deletion of the gabra2 gene results in hypersensitivity to the acute effects of ethanol but does not alter ethanol self administrationgabra2基因的缺失导致超敏反应的急性影响乙醇但不改变自我管理.pdfVIP

Deletion of the gabra2 Gene Results in Hypersensitivity to the Acute Effects of Ethanol but Does Not Alter Ethanol Self Administration Claire I. Dixon, Sophie E. Walker, Sarah L. King, David N. Stephens* School of Psychology, University of Sussex, Brighton, United Kingdom Abstract Human genetic studies have suggested that polymorphisms of the GABRA2 gene encoding the GABAA a2-subunit are associated with ethanol dependence. Variations in this gene also convey sensitivity to the subjective effects of ethanol, indicating a role in mediating ethanol-related behaviours. We therefore investigated the consequences of deleting the a2- subunit on the ataxic and rewarding properties of ethanol in mice. Ataxic and sedative effects of ethanol were explored in GABAA a2-subunit wildtype (WT) and knockout (KO) mice using a Rotarod apparatus, wire hang and the duration of loss of righting reflex. Following training, KO mice showed shorter latencies to fall than WT littermates under ethanol (2 g/kg i.p.) in both Rotarod and wire hang tests. After administration of ethanol (3.5 g/kg i.p.), KO mice took longer to regain the righting reflex than WT mice. To ensure the acute effects are not due to the gabra2 deletion affecting pharmacokinetics, blood ethanol concentrations were measured at 20 minute intervals after acute administration (2 g/kg i.p.), and did not differ between genotypes. To investigate ethanol’s rewarding properties, WT and KO mice were trained to lever press to receive increasing concentrations of ethanol on an FR4 schedule of reinforcement. Both WT and KO mice self-administered ethanol at similar rates, with no differences in the numbers of reinforcers earned. These data indicate a protective role for a2- subunits, against the acute sedative and ataxic effects of