Role of metabotropic glutamate receptor subclasses in modulation of adenylyl cyclase activity by a nootropic NS-105

Abstract

The involvement of metabotropic glutamate (mGlu) receptors in the modulatory actions of a novel cognition enhancer, (+)-5-oxo- d-prolinepiperidinamide monohydrate (NS-105), on adenylyl cyclase activity in rat cerebrocortical membranes and primary neuronal cultures was investigated using selective antagonists and antisense oligodeoxynucleotides for mGlu receptor subclasses. In rat cerebrocortical membranes, the inhibitory action of NS-105 (0.1 μM) on forskolin-stimulated cAMP formation was blocked by a group II mGlu receptor antagonist, (±)-α-ethylglutamic acid, and by a group III antagonist, (+)-2-amino-2-methyl-4-phosphonobutanoic acid (MAP-4), but not by a group I antagonist, (±)-1-aminoindan-1,5-dicarboxylic acid (AIDA), whereas the facilitation of cAMP formation by NS-105 (1 μM) in pertussis toxin-pretreated membranes was abolished by AIDA but not by (±)-α-ethylglutamic acid or MAP-4. In primary cultured neurons of mouse cerebral cortex, the inhibitory action of NS-105 on adenylyl cyclase activity disappeared after treatment with antisense oligodeoxynucleotides for group II (mGlu 2 and mGlu 3 receptors) and group III (mGlu 4 and mGlu 7 receptors) but not group I (mGlu 5 receptor) mGlu receptor subclasses. These findings suggest that the inhibitory action of NS-105 on adenylyl cyclase activity is mediated through group II and group III mGlu receptor subclasses while the facilitatory action is dependent on the group I mGlu receptor subclass.