A high affinity ligand for GABAA-receptor containing α5 subunit antagonizes ethanol's neurobehavioral effects in Long-Evans rats

Rationale. Previously, we reported that the GABA(A) receptor containing alpha(5) subunit played a significant role in the reinforcing actions of EtOH in rats selectively bred to consume alcohol. However, the role of the alpha(5) receptor in regulating the neurobehavioral effects of EtOH in outbred rats is not known. Objective. In the present study, RY024, a novel benzodiazepine (BDZ) inverse agonist with high affinity (K(d)similar to 0.40 nM) and selectivity (similar to67.3-fold) for the alpha(5) receptor, was investigated for its capacity to antagonize EtOH's reinforcing, motor impairing, and sedative effects in Long-Evans rats. Methods. Rats were trained to lever press for EtOH under a fixed-ratio 1 schedule of reinforcement. Subsequent studies evaluated EtOH's motor-impairing effects in an oscillating bar task, while EtOH's sedative effects were measured in the open field. Results. RY024 (0.125-3.5 mg/kg; IP) markedly reduced EtOH-maintained responding with no effects on water responding, except for the highest dose. RY024 (3.0-15 mg/kg; IP) also reversed the motor impairing effects of a moderate (0.75 g/kg), and intoxicating EtOH dose (1.25 g/kg) in the absence of intrinsic effects. Finally, RY024 (7.5 mg/kg) attenuated the sedation produced by the 1.25 g/kg EtOH dose; however, it failed to attenuate the sedation induced by the 0.75 g/kg EtOH dose. Given alone, RY024 exhibited intrinsic effects in the open field. Conclusion. The results suggest the GABA(A) receptor containing alpha(5) subtype plays an important role in regulating the reinforcing, motor-impairing, and sedative effects of alcohol in outbred rats.