Stimulant dependence, compulsivity Stimulant dependence, compulsivity
and dopamineand dopamine
TW Robbins
CLARE HALLCLARE HALL College for Advanced StudyCollege for Advanced Study
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Stimulants are the second most commonly used illicit drugs
worldwide
Stimulants are the second most commonly used illicit drugs
worldwideEffective treatments are needed to meet the growing demand by
increasing numbers of stimulant users.
World Drug Report 2007
Dopamine and Stimulant Dependence
Dopamine and Stimulant Dependence
Stimulant drugs directly increase dopamine levels in the ventral striatum (DiChiara et al 1988)
Chronic stimulant abuse has been associated with reduced availability of D2 receptors in the striatum (Volkow et al 1993,2001)
Reduction in striatal D2 receptors has been shown to be associated with decreased metabolism in the prefrontal cortex.(Volkow et al 1997, 2001)
(Volkow et al 2004)
Everitt & Robbins 2005
Neurobehavioural basis of drug addiction
Hallmarks of Drug Addiction • Compulsive drug-taking
Drug craving
inflexible patterns of drug use that do not cease in the face of negative consequences
persistent drug-seeking underpinned by conditioned stimuli (Everitt & Robbins 2005, Weiss et al 2001)
neuroadaptive changes within fronto-striatal circuits are thought to underlie the development of compulsive drug taking
Obsessive-Compulsive Drug Use Scale (Franken et al 2002)
pathological desire to consume drugs, elicited by the presence of drug-related cues
repeated drug exposure increases the motivation for drugs due to neuroadaptive changes in the mesolimbic dopamine system (Robinson & Berridge 1993, 2003)
General Craving Questionnaire (Tiffany et al 1993)
Attentional Bias
“Stimuli of ‘current concern’ capture the individual’s attention, despite the person’s efforts to ignore them” (Williams et al 1996)
Attentional bias – a new target for treatment?
The degree to which drug users show an attentional bias for drug-related cues predicts their risk of relapse during drug abstinence. (e.g. Carpenter et al. 2006, Cox et al 2002, Marissen et al 2006)
Attentional bias results from an emotional salience of drug-related cues. Drug-induced increase in dopamine in the ventral striatum
facilitates conditioned reinforcement, i.e. previously neutral stimuli that are associated with the drug become salient.
Attentional Bias and Stroop
Addiction Stroop Test
blue green yellowred
bear monkeydog tiger
chang sniff coke charlie
speedbillywhizzuppers
song pianotrumpetflute
target words
neutral words matched fortarget words
Key measure: Mean RT for target words
Mean RT for matches neutral words
= Interference Score
Colour-Word Stroop Test
Measures the degree of involuntary attention to disorder-related words compared with neutral words.
Attentional bias (interference) results from the emotional salience of stimuli which are related to the person’s current concerns.
Attentional bias (interference) results from the emotional salience of stimuli which are related to the person’s current concerns.
t1
t2
n1
subserved by frontal lobe systems
Healthy volunteers Individuals with stimulant dependence
(all non treatment-seeking)
Pharmacological fMRI StudyPharmacological fMRI Study
• Randomised, double-blind study with a placebo-controlled, balanced design using functional MRI
• Study medication: Pramipexole (0.5 mg) D2/D3 agonist Amisulpride (400 mg) D2/D3 antagonist Placebo
• Measures: Attentional bias – Addiction Stroop test
Cognitive control – Colour-Word Stroop test
Craving – General Craving Questionnaire, Visual Analogue Scale
Compulsivity – Obsessive-Compulsive Drug Use Scale
• Study sample:
Study SampleStudy Sample
Control Group Stimulant Group
Number 18 18 (10 cocaine, 8 amphetamine)
Age (years) 32.7 (± 6.9 SD) 34.3 (±7.2 SD)
Gender balance (male : female) 15:03 15:03
Verbal IQ (NART) 108.4 (±6.0 SD) 109.0 (±8.1 SD)
Years of education 12.4 (±1.8 SD) 11.2 (±1.0 SD)
Depressive mood* (BDI-II total score) 1.06 (±4.1SD) 9.28 (±6.8 SD)
Duration of drug use (years) -- 11.7 (±7.4 SD)
Age of drug use onset (years) -- 20.5 (±5.4 SD)
All drug users met the DSM-IV criteria for stimulant dependence but not for any other substance except for nicotine (n=16) and for cannabis (n=2).
