Antisense inhibition of 5-hydroxytryptamine2a receptor induces an antidepressant-like effect in mice

Mol Pharmacol. 1997 Dec;52(6):1056-63. doi: 10.1124/mol.52.6.1056.

Abstract

Treatment with different antidepressants is invariably accompanied by the down-regulation of the 5-hydroxytryptamine2A (5-HT2A) receptor. To determine whether receptor down-regulation is an essential part of antidepressant action, we manipulated levels of the 5-HT2A receptor by using a nonpharmacological approach. Here, we report that down-regulation of the 5-HT2A receptor by intracerebroventricular injection of antisense oligonucleotides resulted in an antidepressant-like effect in mice. Animals with 5-HT2A receptor deficiency showed less immobility in the Porsolt's forced swim test, a well established animal model that is used to identify drugs with an antidepressant effect. The overall locomotor activity of the receptor-deficient animals was not altered, demonstrating the specificity of the behavioral change in the Porsolt's forced swim test. Reduced immobility in this test was accompanied by a greater c-Fos response in piriform cortex. Because 5-HT2A receptors have been localized on gamma-aminobutyric acid interneurons, the inhibitory activity of these neurons may be impaired at low receptor levels, leading to a greater c-Fos response in the piriform cortex and increased mobility in the Porsolt's forced swim test. These experiments demonstrate that down-regulation of the 5-HT2A receptor alone is sufficient to achieve an antidepressant-like effect in mice and suggest that receptor down-regulation may be an essential part of the antidepressant drug action.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology*
  • Behavior, Animal / drug effects
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / physiology
  • Cerebral Cortex / ultrastructure
  • Disease Models, Animal
  • Down-Regulation / drug effects
  • Gene Expression Regulation / drug effects
  • Genes, fos / drug effects
  • Injections, Intraventricular
  • Mice
  • Mice, Inbred BALB C
  • Mood Disorders / drug therapy
  • Mood Disorders / etiology
  • Oligonucleotides, Antisense / pharmacology*
  • Receptor, Serotonin, 5-HT2A
  • Receptors, Serotonin / drug effects*
  • Receptors, Serotonin / metabolism*
  • Receptors, Serotonin / physiology
  • Serotonin Antagonists / pharmacology*
  • Swimming

Substances

  • Antidepressive Agents
  • Oligonucleotides, Antisense
  • Receptor, Serotonin, 5-HT2A
  • Receptors, Serotonin
  • Serotonin Antagonists