Positive allosteric modulation of metabotropic glutamate receptor 5 modulates Akt and GSK3β signaling in vivo

Abstract

Keywords (max 6): metabotropic glutamate receptor 5, Akt, GSK3, striatum, schizophrenia, positive allosteric modulator Declaration of interest: P.J.C. receives research support from Lundbeck Pharmaceuticals and Boehringer Ingelheim. P.J.C. is an inventor on multiple patents for allosteric modulators for metabotropic glutamate receptors. AbstractBackground: Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu5) have behavioral effects predictive of antipsychotic activity in experimental models such as amphetamineinduced hyperlocomotion (AHL). However, the signaling mechanisms that contribute to the antipsychotic-like properties of mGlu5 PAMs are not well understood.Methods: Because the Akt/GSK3β pathway has been implicated in schizophrenia and is modulated by known antipsychotic drugs, we evaluated the effects of systemic administration of two mGlu5 PAMs on Akt and GSK3β signaling using western blot analysis in both naïve and amphetamine-treated adult male rats.Results: In the dorsal striatum, the mGlu5-selective PAM VU0092273 (30 mg/kg) significantly increased Akt phosphorylation at residues associated with enhanced kinase activity, Thr308 and Ser473. Inhibitory phosphorylation of GSK3β at Ser9 was also increased. Similar effects were observed with a second mGlu5 PAM, VU0360172 (56.6 mg/kg). VU0092273 increased Akt phosphorylation levels in amphetamine-treated rats. Effects on Akt/GSK3β signaling were not limited to the striatum, as VU0092273 also increased Akt/GSK3β phosphorylation in the medial prefrontal cortex.Conclusions: These findings suggest that mGlu5 PAMs that have antipsychotic-like efficacy in rats affect signaling pathways that are modulated by known antipsychotics, and raise the possibility that inhibition of GSK3β might contribute to the antipsychotic-like effects of mGlu5 PAMs.