It is recognized that context as well as expectation affects the responses to drugs of abuse; an effect that is believed to be due in part to associative learning. In addicted subjects associative learning results in craving when exposed to drugs or drug related cues. The mechanisms underlying these processes in humans are not well understood. Here we propose: (1) to investigate the effects of expectation on the ability of a psychostimulant drug to increase extracellular dopamine (DA), to effect brain function and to affect its behavioral effects and (2) to investigate the consequences of psychostimulant addiction on the effects of expectation. Our working hypothesis are: ? ? 1. Expectation will enhance the stimulant-induced increases in DA and this effect will be associated with self-reports on """"""""drug liking."""""""" ? ? 2. Expectation will enhance the stimulant-induced increases in prefrontal regions. ? ? 3. In addicted subjects, in whom the saliency of the drug is much greater than in controls, the effects of expectation will be much stronger in enhancing stimulant-induced DA than in controls and in activating prefrontal regions and these effects will be associated wit """"""""drug craving."""""""" ? ? We will use positron emission tomography (PET) in two sequential studies to be done over a 5 year period. One using [11C]raclopride (DA D2 receptor radioligand whose binding to D2 receptors is sensitive to competition by endogenous DA), to measure extracellular DA and the other using FDG to measure brain glucose metabolism to compare the responses to methylphenidate (psychostimulant drug which like cocaine increases extracellular DA by blocking DA transporters) when subjects expect to receive it versus when they expect to receive placebo. In each study we will compare the responses in 20 controls to those in 20 cocaine abusers. Preliminary work from our laboratory support our working hypotheses. The effects of drug expectation on the ability of psychostimulants to increase extracellular DA and activate neuronal circuits associated with reward and motivation and the relationship to the reinforcing and addictive properties of stimulant drugs in humans are not known. A better understanding of the mechanisms underlying the effects of expectation on drug effects will help develop strategies that may be able to counteract the enhanced saliency that drugs of abuse have on the drug addicted subjects and help prevent craving and relapse.
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