The indoleamine, serotonin (5-hydroxytryptamine; 5-HT) is synthesized by neurons in the central nervous system and by peripheral neural and endocrine cells. Pharmacological and molecular biological studies have implicated numerous subtypes of serotonergic receptors in mediating the cellular and broader physiological functions of 5-HT. Among its roles, 5- HT may be an inhibitory signal for the short-term control of feeding. Consistent with this hypothesis, drugs that enter the brain and directly or indirectly activate postsynaptic 5-HT receptors decrease food intake in rats. Nonetheless, these drugs also act peripherally and 5-HT, itself, reduces feeding when given systematically although it probably fails to penetrate into the brain. Previously, 5-HT2 antagonists reversed partially the anorectic actions of 5-HT and its congener, 4-HT. Studies with 5- carboxamidotryptamine (5-CT), which presumably acted peripherally at """"""""5- HT1-like"""""""" receptors, and with alpha-methyl-5-HT, a peripheral 5HT2 agonist, implied that stimulating either peripheral 5-HT2 or 5-HT1 receptors inhibited feeding. 5-HT but not 5-CT reduced gastric sham-feeding. Neither produced true satiety in sham-feeding rats. Central 5-HT2 stimulation also decreased intake but this treatment fragmented feeding. Together, these data suggest that at least two 5-HT receptors mediate at least two peripheral serotonergic actions controlling feeding. The proposed investigation will evaluate the mechanisms for the peripheral 5-HT-related anorexia in rats by: 1) using a lickometer device together with observational methods to compare the effects of peripherally acting and centrally-active 5-HT agonists on the topography of feeding behavior; 2) determining whether depleting central 5-HT enhances the anorectic actions of direct 5-HT agonists in the brain but reduces the actions of peripheral 5-HT agonists and gut peptides; 3) assessing the importance of oral and intestinal stimulation in peripheral serotonergic anorexia during sham-feeding; 4) comparing the effects of peripheral sensory denervation by vagotomy or capsaicin on the anorectic actions of 5HT analogs and gut peptides; 5) assessing whether infusing 5-HT agonists into the hepatic portal vein decreases food intake; 6) assessing whether ablating the area postrema prevents serotonergic anorexia; and 7) determining whether chronically blocking peripheral 5-HT2 receptors increases food intake and modulates peripheral 5-HT2 responses. In concert, these studies may provide significant information concerning the roles of peripheral 5-HT receptors in normal and pathological processes affecting feeding.
