Anxiety-like effects induced by acute fluoxetine, sertraline or m-CPP treatment are reversed by pretreatment with the 5-HT2C receptor antagonist SB-242084 but not the 5-HT1A receptor antagonist WAY-100635

Int J Neuropsychopharmacol. 2001 Dec;4(4):399-408. doi: 10.1017/S1461145701002632.


The possible role of 5-HT1A and 5-HT2C receptors in the anxiety induced by fear, acute treatment with SSRI antidepressants or the 5-HT receptor agonist m-CPP were tested in the social interaction anxiety test in male Sprague-Dawley rats. Fluoxetine (2.5-10 mg/kg, i.p.), sertraline (15 mg/kg, i.p.) and m-CPP (0.5-2.0 mg/kg, i.p.) all had an anxiogenic-like profile (decrease in time of total social interaction and increase in self-grooming compared to vehicle) under low-light, familiar arena test conditions. All these effects were reversed by pretreatment with the highly subtype-selective 5-HT2C receptor antagonist, SB-242084 at doses of either 0.05 or 0.2 mg/kg, i.p. In contrast, the selective 5-HT1A receptor antagonist WAY-100635 (0.05 and 0.2 mg/kg, s.c.) failed to reverse SSRI-induced decrease in time of total social interaction, further, it augmented self-grooming response. SB-242084 (0.2 mg/kg) and WAY-100635 (0.05 and 0.2 mg/kg) reversed hypolocomotion caused by the SSRI antidepressants. SB-242084, tested alone against vehicle under high-light, unfamiliar arena test conditions associated with fear, caused significant anxiolysis at 0.2 mg/kg and higher doses. These results suggest that increased anxiety in rodents, and possibly, also in humans (e.g. agitation or jitteriness after SSRIs and panic after m-CPP), caused by acute administration of SSRI antidepressants or m-CPP, are mediated by activation of 5-HT2C receptors. Blockade of 5-HT1A autoreceptors may exacerbate certain acute adverse effects of SSRI antidepressants. Both 5-HT1A and 5-HT2C receptors are involved in the SSRI-induced decrease in locomotor activity. In addition, our studies confirm data that subtype-selective 5-HT2C receptor antagonists have strong anxiolytic actions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopyridines / therapeutic use*
  • Animals
  • Antidepressive Agents, Second-Generation / antagonists & inhibitors*
  • Antidepressive Agents, Second-Generation / pharmacology*
  • Anxiety / chemically induced*
  • Anxiety / psychology*
  • Behavior, Animal / drug effects
  • Fluoxetine / antagonists & inhibitors*
  • Fluoxetine / pharmacology*
  • Grooming / drug effects
  • Indoles / therapeutic use*
  • Interpersonal Relations
  • Male
  • Motor Activity / drug effects
  • Piperazines / antagonists & inhibitors*
  • Piperazines / pharmacology*
  • Piperazines / therapeutic use*
  • Pyridines / therapeutic use*
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT2C
  • Receptors, Serotonin / drug effects*
  • Receptors, Serotonin, 5-HT1
  • Serotonin Antagonists / therapeutic use*
  • Sertraline / antagonists & inhibitors*
  • Sertraline / pharmacology*


  • 6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline
  • Aminopyridines
  • Antidepressive Agents, Second-Generation
  • Indoles
  • Piperazines
  • Pyridines
  • Receptor, Serotonin, 5-HT2C
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT1
  • Serotonin Antagonists
  • Fluoxetine
  • N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
  • Sertraline
  • 1-(3-chlorophenyl)piperazine