We have previously found that a cognition enhancer [(+)-5-oxo-D-prolinepiperidinamide monohydrate] (NS-105) reversed the inhibition of cyclic AMP formation induced by the GABA(B) receptor agonist baclofen. The GABA(B) receptor has been implicated in the pathophysiology of depressive illness. The present experiment was designed to evaluate the antidepressant activity of NS-105 in the forced swimming and learned helplessness tests in rats. NS-105 (1-100 mg/kg, p.o.) significantly decreased immobility time in the forced swimming test, an effect similar to that of desipramine. Repeated administration of NS-105 also reversed the failure to escape in the shuttle-box test of rats previously exposed to inescapable footshock. Biochemical data showed that repeated administration of NS-105 increased the number of GABA(B) receptors in rat cerebral cortex without affecting the binding properties of beta-adrenoceptors and 5-HT2 receptors. In contrast to other antidepressants, NS-105 did not inhibit monoamine uptake in vitro, nor did it change monoamine concentrations in brain tissues or extracellular fluids. These findings suggest that NS-105, which lacks an effect on monoaminergic systems, has potent antidepressant activity, which may involve up-regulation of GABA(B) receptors after repeated administration.