The objective of this proposed research is to study cocaine's effects on dopamine-sensitive neurons that mediate the effects of cocaine on behavior. Extracellular single-unit recordings will be obtained from the striatum and nucleus accumbens of freely moving rats. Cocaine will be administered both locally, by microiontophoresis, and systemically, by intraperitoneal injection. An important advantage of these studies is that they will be performed without the contaminating effects of anesthesia or paralysis. Instead, recordings will be obtained during the behaviors produced by cocaine (e.g., locomotion). Since locomotion itself, is correlated with changes in neural activity in these structures, a 30 minute control recording following saline injection will be obtained during locomotion on a treadmill. Dose- response curves will then be constructed of neural activity during treadmill locomotion following cocaine. Videotape recordings synchronized with the computer's acquisition of neural activity will be analyzed to isolate cocaine-induced behaviors (stereotypy) that might be correlated with neural activity and thus obscure more direct actions of the drug. The tremendous advantage of microiontophoresis is that cocaine's actions on recorded neurons can be observed directly, without contributions from feedback from the motor behaviors described above, or from activity in other brain areas that project to the striatum and accumbens. In addition to studying cocaine's effects on tonic firing rate, phasic signals will be produced by several methods, including electrical activation of the neocortical and hippocampal synaptic inputs to these structures, as well as sensory-evoked responses. All these patterns of activity will be examined, 1) in terms of cocaine's effects on dopamine-mediated neural activity, 2) in dopamine-depleted animals following 6- OHDA, and 3) in animals chronically treated with cocaine. These studies should have a major impact on our understanding of brain mechanisms related to cocaine's acute and chronic behavioral effects.
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