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.

Public Health Relevance

GABAA receptors are the target structures of clinically used benzodiazepines;however, we have only an incomplete knowledge of the function of individual GABAA receptors subtypes, in large part due to the lack of fully subtype-specific compounds. We are proposing a novel genetic and pharmacological approach to assess the anxiety-reducing and antidepressant-like properties of specific GABAA receptor subtypes. The proposed experiments are expected to clarify the potential role of specific GABAA receptor subtypes as targets for the development of novel antidepressant drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Small Research Grants (R03)
Project #
5R03MH094834-02
Application #
8409823
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Winsky, Lois M
Project Start
2012-01-06
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2014-12-31
Support Year
2
Fiscal Year
2013
Total Cost
$75,840
Indirect Cost
$27,840
Name
Mclean Hospital
Department
Type
DUNS #
046514535
City
Belmont
State
MA
Country
United States
Zip Code
02478
Benham, Rebecca S; Engin, Elif; Rudolph, Uwe (2014) Diversity of neuronal inhibition: a path to novel treatments for neuropsychiatric disorders. JAMA Psychiatry 71:91-3
Rudolph, Uwe; Mohler, Hanns (2014) GABAA receptor subtypes: Therapeutic potential in Down syndrome, affective disorders, schizophrenia, and autism. Annu Rev Pharmacol Toxicol 54:483-507