Memory for Fear Extinction Requires mGluR5-Mediated Activation of Infralimbic Neurons

Consolidation of fear extinction involves enhancement of N-methyl D aspartate (NMDA) receptor–dependent bursting in the infralimbic region (IL) of the medial prefrontal cortex (mPFC). Previous studies have shown that systemic blockade of metabotropic glutamate receptor type 5 (mGluR5) reduces bursting in the mPFC and mGluR5 agonists enhance NMDA receptor currents in vitro, suggesting that mGluR5 activation in IL may contribute to fear extinction. In the current study, rats injected with the mGluR5 antagonist 2-methyl-6-(phenylethyl)-pyridine (MPEP) systemically, or intra-IL, prior to extinction exhibited normal within-session extinction, but were impaired in their ability to recall extinction the following day. To directly determine whether mGluR5 stimulation enhances the burst firing of IL neurons, we used patch-clamp electrophysiology in prefrontal slices. The mGluR5 agonist, (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), increased intrinsic bursting in IL neurons. Increased bursting was correlated with a reduction in the slow afterhyperpolarizing potential and was prevented by coapplication of MPEP. CHPG did not increase NMDA currents, suggesting that an NMDA receptor–independent enhancement of IL bursting via stimulation of mGluR5 receptors contributes to fear extinction. Therefore, the mGluR5 receptor could be a suitable target for pharmacological adjuncts to extinction-based therapies for anxiety disorders

mGluR5 in the nucleus accumbens shell regulates morphine-associated contextual memory through reactive oxygen species signaling

Emerging evidence indicates that metabotropic glutamate receptor 5 (mGluR5) critically modulates drug and drug-related behaviors. However, the role of mGluR5 in the opiate-induced contextual memory remains unclear. Here, we found that microinfusion of the mGluR5 antagonist 3-((2-Methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP) into the nucleus accumbens (NAc) shell, but not into the core, significantly attenuated the expression of morphine conditioned place preference (CPP) in rats. Following the expression of morphine CPP, the protein level of membrane mGluR5 was selectively increased in the NAc shell. In primary striatal neurons, we observed that treatment with the mGluR5 agonist CHPG increased the phosphorylation level of extracellular signal-regulated kinase (ERK), which was dependent on the mGluR5-inositol-1,4,5-trisphosphate-reactive oxygen species (ROS) pathway. Moreover, the microinjection of the ROS scavenger Tempol into the NAc shell of rats blocked the expression of morphine CPP. Further, the administration of t-BOOH, a ROS donor, into the NAc shell rescued the retrieval impairment of morphine CPP produced by MTEP. Our previous study demonstrated that the expression of morphine CPP increased the phosphorylation of ERK selectively in the NAc shell. Thus, results of the present study suggest that mGluR5 in the NAc shell, but not in the core, is essential for the retrieval of morphine contextual memory, which is mediated at least in part, through the ROS/ERK signaling pathway. Uncovering the molecular basis of opiate contextual memory will benefit the development of new therapeutic approaches for the treatment of opiate addiction.</p