Chemokine Receptor Antagonists (CRAs): Characterization in Preclinical Models of Methamphetamine Use Disorder - Methamphetamine (METH) addiction lacks an approved medication, which is different from opioid, alcohol and nicotine addiction. The NIDA therapeutic pipeline for psychostimulant addiction is also limited compared to opioid use disorder. This indicates a need to identify new targets and strategies for METH use disorder (MUD). The neuroimmune system is one promising target. It sits at the crossroads of the immune and central nervous systems. Neuroimmune signaling in brain circuits related to addiction is dysregulated during METH exposure and abstinence, and this dysregulation facilitates METH dependence and relapse. Non-selective anti- inflammatory agents are effective in animal models of psychostimulant addiction but can disrupt normal immune function. We propose a more selective strategy, one which targets a specific element of the neuroimmune system. The element we selected is the chemokine system, namely a trio of chemokine receptors (CCR2, CCR5 and CXCR4) that are (1) expressed in brain circuits that underlie METH dependence and relapse; (2) dysregulated during METH exposure; (3) enhance multiple neurochemical correlates of METH addiction (e.g., dopamine and glutamate transmission); and (4) `druggable' receptors with FDA-approved antagonists and a mechanistically unique preclinical antagonist. The overall hypothesis to be tested is that chemokine receptor antagonists (CRAs) blocking three different chemokine receptors (CXCR4, CCR2, and CCR5) will reduce METH intake, reinforcing efficacy, and relapse in SA assays, counteract anxiety-like effects during METH withdrawal, and normalize dysregulation of chemokine-dopamine crosstalk after chronic METH intake. The CRAs proposed for characterization are not known to be abuse liable, mechanistically distinct, and positioned at different stages of the neuroimmune pipeline. Two of the CRAs (AMD3100, a CXCR4 antagonist and maraviroc, a CCR5 antagonist) are approved for other therapeutic indications and eligible for repurposing. R-103, a preclinical CRA, is mechanistically unique because it blocks multiple chemokine receptors (i.e., CCR2, CCR5, CXCR4), thus offering potential for enhanced efficacy. R-103 also has favorable safety and pharmacokinetic profiles, including rapid brain entry and persistent brain and plasma levels. Since the CRAs proposed for testing may have varying potencies, half-lives, and metabolic/PK parameters, we will also determine the causal role of the specific chemokine receptors in METH intake and relapse behaviors using shRNA knockdown of CCR2, CCR5 and CXCR4 in the mesolimbic pathway. In summary, our results will offer the first comprehensive information about the efficacy of CRAs and the influence of specific chemokine receptors on METH SA behaviors and neurochemical effects. By identifying the most effective CRA, and determining the chemokine receptor with the greatest influence, we expect to pave the way for developing effective chemokine-based medications for METH use disorder.
