Antisense inhibition of 5-hydroxytryptamine2a receptor induces an antidepressant-like effect in mice. Academic Article uri icon

Overview

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 date

  • December 1, 1997

Research

keywords

  • Antidepressive Agents
  • Oligonucleotides, Antisense
  • Receptors, Serotonin
  • Serotonin Antagonists

Identity

Scopus Document Identifier

  • 0031451187

Digital Object Identifier (DOI)

  • 10.1124/mol.52.6.1056

PubMed ID

  • 9415715

Additional Document Info

volume

  • 52

issue

  • 6