attentive behav-ior was suppressed either by the lesion of mesencephalic


dopaminergic neurons (Montaron et al., 1982, 1984) or in-jections of neuroleptics (Bouyer et al., 1980). In contrast,these rhythms were shown amplified by DA precursors(Bouyer et al., 1979). Moreover, the neuronal discharge ofthe dopaminergic neurons recorded at mesencephalic levelin behaving animals correlated with attentional processes(Montaron et al., 1979; Montaron et al., 1982). These datasupport the idea of distracting effects of the dopaminergiclesion, whereas optimal dopaminergic transmission couldcontribute to enhancing focusing of attention. However, therespective role of cortical and subcortical dopaminergic in-fluences in regulating attentional processes remains to be es-tablished because of the not excluded possibility of changesin attention-related rhythms and attentional behavior fol-lowing alteration of subcortical dopaminergic transmission.In this context, it is worth noting the difficulties of concen-tration and selective attention of ADHD children who havebeen reported to be improved by stimulation of dopaminer-gic transmission via psychostimulant administration (Tassinet al., 1978) although the contribution of subcortical struc-tures, particularly of the basal ganglia, to attentional pro-cesses is still a matter of debate. Recent experiments in themonkey showed that a subpopulation of neurons in the pri-mate striatum exhibits changes in activity highly correlatedwith spatial attentional processes (Boussaoud and Kermadi,1997), thus suggesting that this structure is actually partof the network involved in selective attention, probablydue to its close connections with the frontal lobe. Indeed,the frontal lobe syndrome has been interpreted as resultingfrom impairment of selective attention (Nauta, 1971).

In the rat and monkey, evidence has been obtained for“sensory neglect” which may reflect problems in attentionalprocesses following lesion of the dopaminergic neurons.Unilateral or bilateral lesions of the nigrostriatal dopamin-ergic system have been shown to decrease the reactivity to astimulus occurring in the side contralateral to the dopamin-ergic lesion, either in the extrapersonal space or just appliedto the skin (Ljungberg and Ungerstedt, 1976; Marshall andGotthelf, 1979). Such a lack of reactivity when the dopamin-ergic neurons are not firing may be related to the increase inDA detected in the anesthetized cat in response to iterativesensory stimulation (Nieoullon et al., 1977). In the baboon,we also showed a typical sensory inattention syndrome afterunilateral selective lesion of the nigrostriatal dopaminergicsystem (Viallet et al., 1984). However, assessment of thedifferent aspects of attentional processes in animals is diffi-cult and it may be considered that the dopaminergic controlof attentional processes only concerns selective componentsof behavior (Clark et al., 1987; Bushnell, 1998). Besidesits regulatory action on the sensorimotor integration ofbehavior evidenced as the “sensory inattention syndrome”in unconditioned behavior described byLjungberg andUngerstedt (1976)in the rat, dopaminergic activity could,thus, contribute to the detection of novelty. The involve-ment of the dopaminergic neurons in such a detectionof novelty has been emphasized bySchultz (1997) and

Ljungberg et al. (1992), who recorded dopaminergic neu-rons activity in behaving monkeys. They showed similarchanges with novelty at the striatal level, further reinforc-ing the idea of basal ganglia involvement in the attentionalprocesses (Apicella et al., 1991a,b).

Another aspect of the attentional processes concerns spa-tial attention shifts in protocols of cue detection of visual tar-gets. In this case, a contribution of DA was also suspected, asshown by slowed reaction-times in conditioned motor tasksin response to visual stimuli (Ward and Brown, 1996; Carliet al., 1985, 1989), as well as by direct recording of dopamin-ergic neuron activity (Redgrave et al., 1999a). Finally, onecan expect a contribution of DA in stimulus detection andthus attention switching, as illustrated by the experimentsusing the “five-choice serial reaction-time” task (Evendenand Robbins, 1985; Robbins et al., 1986). Although moredifficult to test in animals, it can be considered that sus-tained attention processes are also regulated in some wayby dopaminergic neurons, as shown from pharmacologicalexperiments (Grilly and Gowans, 1988; Grilly et al., 1989;Skjoldager and Fowler, 1991; Brockel and Fowler, 1996).

These observations further emphasize the positive corre-lation that may exist between efficient dopaminergic trans-mission and optimal attentional processes. The data of thelesion experiments can, therefore, be compared with obser-vation of the alteration of attentional processes in patientssuffering from PD. Indeed, testing visuospatial attentionin patients using the recording of event-related evoked po-tentials showed marked alteration in both the detection ofstimuli and potentials (Yamaguchi and Kobayashi, 1998).Moreover, in patients suffering from certain forms ofschizophrenia who exhibit neglect for the behaving context,hyperreactivity may occur. In this case, the question is, how-ever, still open as to whether such impairment is related toinsufficient dopaminergic transmission at the cortical levelor to putative dopaminergic overactivity at the striatal level.

6.3. Further lessons from recording neuronal activity inbehaving animals

Besides examining the behavioral consequences of DAdepletion in selected brain areas, the putative contributionof the dopaminergic neurons to cognitive processes wasalso examined in a series of experiments consisting ofrecording neuronal activity, mainly in the primate. Suchrecordings concerned either directly the dopaminergic neu-rons at mesencephalic level or neurons in the target areas ofthe dopaminergic terminals. As previously mentioned, suchexperiments have been primarily conducted for many yearsby the group of Schultz who focused on the contributionof the dopaminergic neurons to a reward system (Schultz,1997). These neurons have been shown to respond to ap-petite stimuli such as primary rewards and reward-predictingstimuli. For this line of evidence, it has been shown thatappetite deficits mainly occur following impairment in DAtransmission within the nucleus accumbens (Swerdlow and


Koob, 1987), whereas dysfunction of striatal dopaminer-gic transmission results in deficit of movement execution.Nevertheless, the question is still open as to whether thedopaminergic neurons are involved in the processing ofspecific reward information or in general behavioral activa-tion and/or attentional processes. Data showed that, besidesthe response to appetite stimuli, the dopaminergic neuronsare also influenced by attentional stimuli, whereas very fewcorrelations can be made with movement control (Trulsonet al., 1981; Trulson, 1983) although some experiments haveshown positive but rather weak correlations of the dischargeof the dopaminergic neurons with velocity or amplitude ofconditioned movements (Magarino-Ascone et al., 1992) ormotor activation (Schultz et al., 1983). Thus, the responsesof the dopaminergic neurons are suggested to fully dependon unpredictable stimuli. In this respect, they were shownto occur during the early phases of learning procedures inconditioned motor tasks until the reward associated withthe response become entirely predictable. Such a response,therefore, lacks specificity, except that nociceptive stimuliseem only poorly effective in activating the neurons. Fi-nally, no major difference was found in the type of stimuliinfluencing the different subpopulations of dopaminergicneurons at the mesencephalic level (Schultz, 1994).

