THE 5HT1A RECEPTOR - SIGNALING, DESENSITIZATION, AND GENE-TRANSCRIPTION

The hypothesis that antianxiety or antidepressant agents (e.g., 5-HT1A agonists, 5-HT uptake blockers) exert their clinical actions via enha ncement of serotonergic neurotransmission due to desensitization of 5- HT1A autoreceptors predicts that regulation of this receptor plays a c rucial role in the therapeutic actions of these agents. A multidiscipl inary strategy is described for the characterization of the 5-HT1A rec eptor at the level of cellular signaling mechanisms and genetic regula tion, using heterologous expression of the cloned receptor in cell lin es, site-directed mutagenesis, isolation of receptor-positive neuronal cell lines, and promoter analysis of the 5-HT1A receptor gene. These analyses will yield new insights into the possible mechanisms down-reg ulation of 5-HT1A receptor signaling, and may suggest novel sites of i nherent defect involved in anxiety syndromes or major depression.