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TiPS - M ay 2992 [Vol . 231

Drugs of abuse: anatomy,pharmacology and function ofreward pathwaysGeorge F. KoobDrugs of abuse are ve y powerful reinforcers, and even in conditions of limitedaccess (where t he organism is nof dependent) these drugs will motivate highrates of operant responding. This presumed hedonic property and the drugsneuropharmacological specificify provide a means of studying fhe neurophar-macology and neuroanatomy of brain reward. Three major brain systemsappear to be involved in drug reward - dopamine, opioid and GABA. Evidencesuggests a midbrain-forebrain-extrapyramidal circuit with its focus in thenucleus accumbens. Data implicating dopamine and opioid systems in indirectsympathomimetic and opiate reward include critical elements in both fhenucleus accumbens and ventral tegmental areas. Ethanol reward appears todepend on an interaction with fhe GABA* receptor complex but may alsoinvolve common elements such as dopamine and opioid peptides in thismidbrain-forebrain-extrapyramidal circuit. These results suggest thaf brainreward systems have a mulfidetermined neuropharmacological basis that mayinvolve some common neuroanatomical elements.The concepts of reward, motiv-ation and reinforcement are dif-ficult to study from a neurobio-logical perspective primarilybecause quantitative measure-ment is difficult even if these termsare defined operationally. A re-inforcer can be defined operation-ally as any event that increases theprobability of a response. Rewardis often defined similarly but withsome positive affective coloring,such as pleasure. This reviewadopts the latter definition ofreward; measurement will largelybe restricted to reward associatedwith any event (drug) for whichan animal will perform an operantresponse. .Animals will readily self-administer drugs either intra-venously or orally, and drugs thatare self-administered by animalscorrespond well with those ofhigh abuse potential in humans.Drug self-administration behaviorfollows many of the same rules asbehavior reinforced by conven-tional reinforcers such as food,water and sex. In the nondepen-dent state (usually a condition oflimited access), the drug generatesa motivational state much as otherincentives with low drive, such assaccharine. Psychomotor stimu-lant drugs, such as cocaine, areG. F. Koob is Professor in the Department ofNeuropharmacology, Scripps Research nsti -tute, 20666 North TorreyPinesRoad, a olla,kA 92037, USA.

very powerful reinforcers. Even ina limited-access, nondependentcondition, rats will press up to150 times for one injection of0.75 mg kg- of cocaine. In thedependent state, additionalmotivational power is exerted bynegative reinforcement where thedrug blocks or reduces the pre-sumably aversive state of with-drawal.These properties and the neuro-pharmacological specificity ofdrugs make them ideal for studiesof the neurochemistry of reward.Three important neurochemicalsystems - dopamine, opioid pep-tides and GABA - are exploredhere for their role in drug reward.The insights derived from thesestudies are used to propose areward circuit of possible heu-ristic value for future work in drugdependence and psychopathology.Reward: neuroanatomicaldistributionTwo major dopamine systemsoriginate in the ventral midbrain:the nigrostriatal dopamine systemand the mesocorticolimbic dopa-mine system. The mesocortico-limbic dopamine system has beenimplicated in drug reinforcement.The cell bodies of this systemoriginate in the ventral tegmentalarea (WA), originally describedas the A10 group of catecholamineneurons2a3, and project to the fore-brain, largely the nucleus accum-

