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

Abstract

There is an emerging body of data purporting a role of ␥-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 receptorphenylmethyl-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 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 (Ͼ90%) 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.

Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve

“…This difference is consistent with behavioral and neuroendocrine responses seen. In the other analyzed areas (amygdala, hippocampus, and LC), L. rhamnosus (JB-1) administration reduced the expression of GABA B1b mRNA, which is consistent with the antidepressant-like effect of GABA B receptor antagonists (31). L. rhamnosus (JB-1)-fed animals showed an enhanced memory to an aversive cue and context in comparison with broth-fed mice-an observation that implies changes at the level of the amygdala and hippocampus (24).…”

Social Fear Conditioning: A Novel and Specific Animal Model to Study Social Anxiety Disorder

“…One day after SFC, we performed the EPM and the forced swim test (FST) to assess general anxiety-related and depressive-like behavior, respectively (Lister, 1987;Pellow et al, 1985;Slattery et al, 2005). Further, we assessed home cage locomotor activity as described previously (Reber et al, 2007;Slattery et al, 2011; for experimental details see Supplementary Methods).…”

The GABAB Receptor-Positive Modulator GS39783 and the GABAB Receptor Agonist Baclofen Attenuate the Reward-Facilitating Effects of Cocaine: Intracranial Self-Stimulation Studies in the Rat

“…Doses of baclofen were selected based on previous studies showing baclofen reduced selfadministration of cocaine in this dose range. GS39783 has been extensively characterized behaviorally in our laboratories Mombereau et al, 2004;Slattery et al, 2005) and the dose range selected was equal and above that which was behaviorally active in anxiety (0.1-30 mg/kg) and self-administration (3-30 mg/kg) models (Smith et al, 2004). Both GS39783 and baclofen were synthesized by Novartis Pharma AG (Basel).…”