Background: Alcohol's ability to potentiate the activity of γ-aminobutyric acid (GABA) at GABAA 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 α5GABAA 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 α5GABAA receptor agonist QH-ii-066 enhanced and the α5GABAA receptor inverse agonist L-655,708 inhibited alcohol, but not sucrose drinking. The changes in alcohol drinking could be reversed with the α5GABAA receptor antagonist XLi-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 α5GABAA receptor mechanisms in the reinforcing effects of alcohol. Moreover, these results suggest that α5GABAA receptors may represent a novel pharmacological target for the development of medications to reduce drinking. Of ligands modulating this receptor, α5GABAA receptor inverse agonists may hold the most promise as alcohol pharmacotherapies.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951841 | PMC |
| http://dx.doi.org/10.1111/acer.12018 | DOI Listing |
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