The general aim of this study is the investigation of the neurochemical mechanisms underlying cocaine abuse and relapse with neuroimaging. Cocaine produces its reinforcing effects by blockade of the dopamine (DA) transporter. It has been well established in the animal literature that sensitization occurs in the striatum with repeated exposure to psychostimulants. Although behavioral sensitization has been well described in humans, evidence of sensitization has not been demonstrated in the human striatum in neuroimaging studies. Furthermore, it has been reported that relapse may be precipitated by environmental cues or by a priming dose of cocaine. In animal models of cocaine seeking behavior, a low dose of cocaine or a D2 agonist can trigger relapse in rodents previously exposed to cocaine, whereas a D1 agonist will not. This suggests that the priming effect of cocaine is mediated by D2, and not D1, receptor stimulation. In accordance with this model a decrease in D1 receptors may correlate with susceptibility for relapse.
In specific aim #1 we propose to investigate the presence or absence of sensitization in the human brain using the D2/D3 radioligand [11C]raclopride and an amphetamine challenge to elicit dopamine release. The extent of the dopamine release will be compared between normal controls and chronic cocaine abusers.
In specific aim #2 we propose to determine the density of D1 receptors in striatal and extrastriatal fields of cocaine abusers and healthy control subjects. D1 receptors will be visualized using [11C]NNC-112, a D1 and D5 receptor antagonist with a high affinity and specific binding profile. The hypothesis is that a decreased density of D1 receptors will be observed in chronic cocaine abusers.
In specific aim #3 we will determine the D2 receptor density of cocaine abusers and healthy controls with [11C]raclopride. Studies from the Brookhaven National Laboratories have reported a decreased density of D2 receptors in the striatum of abstinent cocaine abusers. We propose to provide an independent replication of this finding in addition to describing potential alterations of D2 receptors in extrastriatal areas. This data as well as the data in specific aim #1, will be obtained from the same scan session with [11C]raclopride.
In specific aim #4, we will examine the D1 and D2 receptor density ratio in the ventral striatum of cocaine abusers and compare this to individual differences in cocaine-induced cocaine self-administration. We hypothesize that a low D1/D2 ratio in the ventral striatum will be associated with a more intense cocaine seeking behavior.
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