INVOLVEMENT OF METABOTROPIC GLUTAMATE RECEPTORS IN G(I)-DEPENDENT ANDG(S)-DEPENDENT MODULATION OF ADENYLATE-CYCLASE ACTIVITY-INDUCED BY A NOVEL COGNITION ENHANCER NS-105 IN RAT-BRAIN

The effect of a novel cognition enhancer [(+)-5-oxo-D-prolinepiperidin amide monohydrate] (NS-105) on cAMP formation was investigated in both slices and membranes of the rat cerebral cortex. NS-105 (10(-8)-10(-6 ) M) inhibited forskolin-stimulated cAMP formation in membranes, howev er, the compound significantly enhanced the cAMP formation in pertussi s toxin-pre-treated membranes, an action that was abolished by cholera toxin. In contrast, in digitonin-permeabilized membranes, NS-105 had no influence on Mn2+-stimulated cAMP formation. Both of the inhibitory and facilitatory actions of NS-105 on cAMP formation were mimicked by a metabotropic glutamate receptor (mGluR) agonist (1S,3R)-1-aminocycl opentane-1,3-dicarboxylic acid (1S,3 R-ACPD) and an adrenergic cu, ago nist UK-14,304, and blocked by a mGluR antagonist 2-amino-3-phosphonop ropanoate but not by an alpha(2) antagonist yohimbine. In cortical sli ces, NS-105 (10(-8)-10(-7) M) inhibited forskolin-stimulated cAMP accu mulation but enhanced isoproterenol-stimulated cAMP accumulation, as d id by a GABA(B) agonist (-)baclofen. On the other hand, (-)baclofen, w hile it significantly inhibited cAMP accumulation in slices, did no lo nger inhibit cAMP accumulation, when treated with NS-105 (10(-8)-10(-5 ) M). Similarly, (-)baclofen-induced inhibition of the cAMP accumulati on was reversed by 1S,3R-ACPD and UK-14,304. NS-105 (10(-6)) increased [S-35]GTP gamma s binding in the intact but not digitonin-permeabiliz ed cortical membranes, as produced by UK-14,304, although the compound (10(-9)-10(-3) M) had no influence on various neurotransmitter recept or bindings, including alpha(2) receptors. These results suggest that NS-105 modulates adenylate cyclase activity by stimulating mGluRs whic h might coupled to both G(i)/G(o) and G(s). (C) 1997 Elsevier Science B.V.