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

BackgroundPositive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu5) have behavioral effects predictive of antipsychotic activity in experimental models such as amphetamine-induced hyperlocomotion (AHL). However, the signaling mechanisms that contribute to the antipsychotic-like properties of mGlu5 PAMs are not well understood.\n\nMethodsBecause the Akt/GSK3{beta} 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 GSK3{beta} signaling using western blot analysis in both naive and amphetamine-treated adult male rats.\n\nResultsIn 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 GSK3{beta} 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/GSK3{beta} signaling were not limited to the striatum, as VU0092273 also increased Akt/GSK3{beta} phosphorylation in the medial prefrontal cortex.\n\nConclusionsThese 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 GSK3{beta} might contribute to the antipsychotic-like effects of mGlu5 PAMs.