5-HT2C receptor gene polymorphisms associated with antipsychotic drug action alter promoter activity

Polymorphisms within the 5-HT2C receptor gene promoter have been associated with several physiological and psychiatric phenotypes. Notably, the –759T allele has been associated with resistance to antipsychotic induced weight gain. This study assessed the activity of four promoter haplotypes expressed as luciferase constructs in the SH-SY5Y human neuroblastoma cell line in the presence or absence of a constitutively active 5-HT2C receptor. The presence of either –759T or –697C alleles reduced promoter activity. In addition a haplotype associated with resistance to antipsychotic induced weight showed under activity compared to the most common haplotype. In the presence of the 5-HT2C receptor a similar pattern of promoter activity was observed. Both –759C/T and –697G/C polymorphic sites are likely to play a role in basal promoter activity. Resistance to weight gain may, in part, be mediated by the consequences of reduced 5-HT2C receptor expression.