In this application for an NIDA-NIH Independent Scientist Award (ISA) a program of research is proposed to elucidate brain opioid mechanisms that facilitate reward during chronic food restriction. A multidisciplinary approach to this problem is planned which exploits recently developed molecular biological methodologies. Previous research indicates that metabolic need states activate a brain opioid mechanism that sensitizes animals to rewarding effects of electrical brain stimulation. Evidence for the involvement of mu and kappa opioid receptors along with dynorphin A peptides has been obtained. In Studies I and II the changes in plasma corticosterone and insulin associated with metabolic need will be investigated as possible triggers of reward sensitization. Studies III and IV follow observations that food restriction produces brain regional changes in dynorphin peptide levels and mu and kappa receptor binding. Solution hybridization and in situ hybridization histochemistry will be used to elucidate these changes by seeking corresponding changes in receptor and prodynorphin gene transcription. In Study V [35S]GTP-gammaS autoradiography will be used to investigate the neuroanatomical distribution of changes in G-protein activation. Since food restriction appears to be accompanied by a tonic increase in opioid peptide release, c-fos immunohistochemistry will be used in Study VI to identify brain regions that display 'rebound' activation in response to naltrexone. Study VII will utilize microinjections of antagonists, antisense oligodeoxynucleotides and antibodies to opioid peptides to identify the brain region(s) and intrinsic peptide-receptor type combinations that mediate the sensitization of reward. In addition to supporting a research program, the ISA will provide the PI with opportunities for training in molecular biological approaches that increase the power of behavioral neuroscientific investigation. This training, which will occur by way of collaboration with several colleagues, will enhance the ability of the PI to bring modern neuroscientific methods to bear on the solution of basic behavioral problems relating to motivation and reward. During the period of ISA support, the Pl, who is Associate Director of the Postdoctoral Training Program, will serve as mentor to trainees as well as residents and fellows in the Division of Alcoholism and Substance Abuse. The long-term support and commitment to the PI's scientific development engendered by the ISA will ensure the stability and productivity of the laboratory, thereby creating an improved setting for research training.
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