177hens, olfactory tubercle, frontalcortex, amygdala and septal area(see Fig. 1). There is a reversetopographic distribution, withventral dopamine neurons in theVTA projecting to dorsal regionsand the dorsal VTA neurons pro-jecting to ventral regions4.Mesocorticolimbic dopamineAs an interface between themidbrain and forebrain, themesocorticolimbic dopamine sys-tem may be one of the moreanterior components of the com-plex isodendritic core of thereticular formations. It has beenhypothesized to modulate the ac-tivity of the ventral striahun, abrain region thought to be in-volved in converting emotion intomotivated action and movement(for review see Ref. 6). Selectivedestruction of the dopamine pro-jection to the ventral striatumcauses decreases in locomotor ac-tivity induced by new environ-ments, in motor activity producedby food presentation, and in ac-tivation produced by scheduledfood delivery (schedule-inducedpolydipsia) (for reviews see Refs 5and 7).Similar lesions have also pro-duced a syndrome of persev-eration with reduced distractioncaused by irrelevant information,and a decrease in behavioralswitching and flexibilie.In learning tasks, animalswith similar 6-hydroxydopaminelesions show impaired spon-taneous alternation, disturbedacquisition of spatial habits anddifficulty in reversing previouslylearned habits5.The effects of direct injection ofdopamine and dopamine antag-onists have implicated the meso-corticolimbic dopamine system inlocomotor activation and the psy-chostimulant actions associatedwith indirect sympathomimetics.Dopamine and amphetamine in-jected into the nucleus accumbensstimulate locomotor activity, andinjection of haloperidol into thenucleus accumbens blocks thelocomotor activation produced byD-amphetamine. A similar block-ade of amphetamine-, cocaine-and methylphenidate-inducedlocomotor activation has beenobserved following L-hydroxy-dopamine lesions of the region ofthe nucleus accumbens. (Forreview, see Ref. 5.)

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cocaineand amphetamine ewardParadiimIntra~Wti e&t&al selbstimulationLateral hypothalamus

Ventral tegmental areaInbacranlalself-administrationMedial prefrontal cortex (cocaine)

Nucleus accumbens (amphetamine)Intravenousself-administrationNoradrenaline receptor antagonists

5-IiT receptor antagonistsP-Opioid receptor antagonistsCl, and D2 dopamine receptor antagonistsNotadrenaline denervation 6-hydroxydopamine)5-W denervation (5,7-dihydroxytryptamine)Doparnine denervation (6-hydroxydopamine)

Nucleus accumbensVentralegmental areaMedial prefrontal area

t , acilitation; 1, inhibition; , no change.

Effecton reward Fig. 1. Sagittal rat brain section illuskafing acocaine and amphetamine neural rewardc ircui t hat ncludes a limbic+extrapyramidaImotor interface. Yellow indicates limbic

F afferenfs to he nucleus accumbens (N Acc.)and orange represenfs efferents from iheT nucleus accumbens thought to be involvedt

in psychomotor stimulant reward. Red indi-cates projections of the mesocotticolimbicdopamine system thought fo be a criticalsubstrate for psychomoror stimulant reward.t This system originates n he A 10 cel l groupof the ventral @mental area (WA) and1

projects to fhe N. Act., olfactory tubercleand ventral striafal domains of the caudateputamen (C-P). VP, ventral pallidurn; LH,

t lateral hypothalamus; SNr, subsfantia nigrapars reficulata; DMT, dorsomedial thalamus;PAG, periaqueductal gray: 01, O/fsC~OrVtract ; AC, anterior commissure; LC, /OCUScoeruleus; AMG, amygdala; Hippo, hippo-campus; Cer, cerebellum. Left: effect ofdifferent experimental paradigms on cocaineand amphetamine reward in at

In the absence of drug adminis-tration, the mesocorticolimbicdopamine system appears to actas a modulator or a filtering andgating mechanism for signalsfrom the limbic regions, signalsmediating basic biological drivesand motivational variables. Thesesignals are thought ultimately tobe translated into motor acts viathe output of the extrapyramidalmotor system (see Refs 5, 6 and 8for more details and review). It isstill not clear why activation ofthis system is reinforcing but sub-stantial evidence suggests that therewarding actions of psychomotorstimulants are mediated by themesocorticolimbic dopamine r:o-

jection (see below). One hypoth-esis is that the mesocortico-limbic dopamine system has acritical role in the species-typicalmotor arousal associated withanticipation of reward. Anotherview is that all addictive drugshave a psychostimulant actionthat contributes to the reward.Dopamine in acute rewardingeffects of psychomotor stimulantsNeuropharmacological studieshave established an importantrole for central dopamine in theacute reinforcing effects ofcocaine (see Woolverton andJohnson, this issue). Low doses ofdopamine receptor antagonists,

when injected systemically, re-liably increase self-administrationof amphetamine and cocaine inthe raP,12. This increased self-administration has been inter-preted as a partial blockade of therewarding actions of cocainebecause rats will compensate fordecreases in the magnitude ofreinforcement with an increase incocaine self-administration (or adecrease in the interval betweeninjections). This increase is simi-lar to the increase observed afterlowering the dose of cocaine inthe self-administration session(see Stolerman, this issue).Adrenoceptor antagonists, suchas phenoxybenzamine, phentol-

