Modeling Stimulant and Opioid Co-use in Rats Provided Concurrent Access to Methamphetamine and Fentanyl

Stimulant and opioid co-use is modeled in rats to better understand how methamphetamine and fentanyl reinforce each other during polysubstance choice. Male Sprague-Dawley rats first self-administer methamphetamine or fentanyl alone, then receive concurrent access using a drug-vs.-drug choice procedure. Some rats co-administer both drugs within sessions or alternate across sessions, while others respond exclusively for one drug. When the cost of the preferred option increases (lower effective unit dose for that drug) or the cost of the non-preferred option decreases, rats shift choice toward the cheaper alternative. After extinction, methamphetamine- or fentanyl-paired cues reinstate responding on both levers, and a priming injection of either drug biases more responding toward the lever previously reinforced by that priming drug. Overall, choice is largely driven by relative “price,” though rats show more co-use than expected if methamphetamine and fentanyl were simple economic substitutes, highlighting the need for better modeling to support treatment development for polysubstance use disorders.