The significance of such neuronal activation is still amatter of debate. It has been proposed that the dopamin-ergic neurons may be involved in learning associated withthe presentation of the unconditioned stimulus, until it be-comes predictable. The response of the dopaminergic neu-rons could also represent an alerting signal to unexpected

Fig. 3. From intention to action: cortical and basal ganglia DA modulation. DA contributes to integration of cortical information underlying motor,limbicand cognitive aspects of behavior, which results in an appropriate strategy selected through the basal ganglia complex.

events, which requires interruption of the ongoing behaviorand further adaptive reaction (Schultz, 1994). The suppres-sion of the dopaminergic neurons could thus result in lossof the adaptive capacities of behavior, as shown in Parkin-sonism.Schultz et al. (1995)have shown that, when the re-ward fails to occur in the course of a learning procedure, thedischarge of the dopaminergic neurons stops at the momentof the predicted event, which could encode an error signalbetween the prediction and the actual occurrence of reward.Since lesioning the dopaminergic neurons affects generalbehavior, these neurons can thus act tonically to modulateneuronal activities in target areas and particularly in relationto the attentional system in the frontal lobe. Consequently,the phasic mode of discharge which is superimposed ontothis tonic activity could efficiently exert its alerting action.Suppressing dopaminergic neurons may correspond to thesuppression of novelty detection and may correlate with thelack of flexibility and reactivity of behavior observed inParkinsonism.

In the target areas, signals characteristic of the DA rewardsystem have been recorded at striatal (Apicella et al., 1996)and cortical levels (orbitofrontal cortex, dorsolateral PFC,cingulate cortex), but also at the level of the STN (Schultz,1997), suggesting the effective contribution of dopaminer-gic signal to the modulation of neuronal activity in all thesebrain structures. Striatal neurons are more responsive toself-initiated movements and discharge preferentially duringthe early stages of behavior corresponding to a preparatoryperiod of the movements (Jaeger et al., 1993). Moreover, weshowed that tonically active neurons are also indifferently


responsive to both appetitive and aversive stimuli unlikethe dopaminergic neurons, which are primarily sensitive toappetite stimuli, as mentioned above (Ravel et al., 1999).That the striatum is not a simple relay of cortical infor-mation is evident from the experiments byJohnstone andRolls (1990)who showed in monkeys discriminatory andmodality-specific neurons during a short-term memory task(Kimura et al., 1992; Rolls, 1994) or from records show-ing that striatal neurons could integrate spatial information(Lavoie and Mizumori, 1994) or deal with the encoding ofa sequence of behavior in monkeys (Jaeger et al., 1995)and rats (Aldridge and Berridge, 1998). We obtained evi-dence that the tonically active striatal neurons are sensitiveto the predicted time of stimuli, further reinforcing the ideaof involvement of the basal ganglia and specially of thestriatum in temporal prediction, as suggested from obser-vations in PD patients (Sardo et al., 2000). However, oneof the most recent examples of the involvement of striatalneurons in cognitive processes was actually reported byJog et al. (1999), who showed in the rat that neuronal activityis progressively reorganized during habit learning towardsan actual “building of neural representation” when the pro-cedure becomes automatized. Thus, the striatum may be thekey structure for selecting the behavioral strategy and DAmay play a major role in having a permissive effect over theselection of the appropriate strategy (Redgrave et al., 1999b)(Fig. 3).

7. Mechanisms

7.1. Complexity of the anatomo-functional organizationof the dopaminergic systems

The dopaminergic neurons show at rest a regular butrather slow rate of discharge that is characteristic of theseneurons (Ljungberg et al., 1992). Their activation representsa typical bursting response, which can be considered veryefficient for promoting the release of the neurotransmitterat nerve terminals. The dopaminergic neurons also show ageneral anatomical organization in such a way that neuronsfrom the substantia nigra (A9) project mainly into the stria-tum, whereas those from the VTA (A10) innervate primarilythe limbic striatal areas—i.e. the nucleus accumbens—andthe frontal cortical areas, but also the septal area, amygdalaand hippocampus (Smith and Kieval, 2000). Such an organi-zation supports the concept of involvement of the dopamin-ergic neurons in the regulation of the different motor, limbicand cognitive aspects of behavior as illustrated from theexperiments mentioned earlier.

One of the most recent advances in knowledge about thedopaminergic neurons emphasizes the presence of neuropep-tides that act as co-transmitters in the different subsets ofthe mesocorticolimbic dopaminergic neurons. Neurotensinwas shown to be present mainly in the neurons innervating

the cortical areas and, to a lesser degree, the limbic striatalareas, whereas the neuropeptide cholecystokinin (CCK)was shown in the limbic subcortical areas and particularlyin the nucleus accumbens (Kalivas, 1985; Seroogy et al.,1988; Jayaraman et al., 1990). The status of the nigrostriataldopaminergic neurons regarding the possible co-expressionof another neurotransmitter is not clear, but recent datasuggest possible co-release of DA with excitatory aminoacids, such as glutamate at striatal level (Sulzer et al.,1998).

The functional significance of such co-expression ofneurotransmitters and further co-release at the level ofthe nerve terminals classically known to release DA israther poorly understood. However, the bursting mode ofthe neuronal discharge could represent an appropriate wayfor inducing release of the peptidergic co-transmitter ifcellular and molecular mechanisms of such a release pro-cess have something in common with what is known fromother neuronal systems where neurotransmitters are alsoco-localized, such as in the peripheral parasympathetic sys-tem (Lundberg and Hokfelt, 1986). Because the membranereceptors for the co-transmitters are also co-expressed to-gether with dopaminergic receptors at the post-synapticlevel, one might expect a functional role of such neurotrans-mitter co-expression at the level of single dopaminergicneurons. For example, the neuropeptide receptors may helpto regulate DA signal transduction through D1 and D2 re-ceptors at the striatal level (Li et al., 1994). In this respect,at a functional level, a possible role of neurotensin as anendogenous neuroleptic has been suggested, since this neu-ropeptide was shown to reduce the action of DA in thestriatum (Nemeroff, 1980).

Neurotensin receptors are differentially expressed anddistributed in the different target areas of the dopaminergicneurones. For example, in the striatum, neurotensin recep-tors are considered to be primarily located at a pre-synapticlevel on dopaminergic nerve terminals. Conversely, withinthe nucleus accumbens, the receptors are found bothpre-synaptically on dopaminergic nerve terminals andpost-synaptically on target neurons of the mesolimbic termi-nals (Quirion et al., 1985). At the cortical level, the receptorsare essentially post-synaptic and not on dopaminergic affer-ent fibers. This distribution pattern indeed correlates withthose of the dopaminergic autoreceptors, which are similarlylocated pre-synaptically on dopaminergic terminals in boththe striatum and nucleus accumbens, but are not present ondopaminergic terminals in the cortex (Mercuri et al., 1997).In this respect, the functional role of co-expression of DAand neurotensin is still a matter of debate and is far fromfully understood, although it can be speculated that someof the symptoms in PD are related to changes in the actionof the neuropeptide. Interestingly,Mercuri et al. (1997)have suggested that the therapeutic effect of DA agonistsin PD could be due to activation of autoreceptors locatedon remaining intact dopaminergic neurons at the level ofthe mesencephalon. Indeed, due to the progressive neuro-


degenerative process, these remaining intact neurons aresupposed to have their basal firing rate increased. DA ago-nists could, therefore, produce their anti-Parkinsonian effectthrough “normalizing” the discharge of the neurons. It is thusnoteworthy that the reactive increased rate of the neuronaldischarge of the dopaminergic neurons could contribute tothe co-release of DA and neurotensin. Interestingly, becausethe dopaminergic neurons projecting into the PFC lackdopaminergic autoreceptors on their cell body in the mes-encephalon, such a corrective effect of the DA agonist willnot occur in this structure, whereas it could counteract theinfluence of excessive release of neurotensin in the striatumand nucleus accumbens. These observations correlate withdata from pharmacological experiments showing oppositeeffects of neurotensin and DA on the striatal release ofDA. Indeed, whereas DA reduced its own release throughautoreceptors, neurotensin conversely promotes DA release(Pozza et al., 1988). Moreover, at the post-synaptic level, DAand neurotensin can have opposite effects in such a way thatthe neuropeptide can reduce the inhibitory influence of DA(Beauregard et al., 1992). Thus, antipsychotic drugs couldact through an increase in neurotensin influence as shownfrom increased expression of the precursor of the neuropep-tide following haloperidol or fluphenazine administration(Merchant et al., 1992). Interestingly, whereas these neu-roleptic drugs influenced the expression of neurotensin in allthe receptive fields of the dopaminergic terminals, clozapineand thioridazine, considered as atypical neuroleptics, onlyincreased the expression of the neuropeptide in the nucleusaccumbens.