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TiPS - May 1992 [Vol. 131 179amine and propranolol, have noeffect on stimulant (amphetamine)self-administration.Recent work using systemic in-jections of selective dopaminereceptor antagonists has shownthat both Dr and D2 receptors maybe important for the reinforcingactions of cocaine in animals (seeWoolverton and Johnson, thisissue).A role for dopamine in thereinforcing properties of cocainewas strengthened by the obser-vation that 6-hydroxydopaminelesions of the nucleus accumbensproduce extinction-like respond-ing in cocaine and amphetamineself-administration, as reflected ina significant and long-lastingreduction in responding overdays13J4. Decreases in the reinforc-ing effects of cocaine have alsobeen observed following 6-hydroxy-dopamine lesions of the nucleusaccumbens using a progressiveratio schedule*. Similar 6-hydroxy-dopamine lesions of the frontalcortex and caudate nucleus fail tosignificantly alter establishedcocaine self-administration**5.Neurochemical studies using inviva microdialysis confirm thatdopamine release is increased inthe nucleus accumbens during i.v.self-administration of cocaine. I.v.self-administration of cocaine inexperienced, trained animalsproduces a gradual increase indopamine levels in _ he nucleusaccumbens that reflects the pat-tern of self-administration, al-though an exact relationship withthe interval between injectionsand the self-administered dosehas yet to be demonstratedlG1.When saline is replaced by co-caine, rats rapidly stop respond-ing and dopamine levels in thenucleus accumbensdecline18. rapidlyDopamine in acute rewardingeffects of ethanolSeveral studies have suggestedthat brain dopamine systems mayalso be involved in the reinforcingproperties of low doses of ethanol.Dopamine receptor antagonistsreduce lever-pressing for ethanolin nondeprived rats20*21 and alsoreduce home-cage ethanol drink-ing*. Dopamine receptors in thenucleus accumbens may have animportant role in ethanol self-administration, since dopaminereceptor antagonists injected into

the nucleus accumbens decreaseoral ethanol self-administration inmale Wistar rats that have notbeen deprived of food or waterand have been trained in a two-lever, free-choice self-adminis-tration tasks. In this task, withinthe dose range of S-10% ethanol,decreases in dose produce de-creases in responses for ethanoland in the amount of ethanolconsumed. The difference be-tween the dose-response functionof ethanol (ascending) and cocaine(descending) probably reflects thedifference in the route of admin-istration - oral for ethanol and i.v.for cocaine.Low doses of ethanol stimulatelocomotor activity in certain strainsof rats= and produce marked in-creases in extracellular dopaminelevels in the nucleus accumbens ofrats26. Extracellular dopaminelevels have also been shown toincrease in nondependent ratsorally self-administering low dosesof ethanol. Extracellular dopa-mine levels in the nucleus ac-cumbens appeared to be directlyrelated to the amount of ethanolconsumed and were much higherin the genetic strain of alcohol-preferring P ratsl*. Thus, there isalso neurochemical evidence thatdopamine systems may be in-volved in the low-dose reinforcingactions of ethanol. These datasuggest that dopamine receptorsin the nucleus accumbens may beinvolved in ethanol reinforcementin the nondependent rat. How-ever, there is some evidence fordopamine-independent ethanolreward in free-choice, home-cagedrinking (24-hour access) (forreview see Ref. 27, and Samsonand Harris, this issue).Opioid peptidesOpioid peptides are distributedthroughout the brain and formthree major functional systemsdefined by their precursor mol-ecules: j3-endorphin from pro-opiomelanocortin, enkephalinsfrom proenkephalin, and dynor-phin from prodynorphin2s. Thesepeptides are involved in threemajor functions: modulation ofthe nociceptive response to pain-ful stimuli and stressors, reward,and homeostatic adaptive func-tions such as food, water andtemperature regulation (for re-views see Refs 29 and 30 andDi Chiara and North, this issue).

