GABA_A Receptor α1 and β2 Subunit Null Mutant Mice: Behavioral Responses to Ethanol

Abstract

Mice lacking either the ␣1 or ␤2 subunit of the GABA A receptor were tested for ethanol, saccharin, or quinine consumption, ethanol-conditioned place preference, ethanol-conditioned taste aversion, ethanol-simulated motor activity, and handlinginduced seizures following chronic consumption of an ethanol liquid diet. The ␣1 null mutants showed decreased ethanol and saccharin consumption, increased aversion to ethanol, and a marked stimulation of motor activity after injection of ethanol.The ␤2 null mutants showed decreased consumption of saccharin and quinine, but not ethanol. Surprisingly, neither mutant showed marked changes in handling induced seizures before or after withdrawal of ethanol. The unique effects of deletion of these two GABA A receptor subunits on ethanol responses are discussed in terms of the distinct changes in different populations of GABA A receptors.

Dopamine and Benzodiazepine-Dependent Mechanisms Regulate the EtOH-Enhanced Locomotor Stimulation in the GABAA α1 Subunit Null Mutant Mice

“…BAC levels indicated a1 ( + / + ) mice consumed pharmacologically relevant amounts of EtOH above and beyond that of the a1 (À/À) mice in the operant chamber (2872.3 vs 2.670.13 mg/dl, respectively). The data from the two EtOH self-administration paradigms and the sucrose operant paradigm parallel those of Blednov et al (2003b) in the 24 h home-cage study with the 12 and 15% EtOH concentrations. Blednov et al (2003b), however, did not differentiate between the two genotypes at the 3, 6, and 9% (v/v) concentrations.…”

“…In addition, germane to alcohol's reinforcing properties, the a1 (À/À) mice have also been used to investigate alcohol's locomotor stimulant actions. Both developing laboratories report that alcohol (0.5-2.5 g/kg) enhances locomotor behavior in the a1 (À/À) mice (Kralic et al, 2003;Blednov et al, 2003b), while the a1 ( + / + ) mice were generally unaffected, or very weakly stimulated (Blednov et al, 2003b). The sedative actions of alcohol, however, were not investigated in either study.…”

“…The rationale for this stems from the fact that previous studies evaluating EtOH or BDZ actions on locomotor behaviors in the a1 mutant and wild-type mice have employed ambulatory counts (Blednov et al, 2003b), total distance (Kralic et al, 2003), and stereotypy (Reynolds et al, 2003) measurements. Thus, by illustrating all three parameters in the present study, a comparison across the three studies can be made before (ie, basal activity) and following drug treatment.…”

“…Specifically, Blednov et al (2003b) demonstrated that the a1 mutants consumed decreased amounts of alcohol and saccharin in the home cage. In contrast, Blednov et al (2003b) reported no differences between the mutants and a1 ( + / + ) mice in a conditioned place preference (CPP) paradigm. These discrepant results are likely due to the different paradigms assessing different reinforcing properties associated with alcohol.…”

“…BACs are important when trying to determine EtOH's neuromechanism of action (Crabbe et al, 1982;Frye and Breese, 1981;Lister, 1987). Third, while low-moderate doses of EtOH (0.50-2.5 g/kg) were used in the previous work (Blednov et al, 2003b;Kralic et al, 2003), it is possible that stimulation could be detected at higher doses (eg, 3.0-4.0 g/ kg) (see Cohen et al, 1997), since the null mutants seem highly sensitive to alcohol motor-stimulating effects, and resistant to alcohol's sedative actions (Blednov et al, 2003b). In addition, higher doses may permit investigation of the a1 receptor in alcohol's sedative actions.…”