The ability of a drug to induce an addictive behavior, characterized by obsessive drug-seeking and drug-taking in both animals and humans, necessitates an interaction between the drug of abuse and specific populations of cells in the brain. Our desire to understand the neuronal basis of this complex, self-perpetuating, and sometimes fatal drug-induced behavior, has fueled an intense research effort at all levels of neuroscience from molecular to behavioral. Much of this research has focussed on the mesocorticolimbic dopamine system as the site of action for the rewarding properties of many classes of abused drugs. However, endogenous opioid peptides have also been implicated as mediators of this phenomenon. Moreover, these peptides, together with GABA, are present in a major output of the nucleus accumbens projecting to the ventral pallidum - a region of the brain strongly implicated in the reward process. This proposal describes experiments designed to provide in vivo neurochemical evidence for a role of these transmitters in mediating both cocaine and opiate reward. Recent developmental work in the P.I.'s laboratory has demonstrated the feasibility of using microdialysis to monitor opioid peptide release in the basal ganglia and limbic system of freely behaving rats. Based on preliminary data, demonstrating a morphine- and cocaine-induced stimulation of opioid peptide release in the pallidum, the proposal will address the following specific aims. 1. To determine the pharmacological and neuroanatomical basis of acute opiate-induced endogenous opioid peptide release in the pallidum using receptor sub-type selective drugs and central administration. 2. To characterize the effects of repeated forced- and self-administration of opiates on opioid peptide release and to examine the effects of withdrawal on extracellular opioid peptide levels. 3. To elucidate the pharmacological and anatomical basis of acute cocaine effects on opioid peptide release in the nucleus accumbens - pallidal system. 4. To investigate the effects of self-administered and long-term cocaine treatment on extracellular opioid peptides. These studies will provide valuable information concerning the mechanism of opiate and cocaine addiction which could ultimately lead to the development of new therapeutic strategies for treatment of substance abuse.
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