When injected intracerebrally,opioid peptides, like opiate drugs,raise nociceptive thresholds with-out altering basic sensory process-ing (touch, temperature and pro-prioception). Endogenous opioidpeptides are thought to modulatebrain nociceptive processing atmany different levels of the neur-axis from the spinothalamic tractin the dorsal horn of the spinalcord to the periaqueductal gray tothe medial thalamus. Stressors caninduce analgesia that is reversedby opioid antagonists3i, suggest-ing a role for endogenous opioidsystems in stress-induced anal-gesia.Opiate drugs and opioid pep-tides alter consummatory be-havior in animals. When injectedintracerebrally, opioid peptidescan induce feeding and drinkingin rats while opioid antagonistsreduce these behavioi?.Opioid peptides, like opiatedrugs, have rewarding properties(see Di Chiara and North, thisissue). Injection of opioid pep-tides into the VTA or nucleusaccumbens facilitates intracranialself-stimulation32. Rats will intra-ventricularly self-administer p-endorphin33, and fi-endorphininjrcted i.c.v. produces place pref-erenceP. Rats will self-administeropioids into the VTA and thenucleus accumbens. Opioid pep-tides injected into these tworegions stimulate locomotor ac-tivity and produce place prefer-ences (see Di Chiara and North,this issue). Other regions support-ing rewarding effects for opioidsare the hippocampus and hypo-thalamus36. Consistent with theseresults, opioid receptor antagon-ists produce robust place aver-sions in nondependent animals3and reverse the lowering of intra-cranial self-stimulation thresholdsprztdlced by psychomotor stimu-

Acute reinforcing effectsof opiatesOpiate drugs such as heroin,like psychostimulants, are readilyself-administered i.v. by animals.If there is limited access, rats andprimates will maintain stablelevels of opiate intake on a dailybasis without any m$or signs ofphysical dependence3 *40.As withcocaine, decreases in the dose ofheroin available i.v. to a non-dependent animal will change

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7iPS -May 1992 Wol. 231

paradlgrnlntmcranialekctrical aalf-atimulationLataralhyPottlalamuslnhuaniil aalkadminialrationNuclausaccumbens

LataralhypothalamusVantraltagmentalaraa

lntmvenouaaelf-admlnlatrationOpioid acapbxantagonistsp-Receptor antagonisk&Receptor antagonistsK-R~tCIr aII~grJfl~

Dopamine receptor antagonistsDopaminedenervation (bhydroxydopamine)

Nucleus accumbens

Efkct on rewardt

:t

i

-r

t , fadrihn; 1, inhibition; , no change; - 4 , mixed results.

Fig. 2. Sagittal rat brain section illustrat-ing opioid peptide-containing neurons(green), some of which may mediateopiate reward. These opioid peptide sys-tems include the local enkephalin circuits(short segments) and the hypothalamicmidbrain /Lendotphin circuit (long seg-ment). These opioid peptide systems aresupertmposed on the neural reward cir-cuit shown in Fig. 1. FC, liontat cortex:VT& ventral @mental area; VP, ventralpallidurn; LH, lateral hypothalamus: SNr,substantia nigra pars reticulata: DMT,dorsomedial thalamus; PAG, peri-aqueductat gray; OT, olfactory t ract; AC,anterior commissure; LC, locus coer-uleus; AMG, amygdata: Hippo, hippo-campus; Cer, cerebellum; C-P, caudate-putamen; IF, inferior colliculus; SC,superior colliculus; ARC, arcuatenucleus. Left: effect of different para-digms on opiate reward in rat.

