Characterization of a novel serotonin receptor subtype, 5HT(1D), in mammalian brain

The purpose of this thesis was to characterize the novel serotonin 5HT{dollar}sb{lcub}rm 1D{rcub}{dollar} binding site, and to determine whether this binding site has properties consistent with a functional serotonin receptor.; A radioligand receptor binding assay was developed for the characterization of serotonin 5HT{dollar}sb{lcub}rm 1D{rcub}{dollar} binding sites in mammalian brain homogenates. The pharmacology and distribution of 5HT{dollar}sb{lcub}rm 1D{rcub}{dollar} sites are distinct from previously identified serotonin receptor subtypes, and are very similar in rat, bovine, porcine and human cortex. Potent compounds for the 5HT{dollar}sb{lcub}rm 1D{rcub}{dollar} site include serotonin, 5-carboxamidotryptamine and yohimbine, and ergot derivatives such as ergotamine, LSD, methysergide and metergoline. Regional distribution studies indicate that 5HT{dollar}sb{lcub}rm 1D{rcub}{dollar} sites are most prominent in the caudate and basal ganglia. Of all the species and brain regions examined, bovine caudate provides the best model system for studying 5HT{dollar}sb{lcub}rm 1D{rcub}{dollar} sites.; The 5HT{dollar}sb{lcub}rm 1D{rcub}{dollar} binding site appears to be biologically relevant since guanyl nucleotides modulate agonist radioligand binding. These findings indicate that 5HT{dollar}sb{lcub}rm 1D{rcub}{dollar} sites interact with a GTP binding protein.; Presently, the physiological and behavioral functions of the 5HT{dollar}sb{lcub}rm 1D{rcub}{dollar} site are unknown. In order to better understand the functional role of 5HT{dollar}sb{lcub}rm 1D{rcub}{dollar} sites in the CNS, the synaptic localization of the 5HT{dollar}sb{lcub}rm 1D{rcub}{dollar} site was determined. Lesioning of brain serotonergic neurons with p-chloroamphetamine revealed a postsynaptic localization for 5HT{dollar}sb{lcub}rm 1D{rcub}{dollar} sites. The observed up-regulation of cortical 5HT{dollar}sb{lcub}rm 1D{rcub}{dollar} sites indicates that 5HT{dollar}sb{lcub}rm 1D{rcub}{dollar} sites receive endogenous 5HT input in vivo.; Collectively, these results are consistent with the hypothesis that the 5HD{dollar}sb{lcub}rm 1D{rcub}{dollar} binding site represents a novel subtype of functional serotonin receptor.