Alpha 7 nicotinic receptor agonist and positive allosteric modulators improved social and molecular deficits of MK-801 model of schizophrenia in rats

Abstract

Schizophrenia is a common psychiatric disease that cannot be fully treated with current antipsychotic drugs. It has shown that glutamatergic NMDA receptor antagonists such as MK-801 cause schizophrenia-like phenotype in rodents. Recent studies indicated that α7 nicotinic acetylcholine receptor (nAChR) deficits contribute to schizophrenia. Enhancing its activity with agonist or positive allosteric modulators (PAMs) may be a valuable approach for treatment. The certain intracellular pathways such as Akt/Glycogen synthase kinase 3 beta (GSK-3β) and phosphodiesterase-4 (PDE-4)/cAMP are associated with the pathogenesis of schizophrenia. In this study, we examined the effect of α7 nAChR agonists and PAMs on the behavioral and molecular phenotype of schizophrenia in the subchronic MK-801 administered rats. Social interaction, the levels of α7 nAChR, and related intracellular pathways (cAMP, PDE4A, PDE4D, p-Akt/Akt, p-GSK-3β/GSK-3β) were measured by behavioral or ELISA and western blot tests. Subchronic MK-801 administration decreased the following behaviors and increased the avoiding behaviors. However, only α7 nAChR agonist (A-582941) increased the following behavior while α7 nAChR agonist, PAMs (CCMI and PNU-120596), and clozapine decreased the avoiding behavior compared to MK-801. For molecular parameters, MK-801 administration decreased the α7 nAChR, p-Akt/Akt, p-GSK-3β/GSK-3β expressions, and cAMP levels while it increased PDE4A, PDE4D expressions in the prefrontal cortex. Besides, MK-801 decreased the α7 nAChR, p-GSK-3β/GSK-3β expressions in the hippocampus. We found clozapine, α7 nAChR agonists, and PAMs reversed the molecular deficits induced by MK-801. Herein, we showed that prefrontal cortex is more sensitive to the devastating effects of subchronic MK-801 administration, especially for PDE4, in rats. In addition to clozapine, α7 nAChR agonists and PAMs found to be beneficial on both social and molecular deficits induced by MK-801 in rats. We suggested that α7 nAChR agonists and PAMs might be valuable approaches to treat negative symptoms of schizophrenia when unmet needs and current limitations considered in this pathology.