Obesity, a multivariate disease, can occur with or without accompanying hyperphagia. There is a growing sense of alarm that a large percentage of eating disorders and obesity may be environmental in origin. Among the environmental factors, neurotoxins and certain neural injury producing infections have drawn considerable attention and concern in recent years. This proposal focuses on the neurochemical basis of obesity produced experimentally by neurotoxins. Our long-term objectives are to understand the operative function of the brain circuitry involved in the development of obesity caused by neurotoxin-induced neural injury. Within the hypothalamus an interconnected network of neuropeptides including Neuropeptide Y, galanin and opioids, evokes normal feeding in the rat. We propose to test the hypothesis that obesity produced by three specific neurotoxins known to inflict varied cellular damage is either due to the increased secretion of one or more of these excitatory neuropeptides or due to an increase in receptor sensitivity in the hypothalamic paraventricular nucleus - perifornical (PVN-PF) area. The following neurotoxins will be employed: Ibotenic acid to selectively destroy cell bodies in the ventromedial hypothalamus; colchicine to block axonal transport in the ventromedial nucleus; 6-hydroxydopamine to damage the ascending ventral catecholaminergic bundle in the mid-brain. Secretion of neuropeptide Y, galanin and opioids will be measured in vivo by the push- pull cannula technique and in vitro in short-term cultures of the PVN-PF, and synthesis will be assessed by quantitation of mRNA and peptide contents will be measured in various hypothalamic sites. The second possibility of increase in receptor sensitivity will be assessed by quantitation of food intake after the intracerebroventricular injection of agonists and antagonists or immunoneutralization of neuropeptides. Neuropeptide receptor affinity and number in membranes from microdissected hypothalamic sites will be measured. It is anticipated that elucidating the patterns of neuropeptidergic signalling associated with neurotoxin- induced obesity will shed light on the etiology of idiopathic obesity.
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