Emotional regulation: Modeling GABA A receptor subtype specific agents in mice

Mclean Hospital, Belmont MA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): GABAA receptors are the target of clinically used benzodiazepines, which modulate multiple GABAA receptor subtypes non-selectively. While some progress has been made in identifying differential functions of GABAA receptor subtypes based on loss of function approaches which opens up the possibility to design novel treatments for CNS diseases such as anxiety disorders and depression, until now truly subtype-specific compounds are not available, thus limiting the information that is available on the function of individual GABAA receptor subtypes. Here we propose to use a novel combined genetic and pharmacological approach to create a model system (triple point-mutated mice + the non-selective drug diazepam) in which diazepam is a true ?1-specific, ?2-specific, ?3-specific, or ?5-specific full agonist, respectively, enabling the highly selective modulation of the activity of specific GABAA receptor subtypes in order to define the physiological and pharmacological functions of these receptor subtypes, in particular in the regulation of anxiety- and depression-related behaviors.