Anorexia is a major complicating factor of neoplastic disease that severely limits the use of available therapeutic options. Although many theories of cancer anorexia have been advanced, few investigations of the causes of the anorexia have been directed at the molecular biochemical level. Therefore we have little information concerning abnormalities in anorectic tumor-bearing (TB) subjects of systems that are thought to mediate hunger and satiety. In preliminary experiments levels of dopamine (DA) metabolites were significantly decreased in the brains of anorectic TB rats and increased in undernourished pair-fed control rats. Brain levels of DA metabolites were nearly doulbed when the anorexia was corrected by insulin injections. Blood levels of insulin were also significantly decreased early in the course of anorexia an concentrations of glucagon were increased during more severe anorexia. The net effect of these alterations in glucoregulatory hormones is to prevent hypoglycemia in the presence of increased glucose utilization. Since increased glucose usage rate is associated with satiety and glucose infusion decreases brain DA release, cancer anorexia may be partially caused by relative hyperglycemia reflected centrally as decreased turnover of DA. This hypothesis will be investigated in the proposed experiments by (1) assessing the effects of correcting cancer anorexia by insulin treatments on concentrations of amine neurotransmitters, precursors and metabolites in nine discrete brain regions; (2) assessing the effects of insulin treatments on blood levels of glucagon and cachexia; (3) examining the release of DA and norepinephrine (NE) in the hypothalamus, septal area, amygdala and corpus striatum of freely-behaving TB and control rats by push-pull perfusion of these brain areas and correlating these changes in catecholamines with plasma levels of glucose, insulin and glucagon; (4) assessing the effects of insulin administration on the release of DA and NE in these brain areas; (5) investigating the anti-anorectic effects of drugs that stimulate DA neurotransmission as possible candidates for pharmacological control of anorexia. These experiments are designed to comprehensively investigate the role of amine neurotransmitters in mediating cancer anorexia. An advantage of these studies is that ongoing peripheral events (changes in glucose) will be correlated with ongoing CNS neurochemical changes and the relationship of both peripheral and central biochemical changes to anorexia and feeding can be established in a freely-behaving animal.
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