the pattern of self-administrationsuch that the interval betweeninjections decreases and the num-ber of injections increasesl. Simi-lar increases in the number ofinjections have been observedafter systemic and central admin-istration of competitive opioidreceptor antagonists4-. Thissuggests that the animals attemptto compensate for opioid antagon-ism by increasing the amount ofdrug injected, and that there is acompetitive interaction betweenantagonist and agonist at thereceptor.The yopioid receptor subtypeappears to be important for thereinforcing actions of opiates. l.4-Receptor agonists produce dose-dependent decreases in heroinse!!f administration and irrevers-

ible p-selective antagonists dose-dependently increase heroin self-administration (Negus, S. S. et al.,unpublished). However, &opioidreceptors appear to have an im-portant role in the opioid motorstimulation that is dopamine (Direceptor) dependent4To determine the location ofcentral opioid receptors importantfor the reinforcing properties ofheroin, a series of studies wasinitiated using intracerebral in-jection of quatemary derivativesof opioid antagonists46,47. Thesequatemary derivatives arecharged, hydrophilic compoundsthat do not readily spread fromthe injection site@.I.c.v. administration of methyl-naloxonium dose-dependently in-creased heroin self-administration

in nondependent rats44. Smalldoses and small volumes ofquatemary nalorphine, a mixedagonist/antagonist, increasedheroin self-administration wheninjected into the VTA but not thenucleus accumbens46.

BY contrast, using largerinjection volumes than in thestudy with quatemary nalor-phine46, a subsequent study withmethylnaloxonium showed theregion of the nucleus accumbensto be particularly sensitive tothe effects of methylnaloxoniumon heroin self-administration4.Methylnaloxonium injected intothe nucleus accumbens dose-dependently increased heroin self-administration at doses signifi-cantly lower than those requiredby the intracerebroventricular

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TiPS -M ay 1992 [Vol . 231

ParadigmIntracranialelectrical self-stimulationLateral hypothalamusIntracranial aelf-admlnlstratlonVentral tegmental areaOral selfadmlnlstratlonGABA* eceptor antagonists

GABA, receptor agonistsOpioid receptor antagonistsDopamine receptor antagonists5-HT receptor agonistsNoradrenaliie synthesis inhiaitors

Effecton rewardtt1T1:

?, facilitation; 4, inhibition.

fig. 3. sagitwratbrain-Bapproximate is t r ibut ion of GA& re-ceptor complexes (pale blue), some ofwhich may mediate sedaM_(ethanol) reward, detemined by therelative di .shlnHion fboih /%Jf lumazeni7binding and express i in of he o-. S- ndy-subuni ts of the GABA , receptor. Thisdis t r ibut ion s sup&~ an he euralreward w+cui t rom ig. 1. Abbrev iat ionsas Fig. 1. GABA* receptor distributiondata from Olsen, R. W. et al. (1990)J. Chem. Neuroanat , 59-76; Sequier,J. M. et al . (1966) Proc. NaU Acad. Sci.USA 85,761~7619; Shivers, B. D. et al.(1969) Neuron 3.327-337. Left: effectfvarious paradigms on sedativ~~nolicreward n rat

route. However, injections ofmethylnaloxonium into the VTAincreased heroin self-adminis-tration only at doses similar tothose required by the intracer-ebroventricular route.Rats will also self-administeropioid peptides directly into theregion of the nucleus accumbens49.In addition, opioid peptides in-jected into either nucleus accum-bens or the VTA produce a dose-related increase in locomotoractiviv. These results suggestthat neural elements in the regionof the nucleus accumbens areresponsible for the reinforcingproperties of both opiates andcocaine.Opiates, like other drugs ofabuse, can increase dopaminerelease in the nucleus accumbensas measured by in viva micro-dialysis in awake, freely movinganimals50*51. However, there is

evidence t o suggest that the re-inforcing effect of opiates in thenucleus accumbens can be inde-pendent of dopamine release. Ratstrained to self-administer cocaineand heroin on alternate daysand receiving 6-hydroxydopaminelesions of the nucleus accumbensshowed a time-dependent de-crease or extinction of cocaineself-administration, whereasheroin self-administration re-turned to near-normal levelss2. Asimilar dopamine-independenteffect fo r both heroin self-admin-istration and heroin-inducedplace preference% has been ob-tained using chronic dopaminereceptor blockade. Nevertheless,opioids are self-administereddirectly into the region containingthe cell bodies of origin of themesocorticolimbic dopamine sys-tem, the VTA. Furthermore,microinjections of opioids into the

