A GABA Pathway to Faster Acting Antidepressants

Mclean Hospital, Belmont MA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): There is converging preclinical and clinical evidence that GABAergic deficits are an important factor in major depressive disorders (MDD). However, the neuronal circuits in which these deficits exist and the individual GABAA receptor subtypes that modulate depressive-like behavior are unknown. By analyzing the response to chronic social defeat stress, a rodent model of depression with construct, face, and predictive validity, we propose to study how ?2- and ?3-containing GABAA receptors in defined neuronal circuits play a role in the behavioral transition from a normal state to a down (i.e. depressed) state and vice versa. Using a novel genetic-pharmacological approach we will further assess whether a highly ?2- specific [or ?3-specific] agonist administered during social defeat can prevent [or promote] the transition from the normal state to the down state. We will also assess whether such an agonist can acutely promote [or prevent] the transition from the depressed state back to the normal state when administered after cessation of chronic social defeat. The proposed studies are expected to demonstrate that ?2-specific agonism generates an acute antidepressant-like effect and will provide proof-of-concept for the development of a novel class of antidepressant agents.