The mesolimbic dopamine system is strongly implicated in processing the incentive properties of psychomotor stimulants and other drugs of abuse. Neurobiological studies that focus on these incentive properties of drugs and their associated stimuli may lead to effective treatment of cocaine abuse. In this proposal, using the high temporal and spatial resolution of single-cell electrophysiology to elucidate neural mechanisms of cocaine self-administration, questions are formulated within the incentive motivational framework. Recordings will be obtained from mesolimbic target neurons in the shell, core and rostral pole of the NAcc. Rats in which lever pressing is maintained on a fixed ratio 1 (FR1) schedule of reinforcement by intravenous infusion of cocaine (0.7 mg/kg) exhibit regular inter-infusion intervals (mean = 6.7 min). Each reinforced lever press is followed by a prolonged period of focused stereotypy that gradually yields to approaches toward the lever and a reinforced lever press, characterized as drug-seeking behaviors. Single-unit recordings from neurons in the NAcc show cyclic patterns of firing synchronized to this behavioral cycle. While certain firing patterns conform to interpretations based on pharmacokinetics, other patterns do not. For example, many neurons show rapid changes in firing rate within <2 sec of the reinforced lever press, in advance of any significant infusion-related increase in cocaine levels in mesolimbic areas (explicitly addressed in Specific Aim 2 by introducing on selected trials a brief delay between the reinforced lever press and the infusion). These rapid changes in firing could reflect the cessation of drug-seeking behavior upon execution of the reinforced lever press or a response to stimuli paired with the infusion. Supporting this interpretation are exciting preliminary results which indicate the feasibility of our design (the basis of Specific Aim 1): a multiple schedule in which FR1, i.e., a response contingent phase, alternates with a noncontingent phase. In the latter, the temporal pattern of cocaine infusions from the FR1 phase is presented noncontingently. Infusions are no longer immediately preceded by approach to and depression of the lever. This non-intrusive manipulation thus selectively and incisively reduces operant behavior, with pharmacokinetics held constant between the two phases. Preliminary results show that operant behavior is both necessary and sufficient for the occurrence of rapid changes in firing rate. Thus, certain phasic NAcc firing patterns do not appear to reflect pharmacokinetics but rather drug-seeking behaviors, consistent with the hypothesis that mesolimbic system neurons process information regarding conditioned incentive stimuli. In light of the explanatory power of incentive-motivational theory as a framework for approaching a neurobehavioral understanding of drug abuse, the present design offers a unique opportunity to test hypotheses directly on mesolimbic neurons which are focal to this theory.
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