1. ¹Department of Medicinal Chemistry, Pharmacy, University of Groningen, Groningen, The Netherlands
2. ²Department of Psychiatry, University of California, San Francisco, CA, USA
3. ³Department of Psychiatry, University Hospital Groningen, Groningen, The Netherlands
4. ⁴H Lundbeck A/S, Copenhagen, Denmark
5. ⁵Neuroscience Program, University of California, San Francisco, CA, USA
6. ⁶Department of Biomonitoring and Sensoring, Pharmacy, University of Groningen, Groningen, The Netherlands

Correspondence: Dr LH Tecott, Associate Professor of Psychiatry, University of California San Francisco, San Francisco, CA 94158-2822, USA. Tel: +1 415 476-7858; Fax: +1 415 476 7838; E-mail: tecott@itsa.ucsf.edu; Dr TIFH Cremers, Department of Medicinal Chemistry, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands, Tel: +31 6 21506340; Fax: +31 50 3636908; E-mail: T.I.F.H.Cremers@farm.rug.nl

⁷Contributed equally to this work

Received 23 September 2003; Revised 2 March 2004; Accepted 5 March 2004; Published online 12 May 2004.

Abstract

The enhancement of central serotonin system function underlies the therapeutic effects of selective serotonin reuptake inhibitors (SSRIs), which have become the most commonly used class of antidepressant agents. However, many individuals experience depressive episodes that are resistant to SSRI treatment. Homeostatic mechanisms that limit the extent to which SSRIs enhance serotonergic neurotransmission have been implicated in this phenomenon. Here, we report a novel strategy for enhancing the efficacy of SSRIs. Using in vivo microdialysis methods in rats, the nonselective 5-HT₂ receptor antagonist ketanserin was observed to produce a robust augmentation of citalopram-, fluoxetine-, and sertraline-induced elevations of hippocampal extracellular serotonin levels. Similar effects were also observed in cortex. The potentiation of SSRI-induced increases in hippocampal serotonin levels was reproduced by the 5-HT_2C receptor-selective antagonists SB 242084 and RS 102221, but not by the 5-HT_2A receptor-selective antagonist MDL 100 907. Although 5-HT_2C receptor antagonists augmented the actions of SSRIs, they had no effect on extracellular serotonin levels or tail suspension responses when administered alone. These results were in strong accord with independent findings using a line of 5-HT_2C receptor-null mutant mice. Although this mutation did not affect baseline extracellular serotonin levels or tail suspension test (TST) behavior, it enhanced fluoxetine effects on serotonin levels and immobility in the TST. These findings reveal an unanticipated pharmacological action of 5-HT_2C receptors that warrants consideration in the development of novel strategies for the treatment of depression.