WA lower the reward thresholdsfor brain stimulation and producerobust place preferences (seeDi Chiara and North, this issue).Others have shown that theplace preferences produced byopioids appear to have a majordopaminergic componenP~55.Thus, the reinforcing actionsof opiates may involve both adopamine-dependent (WA) and adopamine-independent (nucleusaccumbens) mechanism (Fig. 2).GABAGABA is the most widelydistributed inhibitory transmitterin the CNS. Its receptor is amacromolecular complex throughwhich not only benzodiazepinesbut also barbiturates and alcoholmay act (see Samson and Harris,this issue). At the molecular levelGABA increases Cl- ion flux insynaptic neurosomal prepar-

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182 TiPS -May 1992 [Vo l . 13 1ations. This increase in ion flux ispotentiated by benz~~epines,barbiturates and ethanol%. At theelectrophysiological level GABAproduces postsynaptic inhibition.Benzodiazepines, barbituratesand ethanol have been shown topotentiate this inhibition, but thephenomenon has been relativelydifficult to demonstrate forethanol except in certain brainarc?aP*Ethanol, barbiturates and ben-zodiazepines all have classicsedative!hypnotic actions asmeasured in pnarmacologicaistudies, which include euphoria,disinhibition, anxiety reduction,sedation and hypnosis. Theseeffects correlate well with theability of sedative/hypnotics tomodulate GABA-induced Cl-fluxeP. All of these drugsproduce a release of punishedresponding in contlict situations,which correlates well with theirability to act as anxiolytics in thecliniP_ This anxiolytic or tension-reducing property of sedative/hypnotics may be a major com-ponent of their reinforcingactions. Therefore, the neuro-biological basis of their anxiolyticproperties may provide clues totheir reinforcing properties andtheir abuse potential.GABA receptor mechanismshave been hypothesized to beinvolved in the anxiolytic actionsof sedative/hypnotics as a result ofstudies showing that GABA*receptor antagonists block theiranti-conflict effects and GABAAagonists potentiate these effects(for review see Ref. 61). Further,benzodiazepine inverse agonistsand GABAn receptor antagonistshave stress-inducing or anxio-genie properties in many animalmodels and in humans62-61. Theseresults suggest that the status ofthe GABA, receptor complex maydetermine endogenous stresslevels. It follows then that GABAfunction in some limbic and extra-pyramidal regions such as theamygdala, ventral forebrain, ol-factory tubercle and globus pal-lids could easily influence andcontribute to drug reward (seeFig. 3).Role of GABA, receptor complex

Studies of the functional sig-nificance of GABA mechanismsin drug reward have focused onet:ra.rol. While direct i.v. self-

administration of drugs has beenan effective tool for the study ofthe neuropharmacology of thereinforcing actions of drugs suchas cocaine and opiates (see above),i.v. self-administration of ethanol(and most sedative/h~notics) isnot readily obtained in rats. Thealternative model, oral ethanolself-administration in the rat, hasbeen fraught with problems ofconfounding taste and consum-matory behavior and the lack ofreliable blood alcohol determi-nations.Xevertheless, several recentstudies using taste adulterationmethods (sucrose or saccharinesubstitution) have provided re-liable procedures for initiationand maintenance of alcohol in-take. Reliable, sustained operantresponding for 10% ethanol canbe obtained in free-feeding andfree-drinking rats (nondeprived),even after complete removal ofsweetener, provided that thesweetener is withdrawn slowlyz*.GABA has long been hypoth-esized to have a role in the in-toxicating effects of ethanol,since GABAA receptor antag-onists reverse many of the behav-ioral effects of ethanol. GABAAantagonists decrease the abilityof ethanol to produce ataxia,anesthesia and a release of pun-ished responding (anti-conflicteffects)65,66.At a biochemical level,ethanol in the range Xl-50 mMpotentiates stimulation by GABAof Cl- uptake in synaptosomesfrom the cerebral cortex67 and cer-ebellum66.Further support for a role ofbrain GABA is provided by theobservation that the partial inversebenzodiazepine agonist Ro154.513,which has been shown to reversesome of the behavioral effects ofethano156, produces, in non-deprived rats, a dose-dependentreduction of oral ethanol (10%) inan operant self-administration pro-cedure69 and in an operant free-choice situatior?@. GABA-mimeticdrugs also potentiate the effectsof ethanol in many behavioralsituations71.Both barbi~rates and benzo-diazepines, particularly the short-acting compounds such as metho-hexitaP and midazolam, areintravenously self-administeredby rats. While one would expectsome interaction of these drugswith the GABAA receptor complex

