Effect of repeated treatment with fluoxetine on tryptophan hydroxylase-2 gene expression in the rat brainstem

Selective serotonin (5-HT) reuptake inhibitors such as fluoxetine are widely used in the treatment of depression and anxiety; however, the mechanisms underlying their action and particularly the delay in therapeutic onset remain unclear. It is proposed that 5-HT reuptake inhibitors exert their therapeutic activity by increasing serotonergic neurotransmission; therefore, the aim of the present study was to investigate the effects of repeated treatment with fluoxetine (25 mg/kg/day p.o., 14 days) on expression of genes coding for proteins that involved in the synthesis and reuptake of 5-HT. Exposure of animals to plus-maze conditions on the first day of drug administration produced an increase in baseline anxiety on subsequent trial 2 weeks later. Fluoxetine strengthened the anxiogenic effects of maze experience. Two-week fluoxetine treatment also significantly reduced expression of tryptophan hydroxylase-2 (TPH2) and 5-HT transporter mRNAs as determined by RT-PCR in the brainstem. These changes were consistent with the decreased 5-HT levels and 5-HT turnover in the brain, and might contribute to the anxiogenic effects of the drug. The results also suggest that recently found association between treatment responses to fluoxetine and polymorphic variants of human TPH2 gene [Peters EJ, Slager SL, McGrath PJ, Knowles JA, Hamilton SP. Investigation of serotonin-related genes in antidepressant response. Mol Psychiatry 2004; 9:879–889] may be related to the drug effect on the TPH2 gene expression.