Genetic and pharmacological evidence of a role for GABA_B receptors in the modulation of anxiety- and antidepressant-like behavior

Although there is much evidence for a role of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) in the pathophysiology of anxiety and depression, the role of GABA_B receptors in behavioral processes related to these disorders has not yet been fully established. GABA_B receptors are G-protein-coupled receptors, which act as functional heterodimers made up of GABA_B(1) and GABA_B(2) subunits. Using recently generated GABA_B(1)^-/- mice, which lack functional GABA_B receptors, and pharmacological tools we assessed the role of GABA_B receptors in anxiety- and antidepressant-related behaviors. In the light-dark box, GABA _B(1)^-/- mice were more anxious than their wild-type littermates (less time spent in the light; reduced number of transitions). GABA_B(1)^-/- mice were also more anxious in the staircase test. Conversely, acute and chronic treatment with GS39783, a novel GABA _B receptor positive modulator, decreased anxiety in the light-dark box and elevated zero maze tests for anxiety. On the other hand, GABA _B(1)^-/- mice had decreased immobility (antidepressant-like behavior) in the forced swim test (FST). These behavioral effects are unrelated to alterations in locomotor activity. In confirmation of the genetic data, acute and chronic treatment with CGP56433A, a selective GABA_B receptor antagonist, also decreased immobility in the FST, whereas GS39783 did not alter this behavior. Taken together, these data suggest that positive modulation of the GABA_B receptor may serve as a novel therapeutic strategy for the development of anxiolytics, whereas GABA_B receptor antagonism may serve as a basis for the generation of novel antidepressants.