to contribute to the self-adminis-tration of these drugs, there seemto have been no systematic stud-ies to date.Another potential connectionbetween GABA function and drugreward involves the functionaloutput of the nucleus accumbens.The substantia innominata-ventral pallidum has been estab-lished as an impo~~t connectionin the expression of behavioralstimulation produced by ac-tivation of the nucleus accumbens(for reviews see Refs 6 and 74).Furthermore, there are establishedefferent connections from thenucleus accumbens to the sub-stantia innominata-ventral palli-dum that are thought to useGABA (see Fig. 3).

To test the hypothesis thatthe processing of the reinforcingproperties of cocaine and heroinmay also involve the substantiainnominata-ventral pallidum, ratstrained to self-administer cocaineintravenously received bilateralibotenic acid lesions of the regionof the substantia innominata-ventral pallidum75. The lesionssignificantly decreased baselinecocaine and heroin self-adrninis-tration, and when the rats weresubjected to a progressive ratioprocedure they showed a signifi-cant decrease in the highest ratioobtained for both drugr~~~.These results suggest that thesubstantia innominata-ventral pal-lidum may be an important sitefor processing the reinforcingeffects of cocaine and heroin. Thusa GABA-mediated pathway maybe a common output for dragreward.Neurobioiogical circuit fordrug reward

Based on studies of psycho-motor stimulants, opiates andethanol, a reward circuit appearsto involve several common el-ements. The circuitry connectingthe ventral midbrain to the ventralforebrain forms a starting pointfor such a drug reward circuit.Classically known as the medialforebrain bundle, this pathway iscomposed of largely myelinatedfibers connecting the olfactorytubercle, diagonal band of Broca,septum and nucleus accumbenswith the hypothalamus and theVTA. It forms a major afferent andefferent conduction system of thehypothalamus76. In addition,

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TiPS -May 1992 [Vol. 131 183there are the well-documentedascending monoamine pathwaysin the medial forebrain bundlesuch as the mesocorticolimbicdopamine system (see above).The medial forebrain bundlehas been extensively studied as asubstrate for intracranial self-stimulation behavior (for reviewsee Refs 77 and 78). There isevidence that this pathway sup-ports the most robust self-stimu-lation with the least amount ofcurrent ccnpared with all otherbrain reward sites. In addition,lesions of the medial forebrainbundle severely disrupt, but fail toeliminate, intracranial self-stimu-lation. While dopamine is thoughtto be an important component ofthe circuit supporting intracranialelectrical self-stimulation, manyother neuronal systems play arole. Numerous physiologicalstudies have established that ac-tivity within the medial forebrainbundle that supports intracranialself-stimulation involves a de-scending myelinated componentthat is not dopaminergic (forreview see Ref. 79).These same brain structuresconnected by the medial forebrainbundle may be critical for drugreward (see Figs 1, 2 and 3), andthe study of drug reward mayprovide some insight into theneurochemical components of thissystem. Dopamine appears to becritical in the rewarding proper-ties of indirect sympathomimeticssuch as cocaine and amphet-amine. In addition, both the VTAand the nucleus accumbensappear to be important for opiatereward. These same regions andother limbic connections to them,such as the amygdala, may beinvolved in sedative/hypnoticreward.However, a critical role for dopa-mine in both opiate and seda-tive/hypnotic reward is not ascompelling as for the indirectsympathomimetics. There is evi-dence for dopamine-independentopiate and ethanol reward (seeabove). Thus, while dopaminemay contribute to the reinforcingproperties of these drugs, it maynot be essential. The alternateview favored by Wise and col-leaguess suggests that dopamineforms a critical link for all reward,including opiates and sedative/hypnotics. While open to multipleneurotransmitter inputs and out-

