The concept that dopamine (DA) increases in limbic brain regions underlie the reinforcing effects of drugs of abuse has become central in drug abuse research. Cocaine and """"""""cocaine like psychostimulants"""""""" such as methylphenidate (MP) increase extracellular DA by blocking DA transporters (DAT). However, the recent documentation that cocaine and MP are reinforcing in mice that lack DAT, has led to a questioning of the role of DAT and DA on the reinforcing effects of psychostimulants. Since the main strategies on drug development for cocaine addiction target drugs that block DAT as well as drugs that antagonize cocaine-induced DA increases it is important to determine DA's role in psychostimulant reinforcement in humans. This grant proposes to do so by investigating the relationship between DAT blockade, DA changes and the reinforcing effects of MP, a psychostimulant with similar affinity for DAT as that of cocaine, directly in humans. Working hypotheses are that: 1) increases in DA are involved in the reinforcing effects of cocaine and """"""""cocaine like psychostimulants 2) increases in DA are due not only to levels of DAT blockade but also to the baseline release of DA from the terminal. Because DA release is likely to vary among individuals and as a function of adaptation to pharmacological intervention(s), changes in DA should be a better predictor of the reinforcing effects of psychostimulants than DAT blockade and the relationship between DAT blockade and DA changes will differ as a function of timing and route of administration. PET will be used with [11C]cocaine to measure DAT blockade and with [11C]raclopride (a radioligand which competes with DA for binding to DA D2 receptors), to measure changes in synaptic DA induced by MP in normal subjects. In parallel, self reports of drug effects will be recorded to assess their relationship to the biochemical measures. Four experiments that compare the effects of intravenous and oral MP at different times of administration were designed to test the working hypotheses over a 5 year period. Preliminary work from our laboratory support our working hypotheses. In addition to being valuable in understanding the role of DA in the reinforcing effects of psychostimulants, these studies are of relevance in treatment development for cocaine addiction and for understanding the variables that affect the reinforcing effects of MP since there is concern about the potential abuse of MP (drug of choice in the treatment of children with ADHD).
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