We investigated the participation of γ-aminobutyric acid (GABA) neurons of the medial septal area in eight-arm radial maze performance in rats. The intra-septal injection of muscimol, a GABA_A agonist, caused an increase in total error and working memory error. On the other hand, no significant effect was observed with reference memory error. Donepezil and tacrine (cholinesterase inhibitors) antagonized the muscimol-induced spatial memory deficits. Histidine (1500 mg/kg, i.p.) also improved the total error and working memory error induced by muscimol. At this dose, histidine caused a significant increase in the histamine content of the cortex, hippocampus, and hypothalamus in rats. In addition, the intra-hippocampal injection of histamine also antagonized muscimol-induced spatial memory deficits. The practical conclusion is that the GABA_A receptor of the medial septal area plays an important role in working memory, and also, the disturbance of working memory induced by muscimol is mediated not only by cholinergic but also by histaminergic systems in the spatial memory of rats.