PROJECT SUMMARY Opioid Use Disorder (OUD) is a significant problem worldwide and a surge in methamphetamine (MA) use has emerged in chronic opioid users. Given recent increases in co-abuse, there is a dire need for novel treatment strategies that prevent relapse to drug use in both OUD and MA Use Disorder (MUD). Long-term drug exposure induces enhanced glutamate (Glu)-mediated synaptic plasticity, which underlies excessive physiological and behavioral responses to drug-related cues. Opioid and MA exposure also activate microglia and astrocytes, promoting release of pro-inflammatory cytokines. All these factors increase the risk of relapse to drug use. Normalization of aberrant Glu activity caused by chronic drug use represents a novel therapeutic strategy to prevent relapse in OUD/MUD. The activation of metabotropic Glu receptor subtypes 2 and 3 (mGlu2/3) using agonists or positive allosteric modulators (PAMs) decreases psychostimulant self-administration (SA) as well as cue-induced reinstatement (RI) in animals. Moreover, preclinical studies indicate that mGlu2/3 activation has promise for treating stress- and anxiety-related disorders in humans and can systematically augment sleep. However, the relative contribution of mGlu2 versus mGlu3 activation for treating OUD/MUD is not yet known. Activation of presynaptic mGlu2 autoreceptors results in downstream inhibition of Glu release in the nucleus accumbens, which in turn attenuates drug RI. In addition, activation of mGlu3, which is highly expressed in astrocytes, leads to the release of the anti-inflammatory cytokine transforming growth factor beta (TGF-β). The specific localization and signal transduction of mGlu2 and mGlu3 receptors lead to our overarching hypothesis that dual activation of both mGlu2 and mGlu3 will provide a clear advantage for the treatment for OUD and MUD over mGlu2 activation alone. We have recently synthesized and characterized SBI-0799220, a PAM with equal potency for mGlu2 and mGlu3 and SBI-0801315, a PAM with >50-fold selectivity for mGlu2 vs mGlu3. Preliminary data indicate that SBI-0801315 attenuates Oxy cue-induced RI and SA, and that SBI-0799220 attenuates MA SA. However, a direct comparison of mGlu2/3 with mGlu2 PAMs in models of OUD and MUD has not yet been conducted. The goal of this application is to advance mGlu2/3 PAMs as a novel treatment for preventing relapse to OUD, examine their potential for treating MUD, and simultaneously optimize mGlu2/3 PAMs. We will determine the in vivo efficacy of mGlu2/3 and mGlu2-preferring PAMs to attenuate Oxy/MA SA and RI, Oxy/MA-induced withdrawal, MA-induced neuroinflammation, and opioid-induced antinociception in rats. Simultaneously, we will optimize the pharmacological and pharmaceutical properties of our mGlu2/3 PAM series including absorption, distribution, metabolism, excretion, and pharmacokinetics. We have assembled a multidisciplinary team of investigators that has the knowledge and experience to achieve these outcomes. Successful completion of these studies will expedite development of a novel mGlu2/3 PAM towards investigational new drug (IND)-enabling studies and ultimately, a novel treatment for preventing relapse in OUD.

PROJECT NARRATIVE Given recent increases in co-abuse of opioids and methamphetamine, there is a dire need for novel non- opioid treatment strategies that prevent relapse to drug use in both opioid use disorder (OUD) and methamphetamine use disorder (MUD). Based on the localization and signal transduction mechanism of mGlu2 and mGlu3 receptors, there is a strong rationale that dual mGlu2/3 positive allosteric modulators (PAMs) will effectively treat multiple symptoms that contribute to relapse, including attenuation of enhanced responsiveness to drug-cues, physical withdrawal symptoms, neuroinflammation, and sleep disturbances. The overarching goal of this application is to advance mGlu2/3 PAMs as a novel pharmacological treatment for preventing relapse to OUD, examine the potential for treating MUD, and simultaneously optimize additional mGlu2/3 PAMs to identify a preclinical candidate that can be advanced into investigational new drug (IND)-enabling studies.