Antisense inhibition of 5-hydroxytryptamine2a receptor induces an antidepressant-like effect in mice.
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.
Sibille
E
E
Department of Pharmacology, Cornell University Medical College, New York, New York 10021, USA.
Sarnyai
Z
Z
Benjamin
D
D
Gal
J
J
Baker
H
H
Toth
M
M
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects; D007276:Injections, Intraventricular; D051379:Mice; D008807:Mice, Inbred BALB C; D019964:Mood Disorders / Q000188:drug therapy / Q000209:etiology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013550:Swimming
D000928:Antidepressive Agents; D016376:Oligonucleotides, Antisense; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists