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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on August 27, 2004; DOI: 10.1124/jpet.104.073536

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Received for publication July 1, 2004.
Revised August 24, 2004.
Accepted for publication August 26, 2004.

GABAB RECEPTOR ANTAGONIST-MEDIATED ANTIDEPRESSANT-LIKE BEHAVIOR IS SEROTONIN DEPENDENT

David A Slattery 1, Sandrine Desrayaud 1, John F. Cryan 1*

1 Novartis Institutes for BioMedical Research

* Address correspondence to: E-mail: john_f.cryan{at}pharma.novartis.com

Abstract

There is an emerging body of data purporting a role of gamma-aminobutyric acid (GABA) in the pathophysiology of mood disorders. However the role of metabotropic GABAB receptors in depression is not well defined. The modified forced swim test has recently emerged as an excellent tool to assess behaviorally the role of monoamines in antidepressant action. To assess the role of GABAB receptors in antidepressant-related behavior we examined a number of selective GABAB receptor ligands (novel positive modulators and antagonists) on behavior in the modified forced swim test. We demonstrate that the selective GABAB receptor antagonists (CGP56433A [1 - 10 mg/kg] and CGP55845A [3 - 10 mg/kg]) had a similar profile to the selective serotonin reuptake inhibitor fluoxetine; they decreased immobility and increased swimming behavior. The tricyclic antidepressant desipramine decreased immobility but increased climbing behavior. In contrast, the novel GABAB receptor positive modulator GS39783 (10 - 40 mg/kg) did not display antidepressant-like activity in the modified forced swim test. In order to further assess the possible interaction between GABAB receptor antagonism and serotonin, rats were pre-treated with the tryptophan hydroxylase inhibitor para-chlorophenylalanine (pCPA). 5-HT depletion (> 90 %) abolished the antidepressant-like behavior of CGP56433A (10 mg/kg) by attenuating the increase in swimming. Take together, these data demonstrate that GABAB receptor antagonists via an interaction with the serotonergic system display antidepressant-like properties and therefore represent a novel approach for the treatment of depression.


Key words: Forced swim test, GABAB, animal model, antidepressant, depression, serotonin


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