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Modulation of α5 Subunit‐Containing GABA A Receptors Alters Alcohol Drinking by Rhesus Monkeys
Author(s) -
RüediBettschen Daniela,
Rowlett James K.,
Rallapalli Sundari,
Clayton Terry,
Cook James M.,
Platt Donna M.
Publication year - 2013
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.12018
Subject(s) - alcohol , receptor , agonist , inverse agonist , pharmacology , self administration , ethanol , gabaa receptor , chemistry , antagonist , gamma aminobutyric acid , sucrose , medicine , endocrinology , biochemistry , biology
Background Alcohol's ability to potentiate the activity of γ‐aminobutyric acid ( GABA ) at GABA A receptors has been implicated as a key mechanism underlying the behavioral effects of alcohol. The complex molecular biology of these receptors raises the possibility that particular receptor subtypes may play unique roles in alcohol's abuse‐related effects and that subtype‐selective ligands with therapeutic specificity against alcohol might be developed. This study evaluated the capacity of α5 GABA A receptor ligands to alter selectively the reinforcing effects of alcohol. Methods Two groups of rhesus monkeys were trained to orally self‐administer alcohol or sucrose under fixed‐ratio schedules and limited daily access conditions. In addition, following daily self‐administration sessions, the behavior of each monkey was scored for both species‐typical and drug‐induced behaviors. Results Concentrations of 1 to 6% alcohol maintained self‐administration above water levels, engendered pharmacologically relevant blood alcohol levels ranging from 90 to 160 mg/dl, and produced changes in behavior typical of alcohol intoxication. Concentrations of 0.3 to 3% sucrose also reliably maintained self‐administration. The α5 GABA A receptor agonist QH ‐ii‐066 enhanced and the α5 GABA A receptor inverse agonist L ‐655,708 inhibited alcohol, but not sucrose drinking. The changes in alcohol drinking could be reversed with the α5 GABA A receptor antagonist XL i‐093. However, L ‐655,708 increased yawning in both alcohol and sucrose drinkers, possibly indicative of an anxiogenic effect. Conclusions These findings suggest a prominent and specific role for α5 GABA A receptor mechanisms in the reinforcing effects of alcohol. Moreover, these results suggest that α5 GABA A receptors may represent a novel pharmacological target for the development of medications to reduce drinking. Of ligands modulating this receptor, α5 GABA A receptor inverse agonists may hold the most promise as alcohol pharmacotherapies.