The major goal of this proposed research is to understand the role played by enkephalin-containing systems in learning and memory processes, as measured by conditioning performance in rats. Studies are designed to investigate how and where these opioid peptides initiate long-term changes in the CNS that underlie modified behavior. Development of animal models for understanding the neurobiological basis of these long term neuronal changes may lead to strategies for interrupting drug dependence. Experiments are proposed to assess the generality of the involvement of [leu]-and [met] enkephalin in modulation of learning processes, by characterizing their effects on both acquisition (pretraining drug injection) and retention (post training drug injection) of both an appetitively motivated auto-shaped lever press task and an aversively motivated auto-shaped lever press task and an aversively motivated one-way active avoidance task. The opioid receptor subtypes mediating enkephalins' effects on learning of these tasks will be studied with the use of receptor selective agonists and antagonists. Subsequent studies will determine whether one or more circumventricular organs are the primary site(s) of the opioid receptors located outside the blood brain barrier that mediate the effects of the enkephalins on conditioning. These studies will involve investigation of the effects on conditioning produced by infusion of either enkephalin or receptor selective antagonists directly into circumventricular organs. The proposed pathway that modifies learning performance will be followed into the CNS in studies investigating the role of the amygdala on the conditioning changes initiated by enkephalin systems. The final set of studies will determine whether [leu]- and [met] enkephalin modulate acquisition and/or retention of appetitively and/or aversively motivated learning directly or through the production of active metabolites. These studies will investigate the effects of pretreatment with enzyme inhibitors on the ability of enkephalin to modulate conditioning, as well as the relationship between plasma concentrations of intact enkephalins or enkephalin metabolites and conditioning performance.
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