1. Stimulant dependence, compulsivity and dopamine TW Robbins CLARE HALL College for Advanced Study BCNI

2. Stimulants are the second most commonly used illicit drugs worldwide Effective treatments are needed to meet the growing demand by increasing numbers of stimulant users.  World Drug Report 2007

3. 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)

4. Everitt & Robbins 2005 Neurobehavioural basis of drug addiction

5. 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 )

6. 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.

7. Attentional Bias and Stroop Addiction Stroop Test blue green yellow red bear monkey dog tiger chang sniff coke charlie speed billy whizz uppers song piano trumpet flute target words neutral words matched for target 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. t1 t2 n1 subserved by frontal lobe systems

8.  Healthy volunteers  Individuals with stimulant dependence (all non treatment-seeking) Pharmacological 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:

9. Study Sample Control GroupStimulant Group Number18 18 (10 cocaine, 8 amphetamine) Age (years)32.7 (± 6.9 SD)34.3 (±7.2 SD) Gender balance (male : female)15:03 Verbal IQ (NART)108.4 (±6.0 SD)109.0 (±8.1 SD) Years of education12.4 (±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

10. fMRI Stroop Tasks Design Current Cravings Inside the scanner Neutral Colour Neutral Cocaine Practice Outside the scanner Practice Outside the scanner ColourNeutral Colour Block Design response panel Neutral Colour Neutral Speed DRUG COLOUR FIXATION

11. Stimulant drug users show significant attentional bias for drug-related words Amisulpride Placebo Pramipexole Attentional Bias 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 piano trumpet flute

12. on the whole brain from all participants on all drug conditions - Addiction Stroop - L posterior R anterior Contrast: drug words versus matched neutral words General pattern of brain activation

13. Amisulpride Placebo Pramipexole 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 users Controls r=-.56, p<0.05

14. D2/D3 agonist improves performance and brain activation in a subgroup of drug users Amisulpride Placebo Pramipexole Functional MRI Data left inferior frontal gyrus Interference Score: Interference Score: drug words versus matched neutral words sniff coke charlie flute piano trumpet song chang Behavioural Data L R anterior posterior Attentional Bias 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 Main effect of group: left superior frontal gyrus Main effect of drug: no clusters Group x drug: left inferior frontal gyrus

15. Acute stimulant cravings differ with regard to baseline level of compulsive drug use little drug-related compulsivity Craving intensity 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 compulsivity Amisulpride Placebo Pramipexole Main effect of group: F (1,14) = 7.37, p<0.05; Group x drug: F (2,28) = 4.22, p<0.05 Main effect of drug: F (2,28) = 3.28, p=0.053;

16. Summary Drug 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.

17. 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 Clinical Unit Cambridge, the Wolfson Brain Imaging Centre and to all the volunteers! BCNI