Amphetamine-induced Conditioned Place Preference and Changes in mGlu1/5 Receptor Expression and Signaling in the Rat Medial Prefrontal Cortex.

The medial prefrontal cortex (mPFC) is implicated in the rewarding effect of psychostimulants, although molecular mechanisms underlying the rewarding properties of stimulants in this region are poorly understood. Group I metabotropic glutamate (mGlu) receptors (mGlu1/5 subtypes) are believed to be critical in this event. We thus in this study investigated changes in mGlu1/5 receptor expression and function in the rat mPFC in response to conditioned place preference (CPP) induced by amphetamine. Repeated amphetamine administration (2.5 mg/kg, once daily on alternate days for 10 days) induced reliable CPP. In the mPFC, surface expression of mGlu5 receptors was elevated in rats after amphetamine conditioning. mGlu5 receptors were also increased at synaptic and extrasynaptic sites in amphetamine-conditioned rats. Expression of mGlu1 receptors was stable in surface and synaptic compartments, while it was elevated in the extrasynaptic location. In mPFC neurons, the mGlu1/5 agonist-stimulated phosphoinositide signaling pathway was upregulated in its efficacy following amphetamine conditioning. The mGlu1/5 agonist-stimulated Src kinase phosphorylation was also augmented in rats treated with amphetamine. These results demonstrate the sensitivity of mPFC mGlu1/5 receptors to amphetamine-induced CPP. Amphetamine conditioning results in the upregulation of mGlu1/5 receptor expression at subcellular and/or subsynaptic levels and mGlu1/5-mediated postreceptor signaling in mPFC neurons.