puts, this view still holds acentrist position for dopamine inall rewards. An emphasis onmultiple independent neuro-chemical elements, as opposed toa critical role for dopamine, effec-tively places the focus on thenucleus accumbens and its cir-cuitry as an important, perhapscritical, substrate for drug reward.The nucleus accumbens is ana-tomically situated such as toreceive important limbic infor-mation that may then be con-verted to motivational action viaits connections with the extra-pyramidal motor system. Theselimbic structures, such as theamygdala, frontal cortex andhippocampus, may also be im-portant in drug reward via modu-lation of nucleus accumbens ac-tivity. New data suggest that thenucleus accumbens is not a simplehomogeneous structure, and theshell portion (medial and ventral)may be more part of an extendedamygdala system while the coreresembles more the corpus stri-atums2b3. If these anatomicaldistinctions reflect functional dif-ferences, this would give newimpetus to the old hypothesesregarding a role for the amygdalain reward-related functionH.

0 0 qThis review has focused on theneurobiology of the acute reward-ing effects of drugs. Informationabout such actions contributes tounderstanding of the neuro-pharmacology of endogenous sys-tems involved in responses tonaturally hedonic stimuli. In ad-dition, these studies can provide abasis for investigating the neuro-chemistry of drug dependence.Most models of drug depen-dence recognize that, as theorganism reacts to the effects of adrug, adaptive processes are in-itiated to counter these effects.These processes persist after thedrug has been cleared from thebody and result in the withdrawalsyndrome characteristic of drugdependence. An adaptation op-posite to the acute effects of thedrug itself can also have motiv-ational consequencess5.Opponent process theory pro-

poses that reinforcers activatepositive affective and hedonicprocesses, which for drugs arehypothesized to be simple, stable

and occur soon after adminis-tration. As an adaptation to thepresence of the drug, these posi-tive affective processes are fol-lowed by negative affective andhedonic processes, which are slowto build up strength and slow todecays5. The circuitry and neuro-chemical systems outlined instudies of the acute rewardingeffects of drugs could also beimportant for the motivationaleffects of drug withdrawal. Ident-ification of the cellular andmolecular components of theseadaptations may help in under-standing not only drug addictionbut also the function and dysfunc-tion of the reward system in nor-mal and abnormal behaviop.AcknowledgementsThis work was supported inpart by NIDA grants DA04043and DA04398 and the NationalInstitute of Alcohol Abuse andAlcoholism grants AA08459 andAAO6420. The author is grateful tothe Molecular and ExperimentalMedicine Word Processing Centerfor manuscript preparation, to col-leagues and collaborators (pastand present) for their contributionto the hypotheses expressed here-in, and in particular to FriedbertWeiss, Athina Markou, GerySchulteis, Barak Caine and RocioCarrera for help in correcting themanuscript.References1 Koob, G. F., Vaccarino, F. J., Amalric,M. and Bloom, F. E. (1987) in BruinRemnrdSystejnsand Abese (Engel, J. andOreland, L., eds), pp. 35-50, RavenPress __2 Dahlstriim, A. and Fuxe, K. (1964) ActnPhysiol. Stand. 232, 1-553 Lindvall, 0. (1979) in TizeNeurobiologyof Dopamine (Horn, A. S., Korf, J. and

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Note on drugnomenclatureThe longhand chemical struc-ture for SCH23390 has beencited incorrectly in TiPS. Weare advised by Schering-Plough that the correct struc-ture is as follows:7-chloro-2,3,4,5-tetrahydro-3-methyl-1-phenyl-U-I-3-

benzazepine-b-01.We apologize for this error.

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Pharmacol. Biochem. Behav. 27, 665-670Samson, H. H., Tolliver, G. A., Pfeffer,A. O., Sadeghi, K. G. and Mills, F. G.(1987) Pharmacol. Biochem. Behav. 27,517-519Rassnick, S. et al. Ann. NY Acad. Sci. (inpress)Deitrich, R. A., Dunwiddie, T. V.,Harris, R. A. and Erwin, V. G. (1989)Pharmacol. Rev. 41.489-537Pickens, R., Muchow, D. and DeNoble,V. (1981) 1. Pharmacol. Exv. The,. 216,20