The action of CCK acting through CCKB receptors isalso not fully understood. The activation of such receptorsin the nucleus accumbens was shown to increase DA release(You et al., 1996). Although such administration locallywas initially shown to have anxiogenic effects (Crawley,1991; Rompre and Boye, 1993), more recent data using sys-temic administration of a CCKB agonist suggest that CCKcould also improve motivation and attention (Ladurelle et al.,1997), which could be relevant in the case of limbic andcognitive signs of PD. It can be emphasized that CCK canalso influence the activity of the dopaminergic neurons inthe mesencephalon. In this respect, the administration ofCCK in the rat substantia nigra locally increased the re-lease of DA (You et al., 1996) and can further reduce thefiring of the dopaminergic neurons. Thus, CCK as well asneurotensin could have some antipsychotic effects. Becauseof the presence of these neuropeptides associated with DAmainly in the limbic areas and PFC, it is worth noting thatneurotensin and CCK may have functional roles in relationto limbic but also cognitive aspects of behavior, as suggestedfor CCK. However, at present very little is known about theinvolvement of these neuropeptides in the special control ofcognitive processes, but this area has to be further investi-gated, because neurotensin, CCK and associated receptorsrepresent putative sites for development of new drugs withpotential therapeutic properties.

7.2. The action of dopamine at the cellular level

The cellular action of DA is related to the presence of theD1 and D2 subtypes of membrane receptors (Sealfon andOlanow, 2000). These receptors are linked to G protein ac-tivation, suggesting again that the effect of DA signaling isnot of the fast mode but rather slow and long lasting. TheD1 receptor family (D1, D3) is associated with an increasedactivity of adenylate cyclase, whereas the D2 receptor fam-ily (D2L, D2S, D4) is shown mainly to depress such activ-ity. The anatomical distribution of these receptors providesan interesting basis for speculating on the functional roleof these different subsets of receptors. In this respect, it isworth noting the presence of the D2 receptors primarily inthe sensorimotor part of the striatal complex, whereas theD3 receptors are mainly located in limbic areas. Much spec-ulation has been based on the presence of the D4 receptorsin the PFC, but there is a large overlap in the expression ofthe receptor subtypes in the main brain territories innervatedby the dopaminergic neurons. At the cellular level, giventhat the action of DA depends on subtypes of receptors acti-vated, there is still considerable controversy on the putativeco-expression of different subtypes of receptors of the D1and D2 families, particularly in the striatum where the dif-ferent subpopulations of target neurons of the dopaminergicterminals can be identified selectively. In this brain structure,the mRNA encoding the two subsets of receptors are primar-ily segregated into the two main subpopulations of striatalefferent neurons (Gerfen et al., 1990; Lemoine and Bloch,1990). However, the hypothetical segregation process suffersfrom several exceptions (Aizman et al., 2000). For example,in the ventral striatal area neurons are shown to co-expressD3 receptors with D1 or D2 receptors (Lemoine and Bloch,1996). In other striatal efferent neurons, D4 and D5 receptorsare also possibly co-expressed (Smith and Kieval, 2000).Finally, D1 and D2 receptor subtypes are also in a positionto exert pre-synaptic regulation of nerve terminal activity inthe substantia nigra and the striatum, respectively.

The cellular effects of DA are related to these differentreceptors. It can be emphasized that its action through D2receptors generally depresses activity of the target neurons,whereas via D1 receptors DA could contribute to interac-tion with other receptors and particularly those relying onthe action of fast-signaling neurotransmitters, such as theexcitatory amino acids, thus contributing to the modulationof the input to target neurons (Nicola et al., 2000). In thestriatum, the main effect of DA is to reduce spontaneouscell firing or to decrease pharmacologically evoked activ-ity (Siggins, 1978; Brown and Arbuthnott, 1983). However,low doses of DA have occasionally been reported to facil-itate glutamate-evoked firing (Hu and White, 1997). Simi-lar responses have been detected in the nucleus accumbens.Even if the inhibitory effects are related to D2 receptor ac-tivation, the ionic mechanisms of such inhibitory responsesare far from being fully understood. The mechanisms ofD1 receptor activation are paradoxically much more clearly


shown. Indeed, patch–clamp studies have shown that the D1effect of DA is related to decreases in sodium currents andincreases in potassium currents. Moreover, D1 receptor ac-tivation affects calcium currents (Nicola et al., 2000). D2receptors have also been shown to increase potassium chan-nel conductance, but D2 receptors have also been shown toaffect sodium, potassium and calcium conductances in bothdirections (Surmeier et al., 1992). Finally, activation of D2receptors has been suggested to reduce excitatory amino acidevoked responses in the striatum, whereas similar activationof D1 receptors increased it (Levine et al., 1996; Nicola andMalenka, 1998).

The most recent clarifications of the cellular effects ofDA in the striatum concern the influence of DA on synap-tic plasticity. Co-activation of both D1 and D2 receptorsis minimally required for long-term depression (LTD), butnot long-term potentiation (LTP), further suggesting a keyrole of DA in adaptive processes of synaptic transmission(Calabresi et al., 1996). The complexity of the responseselicited by DA has raised the question of its possible mod-ulatory role in terms of regulation of network properties(Walters et al., 2000). DA striatal depletion has been shownto affect synchronization of neuronal activity in the basalganglia (Bergman et al., 1998), whereas both D1 and D2receptor agonists increased the frequency of oscillations infiring rates characteristic of striatal activity (Ruskin et al.,1999). Although the functional significance of such neuronaloscillatory activity is still unclear, it might be essential forthe expression of functional properties of a basal ganglia net-work and particularly for attentional processes (Ehlers andFoote, 1984). However, the low frequency of oscillation ofbasal ganglia nuclei activity compared with that generallymeasured in other brain structures, such as thalamus andcerebral cortex is noteworthy.

7.3. What subtypes of dopaminergic receptors are likelyto be involved in cognitive processes?

Our current knowledge of the localization of the dopamin-ergic receptors in the brain results from immunocytochem-ical studies at the electron microscopic level which havesuggested that the D1 and D2 receptors are present at bothsynaptic and extrasynaptic sites. Such localization would fa-vor a double action of DA, with a phasic influence throughthe stimulation of the synaptic receptors but a strong tonic ef-fect through extrasynaptic receptors. These phasic and toniceffects, respectively, could be related to the correspondingmode of discharge of the dopaminergic neurons, as men-tioned above. Moreover, the probable multiple pre-synapticcontrols, to which DA is suspected to contribute, emphasizesthe putative neuromodulatory role of this neurotransmitter.

