GABAB Receptor Antagonist-Mediated Antidepressant-Like Behavior Is Serotonin-Dependent

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Abstract
There is an emerging body of data purporting a role of γ-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 [[3-{1-(S)-[{3-cyclohexylmethyl)hydroxy phosphinyl}-2-(S) hydroxy propyl]amino}ethyl]benzoic acid; 1-10 mg/kg] and [3-[[1-(S)-3-dichlorophenyl)ethyl]amino]-2-(S)-hydroxy-propyl]phenylmethyl-phosphinic acid hydrochloride; 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. To further assess the possible interaction between GABAB receptor antagonism and serotonin, rats were pretreated with the tryptophan hydroxylase inhibitor para-chlorophenylalanine. 5-Hydroxytryptamine depletion (>90%) abolished the antidepressant-like behavior of CGP56433A (10 mg/kg) by attenuating the increase in swimming. 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.