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Mol Pharmacol. 1997 Dec;52(6):1056-63.

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

Author information

1
Department of Pharmacology, Cornell University Medical College, New York, New York 10021, USA.

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.

PMID:
9415715
DOI:
10.1124/mol.52.6.1056
[Indexed for MEDLINE]

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