The impact of muscarinic and mGlu receptors modulators on MK-801-induced impairments in NO-dependent processes both in vitro and in vivo.

Background: Schizophrenia is a mental disorder with multifactorial etiology including positive, negative and cognitive symptoms. Nitric oxide (NO֗)-related biochemical pathways significantly contribute to the disease's pathophysiology and subsequent antipsychotic treatment. Recently, metabotropic glutamatergic (mGlu) or muscarinic (M) receptors have been considered as potent antipsychotics with the potential to reverse cognitive symptoms. The aim of this study was to investigate how selected mGlu or muscarinic receptor ligands regulate the most important aspects of NO֗-related neurotransmission.

Methods: In this study, MK-801-the tool compound that induces schizophrenia-related changes-was used alone or with mGlu or muscarinic receptor ligands. Positive allosteric modulators (PAM) of mGlu₂ (LY487379), mGlu₅ (CDPPB), M₁ (VU0357017) and M₄ (VU0152100) receptors were administered. cGMP levels, superoxide dismutase (SOD) activity, nitrite and GLT-1 s-nitrosilation processes were investigated in mouse brain and plasma samples, while oxidative stress was measured in vitro with the use of mouse or human astrocytic cell lines.

Results: MK-801 did not change cGMP levels, while a decrease was observed in mice treated with VU0357017 or LY487379 in parallel. Increased SOD activity was observed in the cortex of MK-801-treated mice, and the compounds, with the exception of CDPPB, prevented this effect. The investigated compounds also prevented an MK-801-induced increase in plasma nitrite levels. GLT-1 protein was decreased after MK-801 treatment which was not evident in mice administered with muscarinic or mGlu ligands. GLT-1 S-nitrosilation was increased in all groups. In vitro studies revealed the potency of these compounds in counteracting MK-801-induced oxidative stress.

Conclusions: The present data confirm that both mGlu and muscarinic receptor ligands may exert antipsychotic effects through biochemical pathways regulated by NO֗, in particular by decreasing oxidative stress indicators.