The role of GABA_B receptors in depression and antidepressant-related behavioural responses

There is a growing body of clinical evidence that supports a role for a dysfunction of the GABAergic system in mood disorders. Although it is more than 20 years since GABA_B receptors were first postulated to play a role in major depression, the initial lack of selective tools hindered further research efforts. In the intervening years, a number of new ligands, including specific GABA_B receptor antagonists and positive modulators, as well as genetic tools, GABA_B(1) and GABA_B(2) receptor knockout mice, have enabled the study of the role of the GABA_B receptor in depression and as possible antidepressants. Although initial clinical studies gave rise to the hypothesis that activation of GABA_B receptors may induce antidepressant-like effects, growing evidence suggests that it is in fact GABA_B receptor antagonists that have antidepressant-like potential. This supposition has been reinforced by studies in preclinical models. GABA _B receptor antagonists decrease immobility in the forced swim test, in both mice and rats, and also display antidepressant-like effects in the learned helplessness and chronic mild stress models of depression. While GABA_B receptor knockout mice have not been studied to the same extent behaviourally as pharmacological tools, evidence accumulated so far suggests that deletion of either GABA_B(1) or GABA_B(2) subunits results in antidepressant-like effects; thus recapitulating data from pharmacological studies. GABA_B receptor antagonists have also been shown to increase 5-HT and dopamine neurotransmission, as well as BDNF levels in numerous brain regions. These systems are all implicated in antidepressant actions and may provide indirect mechanisms by which these compounds display their behavioural effects. Together, accumulating evidence suggests an important role of GABA_B receptors in behaviours relevant to depression and that GABA_B receptor antagonists may provide clinical benefit in the treatment of depression.