Role of GABAA α5-containing receptors in ethanol reward: The effects of targeted gene deletion, and a selective inverse agonist

An inverse agonist selective for α5 subunit-containing GABAA receptors improves encoding and recall but not consolidation in the Morris water maze

“…It occupies the benzodiazepine site of rat brain GABA A receptors well and with a potency (occupancy 0.5 h after 1 mg/kg dose of 76%; Fig. 3) that is comparable to that seen in mice (90%; Stephens et al 2005).…”

“…This was achieved by administering an α5-selective inverse agonist, α5IA-II-a compound structurally related to α5IA Street et al 2004;Stephens et al 2005;Dawson et al 2006), before trial 1 (to modulate the encoding phase), after trial 1 (to modulate the consolidation phase) or, after a delay, before trial 2, which occurs 4 h after trial 1 (to modulate the recall phase). To limit the action of α5IA-II to the desired phase of memory processing, the prototypic benzodiazepine site antagonist flumazenil was used to block the action of α5IA-II.…”

Assessing appetitive and consummatory phases of ethanol self-administration in C57BL/6J mice under operant conditions: regulation by mGlu5 receptor antagonism

“…Whereas this technique is amenable to pharmacological manipulation, a disparity between levels of responding and actual levels of consumption was observed (when examined; Middaugh et al 2000a,b). More frequently, consumption of ethanol is examined separately using a two-bottle preference test (measurement of volumes consumed of ethanol solution vs water; Rhodes et al 2005;Roberts et al 2000Roberts et al , 2001Ryabinin et al 2003;Stephens et al 2005). This method, however, does not allow analysis of the pattern of consumption (without the use of lickometer or similar equipment) and the latency to ethanol-seeking behavior cannot be examined; therefore, there is some room for refinement in these models.…”

Alcohol use disorders and current pharmacological therapies: the role of GABAA receptors

“…Mutations to the GABA A R β1 subunit gene (GABRB1) increased alcohol consumption accompanied by spontaneous GABA A R ion channel opening and increased NAcc tonic (extrasynaptic) current, providing an important link between GABA A R function and increased alcohol consumption that may underlie some forms of alcohol abuse [52] . The GABA A R α5 subunit knockout mice showed reduced EtOH preference [31,82,83] . Additionally, GABA A R δ-deficient mice have reduced EtOH preference [82] .…”