5-HT2A and 5-HT2C receptor antagonists have opposing effects on a measure of impulsivity: interactions with global 5-HT depletion

Psychopharmacology (Berl). 2004 Nov;176(3-4):376-85. doi: 10.1007/s00213-004-1884-9. Epub 2004 Jun 30.


Rationale: Global serotonin (5-HT) depletion increases the number of premature responses made on the five-choice serial reaction time task (5CSRT) in rats. In contrast, the 5-HT(2A) receptor antagonist M100907 decreases this measure of impulsivity. Mounting evidence suggests that 5-HT(2A) and 5-HT(2C) receptors have opposing effects on behaviour, and that the 5-HT(2C) receptor antagonist SB 242084 produces a pattern of behaviour similar to 5-HT depletion.

Objectives: To assess the effects of 5-HT(2A) and 5-HT(2C) receptor antagonists on performance of the 5CSRT, to directly compare the effects of these drugs with those of ICV 5,7-dihydroxytryptamine (5,7-DHT) lesions and to investigate whether 5-HT depletion affects the action of these agents.

Methods: The effects of M100907 (0, 0.01, 0.03, 0.1 mg/kg IP) and SB 242084 (0, 0.1, 0.25, 0.5 mg/kg IP) were investigated on performance of the 5CSRT in both ICV 5,7-DHT-lesioned and sham-operated rats. RESULTS. ICV 5,7-DHT lesions, which significantly decreased forebrain levels of 5-HT by around 90%, increased levels of premature responding, decreased omissions and the latency to respond correctly, yet did not affect performance accuracy. M100907 decreased premature responding in sham-operated controls but not in 5-HT-depleted rats. In contrast, SB 242084 increased premature responding in all animals, and also decreased the latency to make a correct response in sham-operated controls.

Conclusions: These data support the view that serotonergic regulation of impulsive behaviour through different members of the 5-HT(2) receptor family is functionally heterogeneous. Although both 5-HT(2A) and 5-HT(2C) receptors participate in controlling this form of impulsive action, their relative contribution may depend on the endogenous state of the 5-HT system.

MeSH terms

  • 5,7-Dihydroxytryptamine / pharmacology
  • Aminopyridines / pharmacology
  • Animals
  • Conditioning, Operant / drug effects
  • Fluorobenzenes / pharmacology
  • Impulsive Behavior / drug therapy*
  • Impulsive Behavior / psychology*
  • Indoles / pharmacology
  • Injections, Intraventricular
  • Male
  • Piperidines / pharmacology
  • Psychomotor Performance / physiology
  • Rats
  • Reaction Time / drug effects
  • Receptor, Serotonin, 5-HT2A / drug effects*
  • Receptor, Serotonin, 5-HT2C / drug effects*
  • Serotonin / physiology*
  • Serotonin Agents / pharmacology
  • Serotonin Antagonists / pharmacology*


  • 6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline
  • Aminopyridines
  • Fluorobenzenes
  • Indoles
  • Piperidines
  • Receptor, Serotonin, 5-HT2A
  • Receptor, Serotonin, 5-HT2C
  • Serotonin Agents
  • Serotonin Antagonists
  • 5,7-Dihydroxytryptamine
  • Serotonin
  • volinanserin