EFFECT OF A NOVEL COGNITION ENHANCER NS-105 ON LEARNED HELPLESSNESS IN RATS - POSSIBLE INVOLVEMENT OF GABA(B) RECEPTOR UP-REGULATION AFTER REPEATED TREATMENT

We have previously found that a cognition enhancer [(+)-5-oxo-D-prolin epiperidinamide monohydrate] (NS-105) reversed the inhibition of cycli c AMP formation induced by the GABA, receptor agonist baclofen. The GA BA, receptor has been implicated in the pathophysiology of depressive illness. The present experiment was designed to evaluate the antidepre ssant activity of NS-105 in the forced swimming and learned helplessne ss tests in rats. NS-105 (1-100 mg/kg, p.o.) significantly decreased i mmobility time in the forced swimming test, an effect similar to that of desipramine. Repeated administration of NS-105 also reversed the fa ilure to escape in the shuttle-box test of rats previously exposed to inescapable footshock. Biochemical data showed that repeated administr ation of NS-105 increased the number of GABA(B) receptors in rat cereb ral cortex without affecting the binding properties of beta-adrenocept ors 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 findin gs 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. (C) 1997 Elsevier Science B.V.