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Please use this identifier to cite or link to this item: http://hdl.handle.net/1807/17452

Title: Probing Mesocorticolimbic Dopamine Function in Alcohol Dependence Using Dextroamphetamine: Behavioural and FMRI Studies
Authors: Balducci, Xavier Laurent
Advisor: Naranjo, Claudio
Sproule, Beth
Department: Pharmacology
Keywords: Alcohol Dependence
Issue Date: 15-Jul-2009
Abstract: Background: A dysfunctional mesocorticolimbic dopamine system has been reported in alcohol dependence and major depressive disorder. Probing mesocorticolimbic dopamine function in severe depression using dextroamphetamine revealed an altered behavioural response and a disrupted mesocorticolimbic circuitry in behavioural and functional magnetic resonance imaging (fMRI) studies. The purpose of this study was to use a similar approach in alcohol dependence. Behavioural Study: to assess dextroamphetamine subjective effects in alcohol-dependent and depressed alcohol-dependent participants. FMRI Study: to assess how the mesocorticolimbic circuitry would respond to a dextroamphetamine challenge in alcohol-dependent participants exposed to alcohol cues. Methods: In both studies, a single oral 30 mg dose of dextroamphetamine was the pharmacological intervention. Behavioural Study: randomized, double-blind, placebo-controlled, between-subject study. Eighteen alcohol-dependent and 22 depressed alcohol-dependent participants were compared using validated self-report drug effect tools (e.g. Addiction Research Center Inventory). FMRI Study: single-blind, between-subject study. FMRI blood oxygen level–dependent (BOLD) activation was measured in 14 alcohol-dependent and 9 healthy control participants during an alcohol-cue exposure task pre- and post-drug. Results: Behavioural Study: DRUG (F1,40=18.6; p<0.001) and GROUP (F1,40=16.6; p<0.001) main effects but no GROUPxDRUG interaction effects (F1,40=0.02; p=0.88) were detected, even when only severely depressed alcohol-dependent individuals were included (F1,30=0.04; p=0.84). FMRI Study: Alcohol-dependent participants exhibited greater ventral striatal activation compared to controls pre-drug and post-drug effect (F1,40=20.1; z=3.8; p<0.001; k>10; (x=10;y=-2;z=-14)). A GROUPxDRUG interaction effect was detected in the medial orbitofrontal cortex (mOFC) (F1,40=21.5; z=4.0; p<0.001; k>10; (x=-12;y=28;z=-20). The alcohol-dependent group exhibited a negligible mOFC response across both pre- and post-drug scanning sessions. In contrast, controls exhibited attenuation of mOFC response post-drug. Conclusion: The lack of significant GROUPxDRUG interaction effects in the Behavioural Study may suggest different neurobiological mechanisms underlying alcohol dependence and depression mesocorticolimbic dysfunction. Alcohol dependence appeared to mitigate the impact of depression severity on participants’ behavioural responses to dextroamphetamine. The FMRI Study data suggest there may be ventral striatal and mOFC disruption in alcohol-dependent participants. We suggest the mOFC may be involved in the reported loss of prefrontal modulation of dopamine cell activity in alcohol dependence. This supports a key role for the mOFC in mesocorticolimbic dysfunction in alcohol dependence.
URI: http://hdl.handle.net/1807/17452
Appears in Collections:Doctoral
Department of Pharmacology and Toxicology - Doctoral theses

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