Role of GABAA alpha 5-containing receptors in ethanol reward: The effects of targeted gene deletion, and a selective inverse agonist
| Authors | |
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| Year of publication | 2005 |
| Type | Article in Periodical |
| Magazine / Source | European Journal of Pharmacology |
| MU Faculty or unit | |
| Citation | |
| Field | Pharmacology and pharmaceutical chemistry |
| Keywords | ethanol; reward; GABA; self-administration; Ro 15-4513 |
| Description | GABAA receptors containing ŚÁ5 subunits have been suggested to mediate the rewarding effects of ethanol. We tested this hypothesis in mice with deletion of alpha5 subunits. Alpha5 knockout mice did not differ from wildtypes in operant responding for 10% ethanol/10% sucrose, but responded less for 10% sucrose. The benzodiazepine (BZ) site inverse agonist, Ro 15-4513, has higher affinity for GABAA receptors containing 5 subunits and dose-dependently (0,27 mg/kg, i.p.) reduced lever pressing for ethanol/sucrose in wildtype mice, but had less effect in knockout mice; lever pressing for sucrose was unaffected. These data suggest that alpha5 subunits are not essential for ethanol reward, but the reduction of operant responding for ethanol by Ro 15-4513 is mediated by alpha5-containing GABAA receptors. In measures of ethanol consumption, alpha5 knockout mice did not differ from wildtypes at low ethanol concentrations (2-8%), but consumed less ethanol at higher concentrations; these differences were not attributable to increased behavioural disruption of the knockout by ethanol, since no differences were seen in sensitivity to ethanol's sedative or ataxic effects. Ro 15-4513's ability to reduce ethanol consumption was unaffected, suggesting that this effect is not mediated by the alpha5 subtype. Secondly, we tested the ability of a novel alpha5-efficacy-selective benzodiazepine receptor ligand, ŚÁ5IA-II, that possesses greater inverse agonist activity at alph5- than at alpha1-, 2- or alpha3-containing GABAA receptors, to influence operant responding. ŚÁ5IA-II (0.03-3 mg/kg) dose-dependently decreased lever pressing for 10% ethanol, the minimally effective dose of 1 mg/kg, corresponding to over 90% receptor occupancy, but did not affect lever pressing for 4% sucrose. Although inverse agonists acting at alpha5-containing receptors reduce ethanol self-administration, alpha5 subunits may not be essential to signaling ethanol reward. |
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