Positive Allosteric Modulation of mGlu and Muscarinic Receptors Differentially Regulate Nitric Oxide-Dependent Signaling in a Scopolamine-Induced Model of Cognitive Impairment

Background/Objectives: The aim of the study was to evaluate the effects of positive allosteric modulators (PAMs) of metabotropic glutamate (mGlu2, mGlu5) and muscarinic (M1, M4) receptors on nitric oxide (NO֗)-dependent pathways. Scopolamine-induced cognitive impairment model reflecting cholinergic dysfunction characteristic of Alzheimer's disease was used.

Methods

The experiments were performed in vivo in Albino Swiss mice and in vitro in astrocytic cell lines (C8D1A, 1321N1). Chronic (14 days) scopolamine and mGlu2 (LY487379), mGlu5 (CDPPB), M1 (VU0357017), and M4 (VU0152100) PAMs were administered in vivo. In brain tissue samples (frontal cortex or hippocampus) cGMP levels (ELISA), total and protein-specific S-nitrosylation (biotin switch assay), and neuronal (nNOS) or endothelial (eNOS) synthase-dependent (NO֗) release (nanoelectrochemical detection) were measured. In vitro oxidative stress (NBT assay) was performed.