Modulation of α5 Subunit‐Containing GABA_A Receptors Alters Alcohol Drinking by Rhesus Monkeys

Abstract

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. Additionally, following daily self-administration sessions, the behavior of each monkey was scored for both species-typical and drug-induced behaviors. Results Concentrations of 1–6% alcohol maintained self-administration above water levels, engendered pharmacologically-relevant blood alcohol levels ranging from 90–160 mg/dl, and produced changes in behavior typical of alcohol intoxication. Concentrations of 0.3–3% 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.

Little Evidence of a Role for the α1GABAA Subunit‐Containing Receptor in a Rhesus Monkey Model of Alcohol Drinking

“…One study in nonhuman primates also reported reductions in alcohol drinking following 3-PBC administration, but at higher doses (18 mg/kg) than the doses used in the present study (Kaminski et al, 2012). We chose not to test higher doses due to the emergence of behavioral effects on the observation measures, which indicated the doses were behaviorally active and possibly anxiogenic (Major et al, 2009, Ruedi-Bettschen et al, 2013), but likely not sedative. This study also reported a significant reduction in number of alcohol drinks in the initial 20 minutes of each daily session, corroborating our observation of increased latency to sipper extension (3-PBC: 9 vs 86 sec; βCCT: 4 vs 187 sec).…”

“…Although nonselective negative modulation (i.e., inverse agonism) of the GABA A receptor was able to alter drinking behavior, these drugs are often hampered by the emergence of side effects. Notably, inverse agonist modulation at the α5GABA A receptor has been shown to selectively reduce alcohol drinking in the absence of severe side effects while a neutral α5GABA A -selective antagonism did not (Ruedi-Bettschen et al, 2013). …”

“…The behavior of each monkey was recorded for 5 min each day immediately following the conclusion of the day’s self-administration session, using a focal animal approach as described in Platt et al, (2000, 2002) and modified for the rhesus monkey (see Ruedi-Bettschen et al, 2013; Table 1). Briefly, a trained observer blind to the drug treatments watched a specific monkey for 5 minutes and recorded each instance that a particular behavior (as defined in Ruedi-Bettschen et al, 2013; Table 1) occurred during 15-second intervals.…”

“…Briefly, a trained observer blind to the drug treatments watched a specific monkey for 5 minutes and recorded each instance that a particular behavior (as defined in Ruedi-Bettschen et al, 2013; Table 1) occurred during 15-second intervals. Scores for each behavior were calculated as the number of 15-second bins in which the behavior occurred (e.g.…”

“…The α-subunit subtypes in particular may contribute differentially to the diverse behavioral and abuse-related effects of alcohol (Boehm et al, 2004), which raises the possibility for development of targeted therapeutic compounds to treat alcohol dependence. For example, we have demonstrated recently a critical role for α5GABA A subunit-containing receptors in alcohol drinking in monkeys (Ruedi-Bettschen et al, 2013); however, the role of the other α-subunit containing receptors remains to be explored in this model.…”