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The Journal of Neuroscience, August 1, 2002, 22(15):6766-6772

Serotonin Clearance In Vivo Is Altered to a Greater Extent by Antidepressant-Induced Downregulation of the Serotonin Transporter than by Acute Blockade of this Transporter

Saloua Benmansour¹, William A. Owens¹, Marco Cecchi¹, David A. Morilak¹, and Alan Frazer^{1, 2}

¹ Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, and ² South Texas Veterans Health Care System, San Antonio, Texas 78284

Serotonin uptake, mediated by the serotonin transporter (SERT), is blocked acutely by antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), but such blockade does not correlate temporally with the onset of therapeutic improvement. Treatment with SSRIs for 21 d induced downregulation of the SERT (Benmansour et al., 1999). The time course of SERT downregulation as well as the time course for its recovery after cessation of treatment with the SSRI sertraline were investigated using tritiated cyanoimipramine to measure SERT binding sites. To determine if there was a temporal correlation between the time when sertraline induced downregulation of the SERT and when marked alteration in SERT function occurred, clearance of locally applied 5-HT into the CA3 region of hippocampus was achieved using in vivo electrochemistry. After 4 or 10 d treatment with sertraline, SERT binding sites decreased very little (15-30%), and the chronoamperometric signals for serotonin in sertraline-treated rats were comparable with ones obtained in control animals. By contrast, after 15 d of treatment, when SERT binding sites were markedly reduced by 80%, there was robust decrease in the clearance of 5-HT. Moreover, the functional consequences of SERT downregulation as measured by chronoamperometry were significantly greater than those seen after acute blockade of the SERT by SSRIs. SERT binding sites decreases are not a consequence of reduced SERT gene expression, as revealed by in situ hybridization measurements. SSRI-induced downregulation of the SERT may be a key component for the clinical response to SSRIs.

Key words: serotonin transporter; antidepressant; sertraline; chronoamperometry; downregulation; mRNA

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22156766-07$05.00/0

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