Antipsychotic Drugs Reverse MK801-Inhibited Cell Migration and F-actin Condensation by Modulating the Rho Signaling Pathway in B35 Cells

Abstract

Background and Aim. MK801-induced psychotic symptoms and also the Ras homolog family member A (RhoA) expression and cell division control protein 42 (cdc42) mRNA modulation in the rat brain have been investigated. Antipsychotic drugs (APDs) have been reported to induce Rho GDP-dissociation inhibitor (RhoGDI) pathway regulation related to cytoskeleton reorganization in neuronal cells. It will be necessary to clarify the effects of APDs on MK801-induced RhoGDI signaling regulation in neuronal cells. Methods. B35 neuronal cells were treated with MK801 for 7 days then treated with MK801 in combination with haloperidol or clozapine for a further 7 days. Cell migration, F-actin condensation, and RhoGDI signaling regulation were examined to investigate the regulatory effects of MK801, haloperidol, and clozapine in B35 neuronal cells. Results. MK801 reduced B35 cell migration, whereas both haloperidol and clozapine reversed the reduction in cell migration induced by MK801. Haloperidol and clozapine restored F-actin condensation after it was diminished by MK801 in B35 cell nuclei. MK801 increased the RhoGDI1 and RhoA expression, which was diminished by the addition of haloperidol and clozapine. MK801 reduced the CDC42 expression, which was restored by haloperidol and clozapine. MK801 reduced the Rho-associated coiled-coil containing protein kinase 1 (ROCK1), profilin1 (PFN1), and neuronal Wiskott–Aldrich Syndrome protein (N-WASP) expression, which was further reduced by haloperidol and clozapine. MK801 also increased the phosphorylated myosin light chain 2 (p-MLC2), postsynaptic density protein 95 (PSD-95), and c-jun expression, which was decreased by haloperidol and clozapine. p21 (RAC1-) activated kinase 1 (PAK1) expression was not affected by MK801.

Neurobehavioral Differences of Valproate and Risperidone on MK-801 Inducing Acute Hyperlocomotion in Mice

“…MK-801 (dizocipline), an uncompetitive NMDA receptor antagonist, has been proven to induce acute excitation, agitation, or aggressive behaviors in different animal models [ 5 , 15 , 16 ]. Memory impairment and learning impairment were also seen in the MK-801 animal model, resembling negative symptoms of schizophrenia through modulation of Rho family protein-related signaling [ 17 ]. MK-801-induced neurobehavioral alteration was adapted as an acute schizophrenic-like model in animal studies [ 15 , 18 ].…”