Amphetamine, cocaine, and like stimulants induce a dose- and chronicity-related transition from generalized arousal to stereotypies, and the mechanisms underlying this transition may have important implications for drug abuse. The recent application of microdialysis methodology has provided the opportunity to more directly evaluate neuronal-system/behavior relationships, and data obtained using this methodology confirm the profound effects of these stimulants on dopamine systems. However, our concomitant behavior/biochemistry characterizations using custom-designed microdialysis methodology have revealed a clear dissociation between the expression of specific stimulant-induced behaviors and the quantitative aspects of the caudate and accumbens dopaminergic response. Thus we have hypothesized that the behavioral transition from locomotion to stereotypy cannot be explained by the quantitative changes in dopamine alone, but rather involves the interaction of dopamine with other transmitters, including serotonin and norepinephrine in several forebrain structures. In addition, on the basis of our more recent results, we have hypothesized that (1) differences in the levels of impulse flow and the availability of catechol-O-methyl transferase between caudate and accumbens contribute to a preferential response of accumbens to dopamine uptake blockers but not dopamine releasers; (2) interaction of amphetamine with the uptake carrier and not the size of the cytoplasmic dopamine pool limits the release of dopamine; (3) cocaine-induced enhancement of extracellular dopamine is not strictly dependent on uptake blockade. To test these hypotheses, we will first extend our characterization of the effects of amphetamine and other stimulants with differing mechanisms of action on regional dopamine, serotonin and norepinephrine. A variety of manipulations will be used to examine the contribution of dopamine neuronal impulse flow, catechol-O-methyl transferase activity, and the dynamics of the cytoplasmic and vesicular pools of dopamine to stimulant-induced dopamine release. Measurement of acetylcholine in caudate dialysates will provide a measure of post-synaptic receptor function to assess the relationship of serotonin and dopamine receptor activation to components of the behavioral response. The direct evaluation of synaptic neurotransmitter dynamics concomitant with behavioral analysis will further elucidate stimulant-neurotransmitter interactions.
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