introduction Mesolimbic and mesocortical systems are involved with reward, planning and salience attribution. This research demonstrates different activity levels between controls and detoxified alcoholics in PFC control, striatal DA activity and subjective pleasure when challenged with the DAT blocker MP. This research demonstrates a correlation between prefrontal regulation of dopaminergic reward circuits in controls but not alcoholics. Subjective pleasure for drug liking and high in alcoholics are substantially reduced Mesolimbic circuits adapt to long term addiction including alcoholism. This research demonstrates profound reductions in DA receptor availability in detoxified alcoholics.

Addiction theory Natural reinforcement: Reward for natural reinforcers such as food and water are mediated through the mesolimbic system. Many addictive drugs including alcohol use the same reward system 1 DA changes in VS are correlated with insula metabolism. Insula region associated with densest DA innervation 7 and addiction Tolerance: Profound reductions in DA activity in VTA is observed on withdrawal from addictive drugs including chronic alcohol abuse 10 Addiction reduces availability of DA receptors in VS 10. Baseline striatal DA receptor availability associated with PFC metabolism in drug abuse 8a,8b. Genetic risks 8c Craving: Reduced receptors in VS associated with increased craving and greater incentive attribution and activation of medial PFC and CG 11. Pleasure vs. reward Disruption to OFC, involved in salience attribution 11 and/or the CG, involved with inhibitory control 6 considered central to addiction The PFC is associated in attribution salience and the addiction process

Striatum Ventral striatum NAc PFC/OFC reward VTA Less DA IN ADDICTS DA schematic INCENTIVE SALIENCE DA Loss of control in addicts Putamen Caudate glut

method Methylphenidate (MP) challenge Subjective behavioural effects PET: Glucose metabolism in PFC (ROI’s OFC, CG, DLPFC) PET: Dopamine release in Striatum (ROI’s CDT, PUT, VS) 20 controls & 20 detoxified alcoholics Single blind crossover design Methylphenidate (MP) challenge Subjective behavioural effects PET: Glucose metabolism in PFC (ROI’s OFC, CG, DLPFC) PET: Dopamine release in Striatum (ROI’s CDT, PUT, VS) 20 controls & 20 detoxified alcoholics Single blind crossover design

results Regression OFC:DA addicts o controls D2/D3 receptor Subjective liking availability in VS and high

discussion Experimental hypotheses: in alcoholics - decreased DA activity; disrupted regulation of PFC; less subjective pleasure. Results show: In controls OFC activity negatively correlated with MP induced DA changes in NAc is consistent 3,4 with OFC regulation of NAc via VTA glutamatergic efferents 5 In alcoholics vs. controls decreased DA release in VS consistent with other drugs of abuse 10 In alcoholics reduced subjective reward as measured by drug high(-70%) and liking(-50%) is consistent with drug tolerance In alcoholics lower baseline receptor availability is consistent with adaptive changes to drugs of abuse and to genetic risk factors 2,8 In alcoholics lower receptor availability is associated with activity in PFC (CG, DLPFC) consistent with other drugs of abuse

Conclusions Loss of OFC modulation in mesolimbic systems of alcoholics and reduced DA increases in VS consistent with reduced reward systems activation Reduced DA cell activity in reward systems consistent with reduced subjective pleasure in alcoholics Reduced rewards and pleasure could lead to increased alcohol consumption Therapy should address both the profound reduction in DA activity and loss of PFC modulation Exploratory confirmation of correlation between DA changes in VS and insula metabolism

Future directions: complex theory Integrated systems DA/NAc reward, +ve reinforcement system 1 Adaptive changes to DA circuits in addiction 2,10 DA decreases in striatum for addicts(cocaine, alcohol) 10 PFC loss of control of VTA in addiction 3 (PFC hypoactive in cocaine addicts 9 ) (Genetic factors associated with reduced DA receptor activity 8c ) To be integrated Opiods needed for reinforcement, opiate receptors sufficient 14 PFC-grey reduction of 10% in alcoholics 12 Psychosocial stress associated with D2 reduced receptor activity and predilection for addiction 13 Incentive salience 11

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Loss of control by prefrontal cortex Reduced reward in detoxified alcoholics