In this context, it is interesting to observe the behavioraleffects of gene inactivation in the mouse, regarding dopamin-ergic receptors. As in DA-deficient mice (Kim et al., 2000),the inactivation of the D2 receptor gene was essentiallyshown to reduce spontaneous locomotor activity (Baik et al.,

1995). The inactivation of the D1 receptor was shown to in-duce different behavioral alterations mainly concerning thelimbic system. For example, such inactivation markedly re-duces responses to cocaine administration (Xu et al., 2000).Regarding cognitive functions, inactivation of the D1 recep-tor gene produced spatial learning deficits (El-Ghundi et al.,1999) which can be related to the involvement of the D1 re-ceptors in working memory processes in the PFC and to thepresence of such receptors in the hippocampus. Thus, studieson these receptors should be relevant for further characteriza-tion of the involvement of DA in the regulation of cognitiveprocesses, as indicated by pharmacological studies.

Other studies using gene inactivation procedures fordopaminergic receptors are also relevant. In contrast to thatseen for D2 receptor gene inactivation, the D3 receptorknockout led to increased locomotor activity (Accili et al.,1996). However, it is noteworthy in that case that these miceapparently exhibit reduced anxiety (Steiner et al., 1997).The increase in locomotor activity related to D3 receptorgene inactivation may reflect some sort of “hyperdopamin-ergic function”, since mice lacking the dopaminergic trans-porter exhibit similar spontaneous hyperlocomotion (Giroset al., 1996). It still remains to be established how thenormal stimulation of the D3 dopaminergic receptors ex-erts a putative inhibitory control over locomotor activity.Finally, in the context of cognitive processes, D4 receptorgene inactivation is associated with reduced exploration ofnovel environmental stimuli (Dulawa et al., 1999), whichcontributes to a further focus on the putative role of DA inadaptive behavioral strategies to environmental changes, asshown from disruption of mesocorticolimbic dopaminergictransmission.

7.4. Further illustrations of dopaminergicmodulation of brain function

One of the best illustrations of the modulation possibly ex-erted by DA on brain function is provided by the effect of DAdepletion on the specific rhythms associated with attentionalprocesses not only in the frontal cortical areas but also atthe level of the parietal cortex, for example (Montaron et al.,1982). However, despite very active research in the fieldof behavioral pharmacology, the functional consequences ofactivating DA receptors are still poorly understood at a cel-lular level. At this cellular level, DA essentially depressesneuronal activity. Filtering of information at the cortical levelcould be one action of enhanced dopaminergic transmission,as demonstrated also in the case of norepinephrine. But, inthe case of the dopaminergic system, there is no clear evi-dence for its contribution to a selection process. DA couldpossibly interfere with the selection of information, as sug-gested from the disputed sensory neglect observed after le-sioning of the dopaminergic systems or the lack in detectionof novelty.

At the subcortical level, however, lesioning the dopamin-ergic system has been shown actually to decrease the


selectivity of discrimination of sensory input in the globuspallidus in the MPTP-treated monkey (Wichmann andDeLong, 1996). Similarly, depressed DA transmission wasshown to increase convergence of information to palli-dal neurons, thus again suggesting decreased selectivityin neuronal integration and dramatic reductions in a fo-cusing effect on salient stimuli (Toan and Schultz, 1985;Filion et al., 1988). It may be of interest to comparedeficiency in focusing attention to pertinent stimuli inschizophrenia or in ADHD in which patients are sensitiveto all stimuli, without any sort of discrimination. Thus, de-pressed DA transmission, possibly at a cortical level, cancontribute to cognitive deficits. The contribution of DA tosome aspects of the cognition may rely on its key role inintegrative mechanisms involving LTP or LTD at the cellu-lar level, notably through active interactions with excitatoryamino acid transmission (Calabresi et al., 2000). For exam-ple, such processes have been proposed to be involved inmemory tasks at hippocampal level and more generally insynaptic plasticity.

7.5. Molecular changes associated with alterations incentral dopaminergic function

At the subcortical level, we have more precise informationon the target neurons of the dopaminergic input and on theeffects exerted by the neurotransmitter on cellular activity,measured in terms of changes in the expression of proteins(neurotransmitters synthesizing enzymes, neuropeptides, re-ceptors, etc.). These changes actually illustrate long lastinginfluences of DA, which can contribute to tonic regulationof the neuronal populations. In the striatum, dopaminergicnerve terminals are present as axonal varicosities, each form-ing about 1000 contacts on dendrites of the spiny neurons,which represent the vast majority of the striatal neurons(Doucet et al., 1986). The dopaminergic input contacting pri-marily the neck of the spine is actually in a position to mod-ulate the input from other neuronal afferents, for example,corticostriatal nerve terminals, which contact the distal partof the spine (Freund et al., 1984). A similar organization hasbeen shown at cortical level (Goldman-Rakic et al., 1989).

In the striatum, we have shown, along with others (Gerfen,2000), that lesioning the dopaminergic system affects dif-ferent subpopulations of neurons contributing to the stri-atal network. For example, expression of the neuropeptideenkephalin, which is contained in one of the major popu-lations of striatal output neurons, was enhanced followingDA depletion, whereas on the contrary, the expression ofsubstance P, a marker of the second major population of thestriatal output neurons, was depressed (Salin et al., 1996;Salin et al., 1997). Moreover, changes in activity of otherneuronal markers such as neuropeptide Y, somatostatin andcholine acetyl transferase (CAT) for the cholinergic neuronsor glutamic acid decarboxylase (GAD) for the GABAergicneurons, were also shown, indicating long-lasting adaptivechanges following striatal DA depletion (Hajji et al., 1996).

In most cases, the changes can be reproduced by directlyacting on DA receptors through selective agonists or antago-nists, thus suggesting that DA acts as a tonic regulator of thedifferent subsets of striatal neurons. Consequently, changesin dopaminergic transmission affect the general processingof striatal information more than specific cellular interac-tion mechanisms, although it has long been suggested thatstriatal DA depletion causes increased cholinergic transmis-sion, which can be related to some aspects of PD (Di Chiaraet al., 1994). The effects of DA agonists are also suggestiveof similar changes in other pathological processes and prob-ably in schizophrenic patients, where it can be speculatedthat “over dopaminergic” transmission can deeply modifythe processing of information, at least within the nucleusaccumbens. Very little is known about equivalent regulatoryprocesses at the cortical level, but it can be speculated thatsimilar control of the cortical neuronal subsets exists, whichcontributes to information processing in cortical areas andthus to cortical function.

7.6. Dopamine in the basal ganglia: the role ofthe basal ganglia in cognition

Because cognitive impairments occur early in PD, it hasbeen suggested that even partial DA depletion limited tothe striatal area could contribute to the neuropsychologicalsymptoms. Taking into account the putative modulatory roleof DA on striatal functioning, the question thus arises as tothe contribution of the basal ganglia to cognitive processes(Oberg and Divac, 1979). Regarding the close relationshipsexisting anatomically between the basal ganglia and cere-bral cortex, as particularly shown in the massive corticalprojection to the striatum, it could be assumed that the basalganglia act as a simple relay of cortical information. Nu-merous studies have emphasized that the behavioral con-sequences of lesioning selected striatal areas are similar tothose produced by lesioning the corresponding cortical areas(Divac, 1968). Thus, impairment of working memory pro-cesses, which were related to PFC alterations, was also beendemonstrated after selected lesions of the caudate nucleusin monkeys (Rosvold et al., 1958; Divac et al., 1967). In thiscontext, it is worth noting the high degree of convergenceof the corticostriatal pathway, which can represent an inte-grative process of the activity of different cortical areas at asubcortical level. Moreover, the same cortical area has beenshown to send projections to multiple striatal sites (Flahertyand Graybiel, 1991; Selemon and Goldman-Rakic, 1985).As mentioned above, DA could play a role in integrativeprocesses, in such a way that it contributes to a focusing ef-fect, thus selecting at the level of the striatal neuron the sig-nificant input corresponding to relevant information for thecontext of behavior, more than coding parameters of action.

