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Neuroscience and Psychiatry |

Diversity of Neuronal Inhibition A Path to Novel Treatments for Neuropsychiatric Disorders

Rebecca S. Benham, PhD1,2; Elif Engin, PhD1,2; Uwe Rudolph, MD1,2
[+] Author Affiliations
1Laboratory of Genetic Neuropharmacology, McLean Hospital, Belmont, Massachusetts
2Department of Psychiatry, Harvard Medical School, Boston, Massachusetts
JAMA Psychiatry. 2014;71(1):91-93. doi:10.1001/jamapsychiatry.2013.3059.
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Benzodiazepines have been used for more than half a century for their anxiolytic, hypnotic, anticonvulsant, and muscle relaxant properties. Benzodiazepines act as positive allosteric modulators of the γ-aminobutyric acid (GABA) type A receptor (GABAAR), amplifying inhibitory neurotransmission. While benzodiazepines provide rapid and effective symptom relief, their use has declined over the years owing to their unfavorable adverse effect profile (eg, sedation when used for daytime anxiolysis, falls related to muscle relaxation and ataxia, development of tolerance, and sometimes dependence after long-term use). While clinically used benzodiazepines modulate several GABAAR subtypes nonselectively, research during the last 25 years has helped to identify and functionally characterize individual GABAAR subunits and subtypes. In this Viewpoint, we provide a synopsis of the research on the role of GABAARs in neuropsychiatric disorders and their treatment, with consideration of targeting individual GABAAR subtypes to achieve selective pharmacological profiles. Owing to space constraints, we mostly cited reviews that identify the underlying original works.

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γ-Aminobutyric Acid Type A Receptors (GABAARs): Composition, Expression, and Contribution to Neuropsychiatric Disorders

A, GABAARs are defined by the assembly of 5 subunits, creating a pore through which Cl ions flow down their concentration gradient to mediate fast synaptic inhibition. The most common subunit assembly is depicted here with 2α, 2β, and 1γ subunits. The receptor is also defined by the presence of GABA and benzodiazepine binding sites, which are formed by α and β or α and γ subunits, respectively. B, The 4 α subunits that bind classic benzodiazepines (α1, α2, α3, and α5) have distinct expression patterns within the brain. C, A simplified summary table indicating potential roles of α subunits in neuropsychiatric disorders or their treatment. The table highlights α subunits based on converging evidence from genetically modified mice and selective compounds. However, many cells in the table have not yet been explored completely. BZ indicates benzodiazepine. Part A reprinted with permission from MacMillan Publishers Ltd (Nat Rev Neurosci. 2008;9[5]:331-343). Part B reprinted with permission from the American Society for Pharmacology and Experimental Therapeutics (J Pharmacol Exp Ther. 2002;300[1]:2-8).

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