Abstract

Treatment with different antidepressants is invariably accompanied by the down-regulation of the 5-hydroxytryptamine_2A(5-HT_2A) receptor. To determine whether receptor down-regulation is an essential part of antidepressant action, we manipulated levels of the 5-HT_2A receptor by using a nonpharmacological approach. Here, we report that down-regulation of the 5-HT_2A receptor by intracerebroventricular injection of antisense oligonucleotides resulted in an antidepressant-like effect in mice. Animals with 5-HT_2A 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-HT_2A receptors have been localized on γ-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-HT_2Areceptor 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.