Vol. 52, Issue 6, 1056-1063, 1997

Antisense Inhibition of 5-Hydroxytryptamine_2a Receptor Induces an Antidepressant-Like Effect in Mice

Etienne Sibille, Zoltan Sarnyai, Daniel Benjamin, Judit Gal, Harriet Baker, and Miklos Toth

Department of Pharmacology, Cornell University Medical College, New York, New York 10021 (E.S., J.G., M.T.), Laboratories of Neuroendocrinology and Biology of Addictive Diseases, Rockefeller University, New York, New York 10021 (Z.S.), Division of Neuropharmacology, Center of Alcohol Studies, Rutgers University, Piscataway, New Jersey 08855 (D.B.), and Cornell University Medical College, Burke Medical Research Institute, White Plains, New York 10605 (J.G., H.B.)

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 -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_2A 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.