One of the most interesting proposals regarding theanatomo-functional organization of the basal ganglia com-plex was presented some years ago byAlexander et al.(1986), who suggested that the cortico-subcortico-cortical


networks connecting the cerebral cortical areas to the basalganglia are organized in five, more or less segregated, loopswhere information processing is parallel in nature, withpartial overlapping of corticostriatal inputs and integrationthrough pallidum, subtantia nigra (pars reticulata) and tha-lamus. In such a way, the information arising, for example,from sensorimotor cortical areas, could reach frontal cor-tical areas through the putamen, pallidum/substantia nigraand ventrolateral thalamus. Similarly, limbic informationarising from anterior cingulate cortical areas (but also sub-cortical structures, such as the hippocampus or amygdala),could reach the frontal lobe via selected ventral striatalareas, the ventral pallidum and the mediodorsal thalamus.Finally, pre-frontal dorsolateral areas could directly influ-ence the frontal cortex through the caudate nucleus andthe ventroanterior–mediodorsal thalamus. One of the endpoints of the basal ganglia projections to the cerebral cortexvia the thalamus is mainly the supplementary motor area(SMA), a region known to play a key role in the integra-tive and preparatory steps of behavioral processes (Tanji,1994; Hoover and Strick, 1993). In this respect, lesions ofthe SMA in the monkey (Denny-Brown and Yanagisawa,1976), as well as in humans (Laplane et al., 1977), areknown to reproduce a Parkinsonian-like akinesia. Althoughsuch an organization could be considered as oversimplified,notably because it fails to fully integrate highly convergentconnections between the different basal ganglia structures,particularly the striatal projections to pallidal and nigral nu-clei (Percheron et al., 1984; Joel and Weiner, 1994), such aproposal has contributed to a better understanding of basalganglia functions (Mink and Thach, 1993). Moreover, sen-sory aspects are probably underestimated, because of thelack of consideration of thalamic input in the vast major-ity of proposals. Such sensory information, which is alsodependent on consistent corticostriatal projections from theprimary sensory areas, could directly contribute to basalganglia cognitive functions, as emphasized byBrown et al.(1997), even if striatal neurons are not generally responsiveto primary sensory input. Taking into account the fact thatDA can modulate the activity of these different loops, notonly at both striatal and cortical levels, but also in the dif-ferent basal ganglia structures themselves (pallidum, STNand substantia nigra), it can hence be suggested that DAmay simultaneously influence different components of thecortico-subcortical circuitry and contribute to the coordi-nation of putative anatomically and functionally separatedcomponents acting for the harmonization of behavior in theperpetually changing conditions of the behavioral context.Moreover, limbic aspects of behavioral responses contribut-ing to the “drive” of action, which is highly dependenton DA, can be reinforced through striatal mechanismsacting through the striatonigral pathway. This influencemay arise from the striosomes, as recently highlightedby Graybiel et al. (2000), since the corticostriatal projec-tion to the striosomes primarily involves cortical limbicareas.

That the striatal area plays a key role in the selection ofbehavioral strategies and thus in the switching and flexi-bility of behavior, has indeed recently been emphasized bymany authors. The basal ganglia are usually considered tobe involved in the automatic selection of previously learnedprocedures contributing to behavioral adaptation. However,they can also contribute to the acquisition of new behavioralprocedures in a “controlled” mode, which probably involvescortico-subcortical loops. Indeed, changes in parallel withlearning and coding of neuronal representation have beenevidenced through cellular recording in the striatum of be-having animals (Jog et al., 1999). Moreover, the striatumalso contained neurons sensitive to attentional processes(Kermadi and Boussaoud, 1995), as well as to spatial ori-entation (Wiener, 1993), as earlier described byHikosakaet al. (1989). Paillard (1985)emphasized the central positionof the striatum in the integrative processes of behavior,particularly in the evaluation of the context of behavior.He proposed that the striatum is in a position to integrateinformation arising from the different associative corticalareas for motor planning. Thus, through the corticostriatalpathway, different aspects of information, which have to betaken into account in the elaboration of behavioral strate-gies, including contextual information from the parietal cor-tex, motivational information from the limbic cortical areasor intentional information from the PFC, could be used forproduction of the appropriate action. This integrative viewof the basal ganglia network (Fig. 3) has more recently beenfurther discussed byGraybiel et al. (1994)and Graybiel(1995)who reinforced the idea of a central contribution ofthe striatal network to motor planning and early stages of ac-tion, including cognitive processes. Interestingly, mnemonicfunctions of the basal ganglia were considered in this con-text by White (1997) and Knowlton et al. (1996), whoemphasized the idea that the striatal areas are not only im-portant for motor action and learning, but also for acquiringnon-motor associations involving interactions between theindividual and his/her perpetually changing environment.Further, such processing would also contribute to the learn-ing of new procedural skills. In this respect, the activationof the cortico-subcortical loops involving the basal gangliawould be only transient, until the training is achieved. Nu-merous data have been obtained by Schultz and colleagues,showing a progressive decrease in neuronal discharge withlearning, as also shown byCarelli et al. (1997). Moreover,data from PET scan studies in humans show that the pro-gressive acquisition of a new behavioral procedure parallelsprogressive extinction of cerebral activation in the caudatenucleus during the experimental session (Jueptner et al.,1997). Such a process could also be related to the “habithypothesis” of Mishkin (Mishkin et al., 1984; Mishkin andPetri, 1984), suggesting that the striatum is involved in theestablishment of automatic associations between a givenstimulus and corresponding behavioral response. Becauselesions of the caudal part of the caudate nucleus in monkeyscaused similar selective behavioral deficits of responses


to stimuli learned by repetition of the task to those fol-lowing inferotemporal cortex lesions (Philips et al., 1988),Mishkin and coworkers suggested the involvement of thecorticostriatal system in stimulus-response associations.

The contribution of the dopaminergic systems in suchlearning could be essential. DA, at both the cortical andsubcortical levels, may contribute to the evaluation of thebehavioral context (Redgrave et al., 1999b). Dopaminergicneurons, considered as detectors of novelty, are particularlysensitive to changes in the environment and can thus informlarge parts of the rostral CNS. Further, the dopaminergicneurons are also sensitive to changes in homeostasic con-stants, which may inform the brain about alterations in in-ternal constraints, thus providing the possibility for adaptivebehavioral reactions, for example to maintain body temper-ature when exposed to cold or warm environments or moregenerally, in response to stress. Because dopaminergic neu-rons play a central role in the response to stress via themesocorticolimbic neurons or their expression of receptorsto corticoids, DA can help to mobilize in coordinated waythe appropriate programs for behavioral reaction. Finally,the key role of DA in synaptic plasticity (Calabresi et al.,2000) and working memory processes at the functional level(Goldman-Rakic, 1995) can be emphasized. Consequently,such putative roles of DA and dopaminergic neurons mayaccount for the deficits that result in patients when disrup-tions occur in central dopaminergic transmission, either asreductions in the efficiency of DA transmission or in a hy-perdopaminergic activity. Moreover, because of local spe-cific roles of this neurotransmitter in the different parts ofthe CNS where the dopaminergic terminals are present, suchchanges have also to be taken into account, regarding themodulation of the activity and function of these specific ter-ritories, at both the cortical and subcortical levels, as dis-cussed previously. The cognitive setting of action (Lawrenceet al., 1998) could thus likely result from the modulation ofinformation processing through dopaminergic neurons.

