Our research is concerned with the common neural substrates for natural rewards (particularly food) and drugs of abuse. The goal of this work is to understand the neurobiology of motivational processes in general and illuminate the high comorbidity of eating disorders and drug abuse. In behavioral studies, a psychophysical curve-shift method is used in rats to measure sensitivity of brain reward circuitry to direct electrical stimulation in the presence and absence of drugs. Using this method, it has been demonstrated that persistent negative energy balance, induced by chronic food restriction, enhances sensitivity of brain reward circuitry to centrally injected psychostimulants, opiates, dissociative anesthetics and direct dopamine receptor agonists. The enhancement dissipates over a period of weeks in parallel with restoration of body weight when free access to food is restored. Consequently, the involvement of endocrine adiposity hormones, leptin and insulin, are under investigation. The CNS correlates of enhanced behavioral sensitivity to drug challenge in food-restricted subjects include (i) increased functional coupling between striatal D-2 dopamine (DA) receptors and Gi, (ii) increased D-1 DA receptor-mediated activation of the NR1 subunit of the NMDA receptor in nucleus accumbens (NAc), (iii) increased D-1 DA agonist-induced MAP kinase and CaM kinase II activation in NAc, (iv) increased D-1 DA agonist-induced CREB phosphorylation -which is NMDA receptor- and MAP kinase-dependent- in NAc, and (v) increased DA agonist-induced immediate early gene (c-fos) expression in subcortical DA terminal areas and downstream pallidal regions. The involvement of upregulated NAc cell signaling in drug reward and neuropeptide gene expression are under investigation.