Project Summary The development of opioids tolerance and dependence represents a major social and economic burden globally. Opioids exert their effect by the activation of opioid receptors in the mesolimbic system to produce pleasurable effects and relieve pain. Of the three known opioid receptors, the mu type (MOR) is broadly expressed throughout the reward circuit of the brain where both dopaminergic neurons and glutamatergic neurons have been identified as critical components for the opioids reward, dependence, tolerance and withdrawal. Our long-term goal is to understand the cellular mechanisms underlying the effects of opioids on synaptic transmission and plasticity within reward-related neural circuits. Neuroadaptations of ionotropic glutamate receptors occur in response to persistent opioid exposure and emerging evidences suggest that metabotropic glutamate receptors (mGluRs) are also active regulators of MOR actions. mGluRs regulate neurotransmitter release to ensure basal ganglia homeostasis and available data support a role for mGluRs to reduce the release of glutamate that is produced during drug-seeking behaviors. Receptors belonging to group III (mGluR4/7/8) are distributed within the reward circuitry on glutamatergic corticostriatal afferents and GABAergic striatopallidal neurons. Preliminary data in our lab provided evidences that mGluR III type receptors form complexes with extracellular leucine-rich repeats fibronectin type-3 domain protein, Elfn1. This trans- synaptic protein is selectively expressed in cholinergic interneurons of the striatum and its elimination increases rewarding effects of morphine. Here I propose to investigate the functions of Elfn1 proteins and their involvement in the synaptic rewiring of striatal circuits that occurs during repetitive opioid exposure. I will use a combination of whole-cell patch-clamp electrophysiology and behavioral studies to pursue the following aims: In Aim 1 I will identify the subtype of mGluRs at presynaptic terminals interacting with Elfn1 proteins and characterize the synaptic properties of Elfn1 expressing neurons within specific neuronal circuits of the reward system. In Aim 2 I will examine the involvement of Elfn1-mGluRs complexes in the regulation of rewards properties of opioids and investigate their contribution to the synaptic rewiring associated with opioid exposure. The proposed studies will provide the causality between mGluRs modulation of synaptic plasticity in Elfn1-expressing neurons and the behavioral adaptations occurring with opioid exposure, greatly broadening the knowledge of opioid plasticity. Moreover, this research has the potential to identify novel cellular targets for the rewarding effects of opioids, and facilitate the search for better treatments for opioid addiction.