Involvement of metabotropic glutamate receptors in Gi- and Gs-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-

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-prolinepiperidinamide 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, however, the compound significantly enhanced the cAMP formation in pertussis 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-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) and an adrenergic α₂ agonist UK-14,304, and blocked by a mGluR antagonist 2-amino-3-phosphonopropanoate but not by an α₂ antagonist yohimbine. In cortical slices, NS-105 (10⁻⁸–10⁻⁷ M) inhibited forskolin-stimulated cAMP accumulation but enhanced isoproterenol-stimulated cAMP accumulation, as did by a GABA_B agonist (−)baclofen. On the other hand, (−)baclofen, while it significantly inhibited cAMP accumulation in slices, did no longer inhibit cAMP accumulation, when treated with NS-105 (10⁻⁸–10⁻⁵ M). Similarly, (−)baclofen-induced inhibition of the cAMP accumulation was reversed by 1S,3R-ACPD and UK-14,304. NS-105 (10⁻⁶) increased [³⁵S]GTPγS binding in the intact but not digitonin-permeabilized cortical membranes, as produced by UK-14,304, although the compound (10⁻⁹–10⁻³ M) had no influence on various neurotransmitter receptor bindings, including α₂ receptors. These results suggest that NS-105 modulates adenylate cyclase activity by stimulating mGluRs which might coupled to both G_i/G_o and G_s. © 1997 Elsevier Science B.V. All rights reserved.