This is a request for a Mentored Research Scientist Development Award (KO1). The proposed research is designed to elucidate the relationship between the opioid system and the dopamine system as a result of exposure to cocaine. The majority of what we know of cocaine's effects on the endogenous opioid system has been based on investigations carried out in rats. These studies may be of limited relevance however, to cocaine abuse in humans, because of the differences in expression of opioid receptors in rat vs human brain, as well as, neuroanatomical and neurochemical differences between these species. Moreover, the effects of self-administration on opioid receptors are largely unknown. A strategy combining in vivo and in vitro imaging methods is proposed to assess neuroadaptations in opioid and dopamine receptors that accompany cocaine self-administration in a primate model of cocaine abuse. The primary focus of the proposed studies is training in positron emission tomography (PET) imaging to map changes in brain receptor function that occur over time as a consequence of cocaine self-administration and in response to a buprenorphine treatment regimen. One of the strengths of PET is that these parameters can be evaluated longitudinally within the same subjects thereby reducing error that is inherent in a between animal study. The data obtained with PET will be directly compared to data analyzed using in vitro autoradiographic techniques in the same subjects analyzed with PET as well as in groups of animals treated under identical conditions. Because alterations in receptor KD and BMAX values do not always correlate with functional activation of those receptors, the effects of these treatments on functional activation of opioid receptors will also be assessed with the [35S]GTPgammaS autoradiographic method which is used to identify receptor-activated G-proteins. A major strength of this proposal is the utilization of different experimental approaches that complement each other to assess the functional and anatomical distribution of receptors. The multidisciplined nature of this project, which will be conducted under the mentorship of Dr. Robert Mach, and in collaboration with faculty specializing in primate behavior, opioid/cocaine pharmacology and signal transduction, will provide a unique opportunity for the candidate to address issues regarding the long-term effects of cocaine. This project will thus enable the candidate to develop into an independent investigator in the sparsely populated arena of primate neurobiology to investigate the neurobiological substrates underlying the long-term effects of cocaine abuse.
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