The CC Chemokine Receptor 5 (CCR5) antagonist Maraviroc inhibits drug‐choice in Sprague Dawley rats

Abstract

In the twelve months leading up to May 2020, over 81,000 people have died due to drug overdoses. Since then, these numbers have been exacerbated by the Covid-19 pandemic, demonstrating an urgent need to develop novel and effective pharmacotherapies for individuals with substance use disorders. Recently, an inflammation associated chemokine receptor, CC Chemokine Receptor 5 (CCR5), has been linked to opioid abuse. We therefore hypothesized that inhibiting CCR5 could reduce opioid-taking in a food versus drug (fentanyl) choice procedure. Adult male Sprague Dawley rats (n=8) were trained to respond for either food (a grain pellet) on one lever, or increasing doses of fentanyl on the alternate lever under a multiple component, fixed ratio (FR) 5, choice procedure. Food was available in each of five components, with component 1 serving as a no drug control, and increasing unit doses of fentanyl (0.32-10 μg/kg/infusion) available in components 2-5. At baseline, rats responded exclusively on the food lever during the first component, but gradually reallocated their responding towards the fentanyl lever as the unit dose of fentanyl increased, with exclusive choice of fentanyl occurring at the largest dose of fentanyl (10 µg/kg/inf). Pretreatment with the μ-opioid receptor antagonist naloxone (1 and 3.2 mg/kg) significantly reduced choice of fentanyl while increasing both choice of food and trials completed. Pretreatment with haloperidol, a dopamine D2-like receptor antagonist (0.1 and 0.32 mg/kg), did not alter fentanyl choice at doses that did not also reduce trials completed. Pretreatment with Maraviroc (1-10 mg/kg) dose dependently reduced choice of fentanyl while also increasing choice of food and trials completed in later components. These results suggest that Maraviroc may selectively reduce fentanyl's reinforcing effects without affecting behavior maintained by a non-drug reinforcer (food). Future work will seek to determine whether the effects of Maraviroc persist across repeated dosing, and whether the anti-opioid effects of Maraviroc are impacted by opioid dependence and withdrawal.