The selective 5-HT2A receptor antagonist M100907 enhances antidepressant-like behavioral effects of the SSRI fluoxetine

Neuropsychopharmacology. 2005 Dec;30(12):2205-15. doi: 10.1038/sj.npp.1300762.

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-HT(2) antagonists and SSRIs. M100907 has a approximately 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 microg/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 microg/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 microg/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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents, Second-Generation / pharmacology*
  • Brain Chemistry / drug effects
  • Conditioning, Operant / drug effects
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Extracellular Space / drug effects
  • Extracellular Space / metabolism
  • Fluorobenzenes / pharmacology*
  • Fluoxetine / pharmacology*
  • Male
  • Microdialysis
  • Piperidines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT2A / drug effects*
  • Reinforcement Schedule
  • Serotonin Antagonists / pharmacology*
  • Serotonin Uptake Inhibitors / pharmacology

Substances

  • Antidepressive Agents, Second-Generation
  • Fluorobenzenes
  • Piperidines
  • Receptor, Serotonin, 5-HT2A
  • Serotonin Antagonists
  • Serotonin Uptake Inhibitors
  • Fluoxetine
  • volinanserin