Ligand binding techniques have identified multiple types of receptors for 5-hydroxytryptamine (serotonin, 5HT) in the central nervous system. However, little is known of the physiological significance or of mechanisms involved in the regulation of the different 5HT-related binding sites. The major objective of this grant is to examine in greater detail three behavioral responses caused by 5HT agonists. Previous work on this grant has suggested that these behavioral responses are associated with separate populations of 5HT receptors that are defined by ligand binding methods. The proposed experiments will examine the association between alterations of specific 5HT receptors by antidepressant drug treatments, the hormonal environment, or specific 5HT agonists with changes in their corresponding behaviors. The association of behavioral responses with ligand binding sites for 5HT helps to substantiate the sites as physiologically important receptors. These questions have important clinical significance because the ability of long-term administration of various types of antidepressant drugs to reduce the number of 5HT receptors has been suggested to underlie their common clinical therapeutic effects. Although nearly all antidepressant drugs produce reductions in 5HT2 receptors after their chronic administration, and some reduce 5HT1 receptor number as well, the mechanisms involved in these effects are relatively unknown. These experiments will explore systematically three mechanisms that could underlie the biochemical changes in 5HT receptors that produce concomitant changes in behavior. Although chronic antidepressant drug treatment causes common effects at 5HT2 receptors, they probably are producing these effects with different pharmacological mechanisms of action. Still other studies will determine whether the chronic administration of agonists that discriminate separate 5HT receptors can produce selective alterations of behavior and their associated receptors. The establishment of behavioral responses as related to discrete types of 5HT receptors will also provide tools for examining newer compounds with more selective mechanisms of action. These studies emphasize the important regulatory role that may be exerted by multiple types of 5HT receptors in the different behavioral and physiological functions served by central 5HT systems.
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