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Transition to Cocaine Abuse in Monkey:Role of Dopamine

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The goal of this research is to broaden our understanding of the neural and behavioral mechanisms that mediate the transition from recreational cocaine use to cocaine addiction. More specifically, this application proposes a series of studies using models of cocaine self-administration in monkeys, with the brain imaging procedure positron emission tomography (PET), in an effort to better understand the consequences of long-term cocaine use and cocaine abstinence on dopamine (DA) receptor function. In PET studies with monkeys self-administering cocaine, we have observed 20 percent reductions in D2 binding potentials throughout 1 year of cocaine use. We also found that baseline D2 receptor levels correlated with rates of cocaine self-administration, suggesting that D2 receptor levels were associated with "vulnerability." These studies are the first to use a within-subjects design and PET imaging to examine long-term changes in the brains of monkeys self-administering cocaine and during abstinence. The studies proposed in this application are designed to extend our understanding of DA receptor function and compulsive cocaine seeking in male rhesus monkeys (M. mulatta) self-administering cocaine, in an effort to identify a transition "switch" for addiction. Specifically, we propose to study how the DA system, in particular D1, D2 and DA transporters (DAT): 1) is differentially influenced by pattern of cocaine use, comparing cocaine-maintained responding under a second-order schedule to a binge pattern of self-administration; 2) recovers during abstinence and how lifetime cocaine intake modifies the rate of recovery; and 3) is correlated with cocaine seeking in a model of craving that does not involve extinction of cocaine-maintained responding. We hypothesize that the "switch" is a functional interaction between D1, and D2 receptors with cocaine-induced increases in extracellular DA via DAT. Combining PET imaging with our monkey models of cocaine abuse, we will be able to characterize DA receptor function, as it pertains to cocaine seeking, over long periods of time. A better understanding of the neuroadaptation of the DA neurotransmitter system correlated with behavioral outcomes of cocaine use and abstinence will lead to a better understanding of the mechanisms that mediate the transition from drug use to addiction.

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