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Research ArticleArticle

Antisense Inhibition of 5-Hydroxytryptamine2aReceptor Induces an Antidepressant-Like Effect in Mice

Etienne Sibille, Zoltan Sarnyai, Daniel Benjamin, Judit Gal, Harriet Baker and Miklos Toth
Molecular Pharmacology December 1997, 52 (6) 1056-1063; DOI: https://doi.org/10.1124/mol.52.6.1056
Etienne Sibille
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Zoltan Sarnyai
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Daniel Benjamin
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Judit Gal
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Harriet Baker
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Miklos Toth
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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 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-HT2Areceptor 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.

Footnotes

    • Received May 27, 1997.
    • Accepted September 6, 1997.
  • Send reprint requests to: Dr. Miklos Toth, Department of Pharmacology, LC 519, Cornell University Medical College, 1300 York Avenue, New York, NY 10021. E-mail:mtoth{at}mail.med.cornell.edu

  • This work was supported by a grant from the National Alliance for Research on Schizophrenia and Depression.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 52 (6)
Molecular Pharmacology
Vol. 52, Issue 6
1 Dec 1997
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Research ArticleArticle

Antisense Inhibition of 5-Hydroxytryptamine2aReceptor Induces an Antidepressant-Like Effect in Mice

Etienne Sibille, Zoltan Sarnyai, Daniel Benjamin, Judit Gal, Harriet Baker and Miklos Toth
Molecular Pharmacology December 1, 1997, 52 (6) 1056-1063; DOI: https://doi.org/10.1124/mol.52.6.1056

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Research ArticleArticle

Antisense Inhibition of 5-Hydroxytryptamine2aReceptor Induces an Antidepressant-Like Effect in Mice

Etienne Sibille, Zoltan Sarnyai, Daniel Benjamin, Judit Gal, Harriet Baker and Miklos Toth
Molecular Pharmacology December 1, 1997, 52 (6) 1056-1063; DOI: https://doi.org/10.1124/mol.52.6.1056
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