An Emerging Circuit Pharmacology of GABAA Receptors

In the past 20 years we have learned a great deal about GABAA receptor (GABAAR) subtypes, and which behaviors are regulated or which drug effects are mediated by each subtype. However, the question of where GABAARs involved in specific drug effects and behaviors are located in the brain remains larg...

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Bibliographic Details
Published in:Trends in pharmacological sciences (Regular ed.) 2018-08, Vol.39 (8), p.710-732
Main Authors: Engin, Elif, Benham, Rebecca S., Rudolph, Uwe
Format: Article
Language:English
Subjects:
addiction
anxiety
depression
GABAA receptor
hippocampus
memory
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Summary:In the past 20 years we have learned a great deal about GABAA receptor (GABAAR) subtypes, and which behaviors are regulated or which drug effects are mediated by each subtype. However, the question of where GABAARs involved in specific drug effects and behaviors are located in the brain remains largely unanswered. We review here recent studies taking a circuit pharmacology approach to investigate the functions of GABAAR subtypes in specific brain circuits controlling fear, anxiety, learning, memory, reward, addiction, and stress-related behaviors. The findings of these studies highlight the complexity of brain inhibitory systems and the importance of taking a subtype-, circuit-, and neuronal population-specific approach to develop future therapeutic strategies using cell type-specific drug delivery. Both receptor subtype and circuit location determine the physiological and pharmacological functions of GABAA receptor (GABAAR) subtypes. α2 GABAARs in distinct hippocampal microcircuits are required for the anxiety-reducing and the fear-reducing actions of systemically administered diazepam. α5 GABAARs in PCKδ+ neurons of the central amygdala have been linked to modulation of anxiety. α5 GABAARs in dentate gyrus granule cells are required for learning and memory tasks involving memory interference. Positive allosteric modulators of α5 might be useful to attenuate interference-related cognitive symptoms and hippocampal hyperactivity in some psychiatric disorders. In the mesolimbic dopamine system, both α1 GABAARs in GABAergic ventral tegmental area interneurons and α2 GABAARs in medium spiny neurons in the nucleus accumbens are required for full reinforcing effects of benzodiazepines.
ISSN:0165-6147
1873-3735
DOI:10.1016/j.tips.2018.04.003