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

Treatment with different antidepressants is invariably accom-panied by the down-regulation of the 5-hydroxytryptamine2A (5-HT2A) receptor. To determine whether receptor down-regu-lation is an essential part of antidepressant action, we manip-ulated levels of the 5-HT2A receptor by using a nonpharmaco-logical approach. Here, we report that down-regulation of the 5-HT2A receptor by intracerebroventricular injection of anti-sense 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 antidepres-sant effect. The overall locomotor activity of the receptor-defi-cient animals was not altered, demonstrating the specificity of the behavioral change in the Porsolt’s forced swim test. Re-duced immobility in this test was accompanied by a greate