In both the human clinical situation, and animal models of drug abuse, there are substantial differences between individuals in the amounts of drugs consumed. In an attempt to understand the neurobiology of drug abuse, and relapse following abstention, biochemical correlates of vulnerability to amphetamine self-administration in the rat will be studied. These studies will expand upon recent findings which demonstrate that certain behavioral measures (novelty-and amphetamine-induced locomotion) predict the amount of amphetamine self-administered by animals. Because of the role of the mesoaccumbens dopamine system in supporting both self-administration and amphetamine-induced locomotion, these studies will primarily focus on this system. This proposal is based on the hypothesis that the individual differences between animals which render some more vulnerable to drug self-administration are reflected in measurable biochemical differences. Measurable indices of both pre-and postsynaptic dopaminergic transmission in the nucleus accumbens will be examined. There are four basic aims of this proposal. The first will be to determine to what degree differences in presynaptic dopamine function correlate with differences in novelty-and amphetamine-induced locomotion. Specific experiments will examine amphetamine-induced dopamine release in vivo following local perfusion through a microdialysis probe: 2) amphetamine-induced dopamine release in vitro; 3) whole tissue measures of dopamine and metabolite under basal conditions; 4) dopamine uptake site density. The second specific aim examines mechanisms post-synaptic to dopaminergic actions in the nucleus accumbens for correlation with behavioral predictors: 1) dopamine receptor binding in the accumbens and striatum, 2) dopamine receptor mediated changes in cyclic AMP using accumbens and striatal tissue in vitro, and 3) gamma-aminobutyric acid receptor binding in the ventral pallidum. The third specific aim will determine the correlation between behavioral predictors and the following measures which attempt to determine the """"""""degree of behavioral sensitization"""""""" in individual animals: 1) systemic amphetamine-induced dopamine release in vivo, measured by microdialysis in awake rats: 2) morphine-induced locomotion and dopamine release in vivo; 3) stress (novelty) induced increases in extracellular dopamine in the prefrontal cortex and nucleus accumbens. G-protein levels will be determined for correlation with novelty-induced locomotion, novelty-and amphetamine- induced increases in extracellular dopamine, and the effects of pertussis toxin treatment in the ventral tegmental area will be studied. The fourth specific aim will determine if selected parameters (assessed post-mortem) which were shown to correlate with novelty-induced locomotion also correlate with amount of amphetamine self-administered previously in an operant chamber. These studies may substantially enhance our knowledge of the possible biochemical bases of drug abuse and addiction, and therefore increase the prospects for rational therapeutic intervention.
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