GABA_B receptor antagonist-mediated antidepressant-like behavior is serotonin-dependent

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 GABA_B 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 GABA_B receptors in antidepressant-related behavior, we examined a number of selective GABA_B receptor ligands (novel positive modulators and antagonists) on behavior in the modified forced swim test. We demonstrate that the selective GABA_B 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 re-uptake inhibitor fluoxetine; they decreased immobility and increased swimming behavior. The tricyclic antidepressant desipramine decreased immobility but increased climbing behavior. In contrast, the novel GABA_B 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 GABA_B receptor antagonism and serotonin, rats were pretreated with the tryptophan hydroxylase inhibitor parachlorophenylalanine. 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 GABA_B receptor antagonists via an interaction with the serotonergic system display antidepressant-like properties and therefore represent a novel approach for the treatment of depression.