Stress exerts complex effects on learning and memory; however, the understanding of the molecular mechanisms involved in stress effects on brain and behavior is rather limited. In this study, we investigated the regulation of the activation of MAPK (mitogen-activated protein kinase) cascades in the rat brain by GABAA receptor in a learning and memory task under acute restraint stress conditions. We found that the acute restraint stress improved the performance of the rats in the Morris water maze. Furthermore, the acute restraint stress significantly increased the phosphorylation of ERK and JNK in the hippocampus and prefrontal cortex (PFC), but not in the striatum. The increase paralleled the time course of the decrease of the level of GABAA receptor alpha1 subunit. The increase of P-ERK levels was inhibited by the agonist of GABAA receptor, muscimol, and further increased by the antagonist of the receptor, bicuculline. However, neither muscimol nor bicuculline affected the levels of P-JNK and P-p38. Finally, injection of muscimol partly reversed the acute restraint stress-induced enhancement of performance in the Morris water maze, and injection of bicuculline improved it. These results demonstrated that the changes in ERK phosphorylation in hippocampus and PFC were regulated by GABAA receptor in a learning and memory paradigm under acute restraint stress conditions.