8. Are cognitive deficits sensitive to stimulation ofdopaminergic transmission?

8.1. l-DOPA and dopamine agonists inParkinson’s disease

The standard treatment of PD is based on the admin-istration of l-DOPA and/or DA receptor agonists. Theimprovement in the motor signs of the disease is oftenspectacular in the vast majority of patients, until the sideeffects lead to a reconsideration of the treatment, due todramatic motor fluctuations and dyskinesia. One possi-bility for reducing the side effects ofl-DOPA therapy isto associate or substitutel-DOPA with DA receptor ago-nists. The use of such agonists could theoretically providethe advantage of selectively stimulating a given set of thedopaminergic receptors, given their structural diversity.

Thus, attempts have been made to produce selective agonistsfor the D1–D5 receptor subtypes, but the selectivity remainsrelative, although rather satisfactory results have been ob-tained in terms of improvement of the motor symptoms ofParkinsonism. Indeed, the ergot-derivatives bromocriptine,pergolide, lisuride and cabergoline have been shown to im-prove tremor, rigidity and bradykinesia and to reduce motorfluctuations related tol-DOPA administration, thus show-ing clear anti-Parkinsonian effects, although high dosesof the compounds can induce psychosis. Besides apomor-phine, a non-selective DA receptor agonist, new classes ofdopaminergic agonists primarily acting on the D2/D3 andD4 receptors, such as piribedil, which acts primarily onD1/D2 receptors (Ziegler and Lacomblez, 2000), pramipex-ole and ropinirole, are also efficient in reducing motor signsin Parkinsonism.

Very little is known, however, about the capacity ofl-DOPA and DA receptor agonists to improve cognitivedeficits in PD. In the early 1970s, many studies suggesteda positive effect ofl-DOPA on cognitive signs (Boshesand Arbit, 1970; Beardsley and Puletti, 1971), but it wasconcluded thatl-DOPA “improves attention span or vig-ilance without increasing the patient’s overall cognitiveability” (Bowen et al., 1976). Robbins and co-workers(Downes et al., 1989) have more recently failed to evi-dence clear extra-dimensional shift differences in medicatedand non-medicated Parkinsonian patients regarding visualdiscrimination learning. However, they have noticed anelevated sensitivity of the non-medicated patients to dis-tractibility, thus suggesting that the attentional deficit couldbe corrected at least partly byl-DOPA therapy. Later on,the influence ofl-DOPA on cognitive functions has been as-sessed in patients subjected to controlled withdrawal. Datashowed that certain, but not all, aspects of the cognitivefunctions were altered, emphasizing putative dopaminergiccontrol on frontal lobe related functions such as work-ing memory or executive functions (Lange et al., 1992).These data have been extended by the study byMalapaniet al. (1998), showing that time estimation in ON phasemedicated Parkinsonian patients is highly improved, com-pared with non-medicated patients and normal comparedwith matched controls, suggesting in that case a possibledopaminergic control of time-processing mechanisms. Infact, the cognitive effect ofl-DOPA might not depend ona neuropsychological specificity of the drug or the severityand progression of the disease, as recently mentioned byKulisevsky (2000), but, more likely, may be a function ofDA depletion in the different parts of the basal gangliaand PFC, since improvement or impairment of cognitivefunction with DA treatment is partial and task-related.

In fact, the effects ofl-DOPA on cognitive functions havebeen reported as beneficial as well as deleterious (Gothamet al., 1988; Kulisevsky et al., 1996; Kulisevsky, 2000;Swainson et al., 2000). In a recent paper,Cools et al. (2001)studied in PD the effects ofl-DOPA administration on be-havioral tasks associated with the different components of


corticostriatal circuits described byAlexander et al. (1986).The data showed that switching between two tasks, whichrequires high level of attentional control and involves thedorsolateral part of PFC and parietal cortex, is improvedby l-DOPA treatment, whereas probabilistic reversal learn-ing, associated with the orbitofrontal loops, is impaired.Consequently, it can be speculated that doses ofl-DOPAnecessary to improve motor aspects of PD also contributeto facilitate DA transmission in dorsolateral-parietal corti-cal areas, but may “overdose any area where DA regionsare relatively intact”, such as the orbitofrontal cortical ar-eas (Cools et al., 2001). These results are consistent withthe view that impaired, as well as excessive, DA transmis-sion in the PFC impairs working memory (Williams andGoldman-Rakic, 1995).

Such a view is reinforced by the data byWeder et al.(1999), showing that working memory and direct attentiondeficits correlate at subcortical levels with a specific decreasein dopaminergic innervation at the level of the caudate nu-cleus and not at the level of the putamen. Moreover,Hersheyet al. (2001)showed altered cortical blood flow responsesto l-DOPA in chronically treated Parkinsonian patients. Insuch PET scan experiments,l-DOPA was shown to increasethe cortical blood flow in both PFC and motor cortex in con-trols, whereas in chronically-treated patients the blood flowwas decreased in the same areas. Such a decrease in theventrolateral PFC was shown in that case to correlate withmini mental state (MMS) scores. Thus, it was concludedthat chronic treatment withl-DOPA might, in some cases,increase disease severity.

8.2. Schizophrenia and attentional deficits in children

The positive signs of schizophrenia are sensitive to neu-roleptic medication, thus emphasizing the contribution ofthe dopaminergic receptors to the expression of the disease.However, the negative signs of the disease, in which theplace of the dopaminergic dysfunction is still to be clari-fied, as well as the cognitive deficits of the disease, exhibitlittle improvement (Scatton and Sanger, 2000). Besides thedevelopment of the atypical neuroleptics, recent advancesin pharmacology have been focused on producing selectiveDA receptor subtype antagonists. Very little is known of theclinical effects of the few compounds introduced for clinicaltrials, but preliminary data have been rather disappointing,regarding putative antipsychotic effects of selective D1 orD2 family antagonists. However, recent studies have sug-gested that impairment of attentional processes and someneuropsychological performances are positively correlatedwith elevated D2 receptors in frontal lobe (Oades et al.,2000). As mentioned previously, concerning ADHD, psy-chostimulant administration was shown to improve children,highlighting the contribution of a dopaminergic hypoactiv-ity to attentional deficit or hyperactivity (Solanto, 1998).Nevertheless, the specific contribution of the DA receptorsubtypes remains to be demonstrated, because the psychos-

timulants used to treat the patients are mainly DA uptakeinhibitors such as methylphenidate ord-amphetamine.

