Serotonin (5-hydroxytryptamine; 5-HT) is an indoleamine that is synthesized in neurons of the peripheral and central nervous systems and within enterochromaffin cells of the gastrointestinal mucosa. Among its diverse roles, 5-HT has been implicated in mediating the inhibitory control of feeding in mammals. Research has focused primarily on serotonergic systems in the forebrain in this function. Nonetheless, substantial evidence now exists that peripheral actions of 5-HT also decrease food intake. Previously, studies using serotonergic antagonists and analogs of 5-HT as agonists established that peripherally administered 5-HT reduced feeding by stimulating 5-HT1-like and 5-HT2 receptors. The pharmacological profiles for these receptor mechanisms corresponded to those involved in contracting the pyloric region (5-HT2) in vitro and increasing intragastric pressure (5-HT1-like) after gastric denervation in anesthetized rats. The effect of 5-HT to reduce food intake survived total abdominal vagotomy and was blunted but not eliminated by ablating the area postrema in the hindbrain. Thus, existing data have identified classes of receptors, candidate targets in the gastrointestinal system and pathways for neuronal processing of the peripheral serotonergic signal for satiation. The proposed investigation tests specific hypotheses about the nature of the primary target sites in the periphery and the path of the neuronal circuitry mediating peripheral serotonergic satiation. The experiments will: l) use receptor autoradiography, assays of smooth muscle contraction in vitro and feeding tests with the peripheral 5-HT2 agonist, alpha- methyl-5-HT, in pylorectomized rats to assess the role of the pylorus in 5-HT2-related satiety; 2) compare, in behaving rats, the pharmacological profiles for the peripheral 5-HT1-like agonist, 5-carboxamidotyyptamine (5-CT) to increase intragastric pressure and reduce food intake; 3) test whether interrupting sympathetic viscerosensory input to the CNS, by celiac ganglionectomy plus splanchnicotomy, will inhibit peripheral serotonergic satiation; and 4) analyze the roles of the nucleus of the solitary tract, parabrachial nucleus and central oxytocinergic mechanisms in peripheral 5-HT-induced decreases in food intake. The behavioral patterns of the rats in response to serotonergic stimulation will be recorded and analyzed routinely. Separate experiments will characterize further the role of oropharyngeal factors in peripheral serotonergic satiation. Finally, studies using central administration of 5-HT(1B) agonists, receptor autoradiography and antisense oligodeoxynucleotides will begin evaluating the role of serotonergic 1B receptors in the caudal brainstem in inhibiting feeding. In concert, these experiments should establish further the mechanisms by which peripheral serotonergic stimulation enhances satiation. Furthermore, the investigation broadens the framework of the project to develop a model for the convergent influences of central and peripheral serotonergic modulation of brainstem mechanisms that control feeding. Thus, these studies may provide significant information concerning the role of 5-HT in normal and pathological processes regulating energy intake and body weight.
