Antidepressant-like and reward-related functions of a2-containing GABAA receptors

Mclean Hospital, Belmont MA

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Abstract

DESCRIPTION (provided by applicant): This is an application for funding of a study examining the role of a2-containing GABAA receptors animal models of depression. It has been shown previously that mice which display reduced GABAergic inhibition (32 mice) display a phenotype reminiscent of depression. It is not known which GABAA receptor subtypes mediate antidepressant-like actions, while we have recently obtained preliminary data suggesting that 13-containing GABAA receptors mediate prodepressant-like actions. Whereas dopaminergic neurons in the ventral tegemental area express primarily a3-containing GABAA receptors, the GABAergic neurons in the nucleus accumbens primarily express a2-containing GABAA receptors. Using mice lacking the a2 subunit, we want to test the hypothesis that a2-containing GABAA receptors mediate an antidepressant-like action in the despair-based forced swim test, the conflict-based novelty-suppressed feeding test and the reward-based intracranial self-stimulation paradigm. The identification of the GABAA receptor subtype responsible for antidepressant-like effects would represent an important advance for understanding mood regulation and would provide a new avenue for the development of novel antidepressant agents. Depression and related mood disorders are among the greatest public health problems;severe forms of depression affect 2-5% of the U.S. population, and up to 20% of the population suffer from milder forms of the illness. Symptoms of depression include a reduced ability to experience reward (anhedonia), dysphoria, anxiety and despair, and a substantial number of patients do not respond satisfactorily to current treatment options. Identification of the a2-containing GABAA receptor as having antidepressant and in particular reward-enhancing functions would identify this receptor subtype as a target for the development of antidepressants with a novel mechanism of action.