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

Stimulant dependence, compulsivity Stimulant dependence, compulsivity

and dopamineand dopamine

TW Robbins

CLARE HALLCLARE HALL College for Advanced StudyCollege for Advanced Study

BCNIBCNI

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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