5-HT1A autoreceptor regulation and functional polymorphisms that modify the serotonin system and their association with depression and schizophrenia

The serotonergic system, and in particular the 5-HT1A receptor, are involved in the etiology and treatment of depression. The hypothesis that antidepressants downregulate 5-HT1A autoreceptor gene expression was investigated by examining 5-HT1A agonist effects on 5-HT1A promoter activity using reporter construct assays and on 5-HT1A mRNA levels by quantitative real-time PCR in raphe primary cultures. 8-OH-DPAT had no effect on 5-HT1A autoreceptor expression in either paradigm. To elucidate the genetics of mental illness, monoaminergic receptor gene polymorphisms were analyzed. An association of the 5-HT2A A(-1438)G SNP with MDD was significant in males, and a trend was seen for the 5-HT1A C(-1019)G SNP with MDD. No association of these or a D2 SNP was detected with schizophrenia. Sequencing the macaque 5-HT1A promoter and human-primate comparisons revealed potentially functional novel polymorphisms and interspecies differences. These results contribute to our understanding of the 5-HT1A receptor's role in both normal affect and psychiatric disorders.