Cocaine addiction is characterized by a pattern of compulsive self- administration at the expense of life preserving behaviors. The brain dopamine (DA) system appears to be central to reinforcing and addicting properties of cocaine. Studies in our laboratory have provided the first evidence of abnormalities in the brain DA system in the living human cocaine abuser and have documented decreases in DA D2 receptor availability and in [11C]cocaine binding in the basal ganglia. Moreover, these changes were associated with decreased metabolism in frontal areas. Building on these observations, we propose to investigate the functional significance of these changes from the perspective that the symptoms experienced by the cocaine abuser may be a resultant of dysfunction of brain areas modulated by DA. We will use positron emission tomography (PET) and a dual tracer ([11C]raclopride and 18FDG) -stimulant-challenge experimental design to determine whether decreased frontal metabolism is related to decreased function in presynaptic DA neurons (PDN). We will evaluate PDN in cocaine abusers and in normal controls and we will assess the effects that changes in DA concentration have on frontal metabolism. PDN function will be assessed by monitoring DA release in response to a challenge by methylphenidate (MP), a drug which, similar to cocaine, increases synaptic DA by inhibiting the DA transporter. Changes in synaptic DA concentration will be monitored indirectly by measuring changes in [11C]raclopride binding in response to .MP challenge. Because DA competes with [11C]raclopride for DA D2 receptors, this strategy will enable us to measure relative changes in synaptic DA induced by MP challenge. To assess the relationship between changes in brain DA and regional brain function, each subject will also be studied with 18FDG to measure regional brain glucose metabolism. We hypothesize that: (l) Cocaine abusers have decreased function of PDN which will show as reduced changes in synaptic DA secondary to methylphenidate challenge. (2) Reduced frontal metabolism in the cocaine abusers is in part due to decreased function of PDN. Thus when given methylphenidate (to increase DA activity) cocaine abusers will show an increase in frontal metabolism. Recent pilot studies from our laboratory support these hypotheses and the experimental design and methodology proposed. Evaluation of the functional significance of changes in brain DA in the cocaine abuser may help to identify and link the neurochemical and neuroanatomical substrates which underlie cocaine addiction.
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