MECHANISMS AND REGULATION OF 5-HT RECEPTORS IN THE CNS

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Serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter in the brain. Since its discovery, more than 40 years ago many studies have defined its distribution in the nervous system, the mechanisms involved in its synthesis and degradation and the factors that regulate its release. More recent studies have concentrated on understanding the receptor subtypes used by serotonin and the mechanisms by which these receptors signal their actions. These studies are important since they provide the molecular framework for understanding the mechanisms by which serotonin acts in the normal brain. Moreover they provide a window for understanding how abnormal serotonergic function can contribute to neurological and psychiatric conditions. The long term goal of the PI's laboratory is to understand the actions signaled by different serotonin receptor subtypes in the central nervous system and the ionic and molecular mechanisms underlying this signaling. This application proposes to continue work initiated by the PI during the previous funding cycle by elucidating the mechanisms by which serotonin receptors of the 5-HT4 subtype increase membrane excitability. These studies will use electrophysiological techniques in in vitro brain slices and will examine the possible role of the cAMP signaling cascade as well as the role of specific ionic currents in mediating 5-HT4 responses in the brain. This work will contribute to our understanding of serotonergic function in health and also in disease states thought to involve serotonergic dysfunction such as intractable pain, depression, obsessive compulsive disorder and suicide. Moreover it is anticipated that this work will contribute to the development of novel pharmacological therapeutic interventions aimed at serotonergic systems.