Drug users were all non-abstaining from stimulants and non treatment-seeking.
Urine samples were analysed for undeclared drugs prior to testing.
* Depression: BDI-II >15
fMRI Stroop Tasks DesignfMRI Stroop Tasks Design
Current Cravings
Current Cravings
Inside the scanner
Neutral
Colour
Neutral
Cocaine
PracticeOutside the scanner
PracticeOutside the scanner
Colour Neutral
Neutral Colour
Block Design
response panel
Neutral
Colour
Neutral
Speed
DRUGDRUG COLOURCOLOUR FIXATIONFIXATION
Stimulant drug users show significant attentional bias for
drug-related words
AmisulpridePlaceboPramipexole
Att
entio
nal B
ias
Main effect of group: F(1,32)= 11.16, p<0.01
Main effect of drug: F(2,64)= 0.47, n.s.
Group x drug: F(2,64)= 0.23, n.s.
chang sniff coke charlie
song pianotrumpetflute
on the whole brain from all participants on all drug conditions
- Addiction Stroop -
on the whole brain from all participants on all drug conditions
- Addiction Stroop - L
posterior
Ranterior
Contrast: drug words versus matched neutral words
General pattern of brain activation
General pattern of brain activation
AmisulpridePlaceboPramipexole
On placebo, drug users and controls do not use the same
neural network during the Addiction Stroop
r=-.83, p<0.01
Ventrolateral prefrontal cortex
Posterior cingulate gyrus
r= .63, p<0.01
Right middle temporal gyrusBehavioural Performance
Controls
Drug usersControls
r=-.56, p<0.05
D2/D3 agonist improves performance and brain activation in a subgroup of
drug users
AmisulpridePlaceboPramipexole
Functional MRI Dataleft inferior frontal gyrus
Interference Score:Interference Score: drug words versus matched
neutral words
Interference Score:Interference Score: drug words versus matched
neutral words
sniffcoke charlie
flutepiano trumpetsong
chang
Behavioural DataLR
anterior
posterior
Atte
ntio
nal B
ias
Main effect of group: F(1,16)= 9.97, p<0.01
Main effect of drug: F(2,32)= 0.60, n.s.
Group x drug: F(2,32)= 5.40, p<0.01
Imaging Contrast:Imaging Contrast: drug words versus matched
neutral words
Imaging Contrast:Imaging Contrast: drug words versus matched
neutral words
Main effect of group: left superior frontal gyrus
Main effect of drug: no clusters
Group x drug: left inferior frontal gyrus
Acute stimulant cravings differ with regard to baseline level of compulsive
drug use
little drug-related compulsivity
Cra
vin
g i
nte
ns
ity
Stroop test was conducted 2 hours after drug administration. Stroop test was conducted 2 hours after drug administration.
• Colour-naming of drug-related words does not seem to increase drug cravings.
• Effects were irrespective of last stimulant use prior to testing.
high drug-related compulsivityAmisulpridePlaceboPramipexole
Main effect of group: F(1,14)= 7.37, p<0.05; Group x drug: F(2,28)= 4.22, p<0.05Main effect of drug: F(2,28)= 3.28, p=0.053;
SummaryDrug users show a profound attentional bias for
stimulant-related words.
Colour-naming of stimulant-related words is subserved by different neural networks in stimulant dependent individuals and non-drug using controls.
Attentional bias and craving are amenable to dopaminergic modulation but only when baseline levels of obsessive-compulsive drug use are taken into account.
Low obsessive-compulsives and high obsessive-compulsives drug users respond differentially to the D2/D3 agonist; the reasons for this are not completely clear.
A PET study, measuring D2/D3 receptor levels, would be needed to elucidate the neurobiological underpinnings of this finding.
Acknowledgements Dr Karen Ersche Dr Kevin Craig Dr Sanja Abbott Dr Ulrich Müller Dr Luke Clark Dr Cinly Ooi Dr Graham Murray Dr John Suckling Prof Naomi Fineberg Prof Barbara Sahakian
Prof Ed Bullmore Shaila Shabbir Angela Leah Dr Frank Gray Dr Marc Lucas Dr Emilio Merlo-Pich
Many thanks to staff at the GSK Many thanks to staff at the GSK Clinical Unit Cambridge, the Clinical Unit Cambridge, the Wolfson Brain Imaging Centre Wolfson Brain Imaging Centre and to all the volunteers!and to all the volunteers!
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