8.3. Is the cognitive impairment of normal aging sensitiveto stimulation of the dopaminergic transmission?

Much evidence has been obtained in humans for a declineof dopaminergic transmission with aging, although experi-mental data have not been conclusive in terms of a reductionin the number of mesencephalic dopaminergic neurons.However, a correlation of such progressive impairment ofdopaminergic transmission with cognitive deficits remainsto be fully documented. For example, recent PET scan stud-ies have shown decreases in functionally available D1 andD2 dopaminergic receptors (Suhara et al., 1991; Volkowet al., 1996a) and in DA transporters (Volkow et al., 1996b)with age. More recent studies confirmed previous data andshowed positive correlations between a decline in dopamin-ergic activity with age and alterations of cognitive function(Rinne et al., 2000). Moreover, a positive correlation wasalso found between the level of performance in manyneuropsychological tests, such as the Stroop test and theWisconsin card sorting test and the level of (18F)-l-DOPAaccumulation in the striatum of Parkinsonian patients(Remy et al., 2000). Mental flexibility and executive func-tions have been shown to correlate with the D2 receptoravailability (Volkow et al., 1998; Bäckman et al., 2000) andimpairment in frontal and cingulate metabolism (Volkowet al., 2000). Consequently, it can be proposed that en-hancing dopaminergic activity may improve cognitive and,more generally, neuropsychological performance in theelderly. Accordingly, recent data showed a beneficial ef-fect of d-amphetamine in humans performing a selectiveattention test (Servan-Schreiber et al., 1998). Moreover,bromocriptine, a D2 agonist, was shown to facilitate work-ing memory processes (Luciana et al., 1998) and piribedil,a D1/D2 receptor agonist, was shown to improve behaviorin aging (Ollat, 1992). It is also worth noting the effects ofquinpirole in aged monkeys (Arnsten et al., 1995), com-pared to younger animals. High doses of quinpirole, a D2agonist, in the latter animals improved delayed memoryrecall, whereas low doses impaired it, possibly through anaction on pre-synaptic dopaminergic receptors. In the el-derly monkeys, low doses of quinpirole were not shown tobe effective, thus suggesting a possible deficiency of thedopaminergic terminals in the PFC and further reinforcingthe hypothesis of a regulatory role of the dopaminergicnerve terminals in cortical cognitive functions.

9. Conclusions

9.1. Dopamine as a common regulator of motor,limbic and cognitive aspects of behavior

The prominent distribution of dopaminergic innervationthroughout anatomically segregated neuronal systems that


involve the integration of motor, limbic and cognitive as-pects of behavior and the tonic mode of functioning conferon the dopaminergic subsystems a key role in the coordi-nation and integration of the different aspects of behavior.Lesioning selectively the dopaminergic innervation in agiven target structure frequently reproduces the effects ofthe lesion of the structure itself and disorganizes behavior.The main impairments are shown as dramatic decreases inthe capacity to adapt behavior to environmental changes,thus reinforcing the view of the dopaminergic neurons asan “interface” between external and internal constraints andbehavioral capabilities. Suppression of the main compo-nents of brain dopaminergic innervation does not suppressthe ability to perform behavior, which, however, generallybecame less well adapted to environmental changes, as ex-emplified by a lack of flexibility and shifting capacity. Theintegrative properties of the dopaminergic system are prob-ably associated more with direct contributions to cognitivefunctions at the cortical level, namely in working memory,executive functions and possibly time estimation processes.The contribution of the dopaminergic innervation in theregulation of attentional processes is still a matter of debate.What can be emphasized is a lack of attention focusingand a greater distractibility compared with normal whendopaminergic transmission is impaired, but it is noteworthythat lesioning some dopaminergic components sometimesproduces behavioral effects similar to those observed fol-lowing dopaminergic stimulation, thus suggesting possiblemultiple sites for the dopaminergic regulation.

Since dopaminergic brain activity apparently decreaseswith normal aging, correlated impairment in behavior, suchas lack of flexibility and adaptive capacities, deficits in se-lective attention processes or working memory and execu-tive function deficiencies, may be related to impairment ofcentral dopaminergic transmission. Consequently, stimulat-ing dopaminergic transmission in the elderly could repre-sent a reliable strategy for improving behavioral deficits, asshown in pathological situations, such as in PD, where theimpairment of dopaminergic transmission is massive. Stimu-lating dopaminergic transmission could represent “more dis-crimination, more representative behavioral inhibition andmore attention” (Le Moal and Simon, 1991), leading togreater flexibility and adaptation to environmental and inter-nal changes. In this context, it is interesting to note that themain signs of the pre-frontal syndrome in humans, includ-ing, for example, decreases in interest in the environment,sensory neglect, distractibility, visuomotor impairment, timeestimation deficit, working memory deficit or even the plan-ning of action, are all supposed to be affected by dopaminer-gic regulation. Finally, negative symptoms of schizophreniaor even Alzheimer’s disease, where an alteration of the in-tegrity of the dopaminergic neurons has been reported (Gibbet al., 1989), could be associated with deficits in motivation,which may be due to lack of dopaminergic regulation ontothe cortico-subcortico-cortical circuits involving the limbicpart of the basal ganglia (Brown and Pluck, 2000). Stimu-

lating dopaminergic transmission could, therefore, result inreinforcement of cortical control and enhanced motivation.A decrease in D1 receptor density has been shown in thefrontal cortex of schizophrenic patients to be correlated withthe severity of negative signs, whereas no change was seenin these patients in the striatum (Okudo et al., 1997).

9.2. Dopamine and cognition: is the development of thedopaminergic system parallel to the development ofcognitive functions in human?

In a recent article,Previc (1999)proposed correlatingthe origins of human intelligence to the contribution ofdopaminergic systems in human cognition, because of a keyrole of DA in cognitive skills, which, hypothetically, char-acterize hominid evolution.Previc (1999)also emphasizesa putative essential contribution of cortical DA to executivefunction and also to language production, which critically in-volves working memory processes. The term “intelligence”possibly does not reflect exactly the contribution of DA,although the involvement of the neurotransmitter in the reg-ulation of cognitive functions is a fact. A lateralization ofthe dopaminergic systems with a permanent dominance inthe left hemisphere has been shown in humans and, besidesthe well-documented contribution of the left hemisphere tolanguage production, it has been suggested that motor pro-gramming is solely due to the left hemisphere, (Greenfield,1991). Thus, predominance in the dopaminergic innervationof the left hemisphere supports the theory of a specializa-tion of this hemisphere in regulating cognitive functionsand adaptive brain capacities, although other neuronal sys-tems, such as cholinergic, serotoninergic or noradrenergicsystems, also show some evidence of asymmetrical orga-nization. In rodents, the asymmetrical organization of thedopaminergic systems has been shown for a long time andinvolves about 10% of the striatal DA content. However,no clear correlation has been made at behavioral level withside preference (Glick and Shapiro, 1985), although someside differences in the sensitivity to psychostimulants of thedopaminergic system have been shown.

9.2.1. Phylogenetic evidenceDA is present inC. elegansand Drosophila and the

importance of the dopaminergic system is thought to pro-gressively develop through evolution. Thus, in a Darwinisticview of selection, one can consider that such a developmentof dopaminergic brain innervation may be associated withselection and adaptation of the organism to external (andinternal) constraints. An elementary dopaminergic systemis present in very primitive species, such as fish and lizards,which appear to be able to select information processingand react to changes in environmental conditions in anemotional way (Pani and Gessa, 1997). The developmentof the dopaminergic system through evolution would, thusbasically promote motion and possibly emotional capaci-ties related to pleasure. However, the further expression of


Fig. 4. Rostro-caudal gradient of cortical dopaminergic innervation in humans (adapted fromBrown and Goldman (1977)and Gaspar et al. (1989)).

cognitive functions in mammals correlates more preciselywith adaptive capacities for anticipation from the past (sen-sation) to the future (action). In this respect, the extensionof dopaminergic innervation during evolution could be cen-tral, as suggested from the evolution of the developmentof cortical dopaminergic innervations in different speciesof mammals. In rodents, the dopaminergic terminals arerestricted to the frontal lobe and particularly to the PFC,entorhinal cortex and piriform cortex (Thierry et al., 1973;Berger et al., 1976). In the monkey and also in humans,dopaminergic terminals innervate the entire cortical areasaccording to a rostro-caudal gradient (Brown and Goldman,1977), including motor and pre-motor areas (Figs. 3 and4), which are not subjected to dopaminergic innervation inrodents (Gaspar et al., 1989). This development of corticaldopaminergic innervation during evolution would indeedcorrelate with the progressive involvement of the cortex inthe processing of sensory information through basal gan-glia (Smeets et al., 2000). Finally, it is worth noting thatthe development of cortical dopaminergic innervation couldalso correlate with the dramatic extension of associativeterritories in primates associated with a higher degree ofsensorimotor integration, compared with that occurring insubprimate species (Fuster, 1989).

