In this application for continuation of a NIDA/NIH Independent Scientist Award, a program of research is proposed to elucidate endocrine and brain dopamine mechanisms that underlie the augmentation of drug reward by chronic food restriction in rats. Previous work in this laboratory indicates that chronic food restriction enhances central sensitivity to the rewarding, locomotor- and cellular- activating effects of diverse drugs of abuse. Preliminary results indicate that the augmentation is reversed by one week of restored ad libitum food access or subchronic intracerebroventricular (i.c.v.) insulin injection. In Study I of this application, the sustained subnormal levels of central insulin and leptin that characterize the food-restricted rat are further investigated as possible triggers of the augmenting effect of food restriction on drug reward. Study II examines whether downregulation of the D-3 dopamine receptor could plausibly contribute to the augmentation of drug reward by food restriction. Studies III-VI investigate whether chronic food restriction alters immediate early gene expression and/or signal transduction mediated by multiple dopamine receptor types in limbic forebrain structures that regulate drug reward. Specifically, Study III examines c-fos expression induced by individual and combined administration of dopamine receptor type-selective agonists. Study IV examines functional coupling between D-2 receptors and G-protein by measuring quinpirole- stimulated [35S]GTPgammaS binding. Study V examines D-1-agonist- induced stimulation of adenylyl cyclase. Study VI examines amphetamine-induced activation of extracellular signal-regulated kinase (ERK). Finally, Study VII seeks to establish whether the neuroadaptations identified in Studies III-VI are reversed by the same regimens of restored ad libitum feeding or subchronic i.c.v. hormone administration that reverse the behavioral effects of food restriction. By clarifying the relationship between endocrine adiposity hormones, central neurotransmission, and sensitivity of brain reward circuitry, this work may improve our understanding of organismic variables that affect vulnerability to drug abuse and help explain the high comorbidity of drug abuse and eating disorders.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Scientist Development Award - Research (K02)
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Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Volman, Susan
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New York University
Schools of Medicine
New York
United States
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Cabeza de Vaca, Soledad; Kannan, Pavitra; Pan, Yan et al. (2007) The adenosine A2A receptor agonist, CGS-21680, blocks excessive rearing, acquisition of wheel running, and increases nucleus accumbens CREB phosphorylation in chronically food-restricted rats. Brain Res 1142:100-9
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Hao, Joy; Cabeza de Vaca, Soledad; Pan, Yan et al. (2006) Effects of central leptin infusion on the reward-potentiating effect of D-amphetamine. Brain Res 1087:123-33
Pan, Yan; Berman, Yemiliya; Haberny, Sandra et al. (2006) Synthesis, protein levels, activity, and phosphorylation state of tyrosine hydroxylase in mesoaccumbens and nigrostriatal dopamine pathways of chronically food-restricted rats. Brain Res 1122:135-42
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Cabeza de Vaca, Soledad; Krahne, Lisa L; Carr, Kenneth D (2004) A progressive ratio schedule of self-stimulation testing in rats reveals profound augmentation of d-amphetamine reward by food restriction but no effect of a ""sensitizing"" regimen of d-amphetamine. Psychopharmacology (Berl) 175:106-13
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