A Comparison of Positive and Negative Allosteric Modulators of α5-Containing GABAA Receptors in the Treatment of Affective Disease.

Major depressive disorder (MDD) is a common psychiatric disease that significantly impairs quality of life and productivity. Standard monoamine-based therapies are marred by poor efficacy. Disruptions in the balance of glutamate- and GABA (gamma-aminobutyric acid)-mediated neurotransmission in regions associated with reward, emotion, and cognitive processing likely underpin the neurobiology of depression. Subunit-preferring compounds may positively (GABA-positive allosteric modulators [PAMs]) or negatively (GABA-negative allosteric modulators [NAMs]) modulate the ability of GABA to activate inhibitory GABAA receptors containing α5 subunits, predominantly expressed in these corticolimbic structures. Despite opposing mechanistic actions, both classes of compounds have recently demonstrated promise in preclinical models of depression-like symptoms. This review therefore aims to bridge the gap by summarizing the current preclinical literature of α5-preferring GABA-PAMs and GABA-NAMs in models of affective disease. As MDD is a uniquely human disorder with diverse symptoms, effects in individual rodent behavioral models are further classified into discrete categories of reward behavior, despair-like behavior, anxiety-like behavior, and cognitive behavior. From the literature, we identified a clear trend: α5-preferring GABA-PAMs have greatest preclinical efficacy in anxiolytic behavioral paradigms and generally reduce despair-like behavior. In contrast, α5-preferring GABA-NAMs dramatically reverse reward-seeking behavioral deficits following chronic stress, thus effectively relieving anhedonia-a primary symptom of MDD. However, while α5-preferring GABA-NAMs demonstrate anti-despair-like actions, they are largely not anxiolytic. Both classes demonstrate nootropic effects; however, α5-preferring GABA-PAMs have shown additional efficacy in preclinical models characterized by GABAergic hypofunction. Modulating α5-mediated GABAergic transmission has broad potential to treat psychiatric illness, and compounds that demonstrate efficacy across diverse preclinical behavioral domains represent promising translational candidates.