Another feature characteristic of the evolution ofdopaminergic cortical innervation concerns cortical lamina-tion. In rodents, dopaminergic fibers are present in layersVI and I, whereas in primates, the lamination shows astrong dopaminergic input in the superficial layer and asecond cluster of dopaminergic terminals in layers V andVI. Excepting for primary sensory areas, which are poorlyinnervated, the most striking characteristics are indeed theexpansion of the dopaminergic cortical innervation duringthe latter stages of mammalian evolution. Taking into ac-count the increasing role of motor and pre-motor areas in

the selection and programming of action, the presence ofa peak innervation of the dopaminergic fibers at this level,especially during the later stages of development, wouldhave contributed to setting the mechanisms of selection ofappropriate behavioral strategies. Correlations that can bemade between the development of dopaminergic corticalinnervation and development of cognitive functions are thusremarkable and further support the view of a contributionof cortical DA to regulation of cognitive processes, at leastin areas of the PFC.

An interesting feature of evolutional processes of thedopaminergic systems is to consider that, if the general or-ganization of the dopaminergic nuclei is rather constant inthe main vertebrates subtypes, the number of DA receptorswas conversely highly increased during vertebrate evolu-tion. This increase in receptor subtypes led to the presenceof three subtypes of D1 receptors in mammals, whereasin the cephalochordateAmphioxus, for example, a singleD1 gene is expressed (Kapsimali et al., 2000). In this re-spect, the diversification of the D1 dopaminergic receptorsin mammals will correlate with increased processing ofinformation in mediating higher brain functions, such asselective attention, for example.

9.2.2. Ontogenetic evidenceConsidering the setup of the dopaminergic systems during

ontogenesis can further contribute to assess the hypotheticalrole of DA in the development of behavior and cognitivecapacities in humans. Recent data suggest a role of DA inneurogenesis because of the presence of the dopaminergiccells in the first stages of embryogenesis. For example, inchick embryos, tyrosine hydroxylase is expressed as earlyas on the first day of incubation and DA on the second day.DA neurons are found in the embryos by day 12 in the ratand at 4 weeks gestation in human (Pendleton et al., 1998).


Early disruption of the dopaminergic system in animals wasshown to affect brain maturation, further suggesting a rolefor DA as a factor that can influence embryonic patterning(Lauder, 1988; Lauder, 1993). Indeed, DA was shown toregulate development of its target neurons in the striatum.In vitro, DA was shown to promote neurite extension ofcortical neurons, through D2 receptors (Todd, 1992), butcould exert opposite influences through D1 and D2 receptors(Schmidt et al., 1996). In vivo, the trophic action of DA inthe early stages of development could be primarily linked toD1 receptor activation, since these receptors appear in the ratto develop earlier, compared to the D2 receptors, which arethought to become functional only after birth (Spano et al.,1976).

The development of the dopaminergic system has beenextensively studied in the rat. At birth, dopaminergic activ-ity is considered to represent about one-third of the adultlevel. The concentration of DA in the brain then progres-sively increases up to 3 months and stabilizes up to 12months, as shown for example in the striatum (Coyle andCampochiaro, 1976; Restani et al., 1990; Miguez et al.,1999). In the cerebral cortex, the adult distribution in therat anterior cingulate cortex was not reached until P60(Berger et al., 1985), further illustrating the developmentof the dopaminergic systems during post-natal weeks. Inthe Rhesus monkey, a similar progressive post-natal mat-uration of dopaminergic cortical innervation was shown(Goldman-Rakic and Brown, 1982). At birth, the basic pat-tern of the distribution of the dopaminergic terminals existswith the typical rostro-caudal gradient. The adult level ofthis innervation was shown to be reached by 5 months.However, there are large differences, dependent on thecortical areas considered. Indeed, DA reached adult levelsat birth in the PFC, but these are subject to late develop-ment during infancy and to late myelinization (according toFlechsig; seeFuster, 1989). Moreover, at 5–6 months, thereis a dramatic increase in the development of dopaminer-gic innervation of the motor and pre-motor areas, but thisinnervation was shown to regress after 2–3 years, to reachadult levels. An age-related decline then occurs, so that oldmonkeys have a remaining cortical dopaminergic innerva-tion representing only about 50% of that of young animalsin PFC.

Thus, it is tempting to correlate the development of thedopaminergic cortical innervation with the developmentof cognitive capacities. Reorganization of the superficiallayers of the PFC is shown during the peripubertal period,when the dopaminergic innervation is maximal (Lewiset al., 1998). Because in these areas the dopaminergic in-nervation is maximal at birth, it may be suggested thatthis dopaminergic innervation contributes, via a trophicaction, to the organization of PFC, which could thus in-fluence its later functioning at adult stages. Indeed, thosecortical areas that are critical for further expression ofcognitive capacities are far from being fully developed atbirth. Thus, DA could actually play a “structural role” in

division, migration and differentiation processes of corticalneurons.

The rather late dopaminergic innervation of the motorand pre-motor cortical areas after 5–6 months in monkeysis more difficult to explain, because the motor compo-nents of behavior are fully developed in these animals atthat period. However, it can be speculated that the de-velopment of dopaminergic innervation in these corticalareas correlates with the development of less “automatic”aspects of behavior, i.e. more integrated, less reflexiveand adapted behavior. Regarding changes that can con-cern behavior during corresponding life periods in hu-man, the contribution of the dopaminergic neurons maythus be considered as central in terms of adaptive ca-pacities and the further development of cognitive func-tions.

9.3. Final remarks

The impairment of executive functions in the early stagesof PD, when the neurodegenerative process is thought tobe limited to the dopaminergic neurons, as well as the nu-merous data from lesion and cell recording experimentsin animals, lead us to consider that dopaminergic neuronsplay a key role in controlling cognitive processes. However,it appears that the dopaminergic neurons are not integralparts of the neuronal networks involved in the produc-tion of these functions, but rather regulate such behavioralprocesses, as they do for motor and limbic aspects of be-havior. It seems reasonable to emphasize the hypothesis ofa neuroregulatory role of dopaminergic transmission in per-mitting the CNS to adapt behavior to subtle environmentalchanges. Consequently, changes in brain activity result-ing in impairment or exacerbation of central dopaminergictransmission could probably result in pathologic effectson behavior. If this view is correct, normalizing centraldopaminergic transmission may help to normalize behavior,in the context of permanent environmental changes. In thatcase, anticipating capacities may depend on the integra-tive properties of central dopaminergic transmission. Theuse of pharmacological compounds acting on dopaminer-gic transmission could, thus represent an efficient strategyfor correcting behavioral deficits in pathological statesor even for increasing adaptive capacities during normalaging.

Acknowledgements

The author would like to thank Dr. Marianne Amal-ric, Christelle Baunez and Lydia Kerkerian-LeGoff forhelpful comments and excellent collaboration. This workwas supported by CNRS, the Université de la Méditer-ranée in Marseilles and Eutherapie, Les LaboratoiresServier.


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