Amphetamine, cocaine, and similar stimulants induce a dose-related transition from generalized arousal to stereotypies, and the mechanisms underlying this transition may have important implications for drug abuse. Our previous and ongoing research using in vivo microdialysis in awake animals continues to demonstrate that this transition is dissociated from the regional dopamine response with regard to magnitude and temporal characteristics, and we have hypothesized that the transition involves the interaction of dopamine with other transmitters, including serotonin and norepinephrine. In terms of the magnitude of the dopamine response, the dissociation is particularly evident when dopamine releasers (e.g., amphetamine) and dopamine uptake blockers (e.g., cocaine) are compared, and has also lead us to hypothesize that the magnitude of the transmitter response to releaser stimulants may not always reflect behaviorally relevant synaptic dopamine. To test this hypothesis, we will examine alternative measures of functional dopamine transmission. Furthermore, different drug-specific regulatory processes contribute to the behavioral profiles of these drugs. Thus, AMPH increases extracellular dopamine (and, we hypothesize,. norepinephrine and serotonin) primarily through a release process which is independent of neuronal impulse flow. By contrast, the neurotransmitter response to uptake blockers like cocaine, is dictated by levels of autoreceptor function and impulse flow which we hypothesize play a significant role in the individual variations in behavioral responsiveness and in the regional differences in neurochemical response to cocaine-like stimulants. To test our hypotheses, we will extend our characterization of the effects of uptake blockers and releasers on behavior and regional dopamine, norepinephrine and serotonin. In addition, a variety of pharmacological manipulations will be used to examine the contribution of neuronal impulse flow, autoreceptor function, and the dynamics of cytoplasmic and vesicular transmitter pools to stimulant-induced behavior and changes in extracellular transmitter. This more extended evaluation of synaptic transmitter dynamics concomitant with behavioral analysis should further elucidate the role of various neurotransmitter systems and mechanisms in the transition from stimulant- induced locomotion to behavioral perseveration.
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