Role of serotonin transporter inhibition in the regulation of tryptophan hydroxylase in brainstem raphe nuclei: time course and regional specificity

Drugs that selectively inhibit the serotonin transporter (SERT) are widely prescribed for treatment of depression and a range of anxiety disorders. We studied the time course of changes in tryptophan hydroxylase (TPH) in four raphe nuclei after initiation of two different SERT inhibitors, citalopram and fluoxetine. In the first experiment, groups of Sprague-Dawley rats received daily meals of rice pudding either alone (n=9) or mixed with citalopram 5 mg/kg/day (n=27). Rats were sacrificed after 24 h, 7 days or 28 days of treatment. Sections of dorsal raphe nucleus (DRN), median raphe nucleus (MRN), raphe magnus nucleus (RMN) and caudal linear nucleus (CLN) were processed for TPH immunohistochemistry. Citalopram induced a significant reduction in DRN TPH-positive cell counts at 24 h (41%), 7 days (38%) and 28 days (52%). Similar reductions in TPH-positive cell counts were also observed at each timepoint in the MRN and in the RMN. In the MRN, citalopram resulted in significant reductions at 24 h (26%), 7 days (16%) and 28 days (23%). In the RMN, citalopram induced significant reductions of TPH-positive cell counts at 24 h (45%), 7 days (34%) and 28 days (43%). By contrast, no significant differences between control and treatment groups were observed in the CLN at any of the time points that we studied. To investigate whether these changes would occur with other SERT inhibitors, we conducted a second experiment, this time with a 28-day course of fluoxetine. As was observed with citalopram, fluoxetine induced significant reductions of TPH cell counts in the DRN (39%), MRN (38%) and RMN (41%), with no significant differences in the CLN. These results indicate that SERT inhibition can alter the regulation of TPH, the rate limiting enzyme for serotonin biosynthesis. This persistent and regionally specific downregulation of serotonin biosynthesis may account for some of the clinical withdrawal symptoms associated with drugs that inhibit SERT.