1. ¹Department of Psychiatry, Yale School of Medicine, Connecticut Mental Health Center and the Ribicoff Research Facilities, New Haven, CT, USA
2. ²Department of Neurochemistry, Institut d'Investigacions Biomèdiques de Barcelona, CSIC (IDIBPAS), Barcelona, Spain

Correspondence: Dr GJ Marek, Eli Lilly and Company, Lilly Corporate Center, Mail Drop 0510, Indianapolis, IN 46285, USA. Tel: +317 651 4776; Fax: +317 276 7600; E-mail: marekgj@lilly.com

Received 1 November 2004; Revised 3 March 2005; Accepted 4 April 2005; Published online 11 May 2005.

Abstract

The addition of low doses of atypical antipsychotic drugs, which saturate 5-HT_2A receptors, enhances the therapeutic effect of selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) in patients with major depression as well as treatment-refractory obsessive-compulsive disorder. The purpose of the present studies was to test the effects of combined treatment with a low dose of a highly selective 5-HT_2A receptor antagonist (M100907; formerly MDL 100,907) and low doses of a SSRI using a behavioral screen in rodents (the differential-reinforcement-of low rate 72-s schedule of reinforcement; DRL 72-s) which previously has been shown to be sensitive both to 5-HT₂ antagonists and SSRIs. M100907 has a 100-fold or greater selectivity at 5-HT_2A receptors vs other 5-HT receptor subtypes, and would not be expected to appreciably occupy non-5-HT_2A receptors at doses below 100 g/kg. M100907 increased the reinforcement rate, decreased the response rate, and shifted the inter-response time distributions to the right in a pattern characteristic of antidepressant drugs. In addition, a positive synergistic interaction occurred when testing low doses of the 5-HT_2A receptor antagonist (6.25–12.5 g/kg) with clinically relevant doses of the SSRI fluoxetine (2.5–5 mg/kg), which both exerted minimal antidepressant-like effects by themselves. In vivo microdialysis study revealed that a low dose of M100907 (12.5 g/kg) did not elevate extracellular 5-HT levels in the prefrontal cortex over those observed with fluoxetine alone (5 mg/kg). These results will be discussed in the context that the combined blockade of 5-HT_2A receptors and serotonin transporters (SERT) may result in greater efficacy in treating neuropsychiatric syndromes than blocking either site alone.