The neurotransmitter serotonin modulates diverse behavioral and developmental processes, underlies the actions of commonly-used psychotherapeutic drugs, and has putative roles in the etiology of many psychiatric conditions. The mechanisms through which serotonin systems produce these effects are poorly understood. The actions of serotonin may be dissected through the examination of the functional roles of individual serotonin receptor subtypes. The proposal focuses on the serotonin 5-HT2C and 5-HT2A receptor subtypes, which have been posited to mediate numerous physiological and behavioral effects of serotonin. A goal of this proposal is to examine the roles of these receptors in the physiology and behavior of the whole animal. This will be accomplished using transgenic methods to generate mice devoid of these receptor subtypes. One such strain of lacking functional 5-HT2C receptors has been generated and exhibits both obesity and a genetic epilepsy syndrome. The application of molecular, physiological, anatomical and behavioral approaches to the characterization of these and other phenotypic alterations in mice with serotonin receptor alterations is proposed. Mice lacking 5-HT2C receptors may prove valuable for the study of serotonergic mechanisms in epilepsy and obesity. Insights provided by the study of such animals may guide the development of selective therapeutic agents for these and other conditions in which serotonin systems are involved. Observations of behavioral deficits in these animals could spur a search for genetic and developmental abnormalities of serotonin receptor function in mental illnesses.
