Abstract
The addition of low doses of atypical antipsychotic drugs, which saturate 5-HT2A 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-HT2A 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-HT2A receptors vs other 5-HT receptor subtypes, and would not be expected to appreciably occupy non-5-HT2A receptors at doses below 100 μg/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-HT2A receptor antagonist (6.25–12.5 μg/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 μg/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-HT2A receptors and serotonin transporters (SERT) may result in greater efficacy in treating neuropsychiatric syndromes than blocking either site alone.
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Acknowledgements
This work was previously presented at the 2001 Society for Neuroscience meeting (San Diego, CA) and the 2001 meeting of the American College of Neuropsychopharmacology (San Juan, Puerto Rico). This study was supported by PHS Grants K08 MH01551, R01 MH62186, a NARSAD Young Investigator Award (1999 Fairfax Investigator Award), the state of Connecticut (GJM), and National Institutes of Health Grants FIS 01/1147 and SAF2001-2133 (FA) We appreciate Dr Younglim Lee's review of the manuscript. We thank Nigel Henry, Sara Heron, Andrew Kwak, Megan Lennon, Boting Zhang, and Leticia Campa for technical assistance. We also thank Leslie Rosello for secretarial assistance.
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Marek, G., Martin-Ruiz, R., Abo, A. et al. The Selective 5-HT2A Receptor Antagonist M100907 Enhances Antidepressant-Like Behavioral Effects of the SSRI Fluoxetine. Neuropsychopharmacol 30, 2205–2215 (2005). https://doi.org/10.1038/sj.npp.1300762
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DOI: https://doi.org/10.1038/sj.npp.1300762
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