Effect of co-administration of the selective 5-HT1A receptor antagonist WAY 100,635 and selective 5-HT1B/1D receptor antagonist GR 127,935 on anxiolytic effect of citalopram in conditioned fear stress in the rat

Eur J Pharmacol. 2008 May 31;586(1-3):171-8. doi: 10.1016/j.ejphar.2008.01.040. Epub 2008 Feb 5.

Abstract

This study investigated the effect of co-administration of the selective 5-HT1A receptor antagonist WAY 100,635 and selective 5-HT(1B/1D) receptor antagonist GR 127,935 with a subactive dose of citalopram [selective serotonin (5-HT) reuptake inhibitor (SSRI)] on the expression of conditioned freezing, an index of fear. In the present study, acute administration of citalopram (s.c.) reduced freezing significantly at high doses (10, 30 and 100 mg/kg), while showing no significant effect at low doses (1 and 3 mg/kg). Co-administration of WAY 100,635 (0.15 mg/kg) with citalopram (3 mg/kg) reduced freezing markedly and significantly, as compared with either drug alone. However, the addition of GR 127,935 (4 mg/kg) did not potentiate the effects of citalopram (3 mg/kg) on freezing and did not enhance the effect of WAY 100,635 (0.15 mg/kg) with citalopram (3 mg/kg). Co-administration of WAY 100,635 (0.15 mg/kg) or GR 127,935 (4 mg/kg) gave no effect on high-dose citalopram (30 mg/kg)-induced inhibition of freezing behavior. These results suggest that co-administration of WAY 100,635 (0.15 mg/kg) strengthens the anxiolytic effect of citalopram (3 mg/kg) by facilitating central 5-HT neurotransmission. Since GR 127,935 (4 mg/kg) failed to accelerate the inhibition of freezing induced by citalopram (3 mg/kg) with WAY 100,635 (0.15 mg/kg) or citalopram (3 mg/kg) alone, it is suggested that blocking 5-HT1A receptors is more effective in facilitating the anxiolytic effect of citalopram than blocking 5-HT1B/1D receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Anxiety Agents / pharmacology*
  • Behavior, Animal / drug effects
  • Citalopram / pharmacology*
  • Conditioning, Psychological
  • Data Interpretation, Statistical
  • Fear / drug effects
  • Fear / psychology*
  • Male
  • Motor Activity / drug effects
  • Oxadiazoles / pharmacology*
  • Piperazines / pharmacology*
  • Pyridines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT1A / drug effects*
  • Receptor, Serotonin, 5-HT1B / drug effects*
  • Receptor, Serotonin, 5-HT1D / drug effects*
  • Selective Serotonin Reuptake Inhibitors / pharmacology*
  • Serotonin Antagonists / pharmacology*
  • Stress, Psychological / drug therapy
  • Stress, Psychological / psychology*
  • Synaptic Transmission / drug effects

Substances

  • Anti-Anxiety Agents
  • Oxadiazoles
  • Piperazines
  • Pyridines
  • Receptor, Serotonin, 5-HT1B
  • Receptor, Serotonin, 5-HT1D
  • Serotonin Antagonists
  • Serotonin Uptake Inhibitors
  • Citalopram
  • Receptor, Serotonin, 5-HT1A
  • GR 127935
  • N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide