Fixed-proportion mixtures with the α2-adrenergic agonist clonidine or lofexidine do not alter fentanyl self-administration in non-opioid-dependent male and female rats.

Illicitly manufactured fentanyl has increasingly been adulterated with other chemical substances such as α2-adrenergic agonists. Although xylazine was the initial α-2 agonist reported to be in the illicit fentanyl supply, other α-2 agonists are increasingly being identified, suggesting that xylazine adulteration of illicit fentanyl is intentional to augment fentanyl effects. The aim of the present study was to determine the interactions between 2 clinically available α-2 agonists, clonidine and lofexidine, and fentanyl on reinforcement endpoints in male and female rats. Three drug self-administration experiments were conducted. First, clonidine and lofexidine self-administration dose-effect functions were determined under a fixed-ratio 5 schedule to assess whether clonidine or lofexidine functioned as reinforcers in rats. Second, behavioral economic demand functions were determined for fentanyl alone, α-2 agonists alone, or several fixed-proportion fentanyl/α-2 agonist mixtures. Lastly, fentanyl/α-2 agonist interactions were determined under a concurrent schedule of fixed-proportion fentanyl/α-2 agonist mixture and food availability. Neither clonidine nor lofexidine functioned as reinforcers under the fixed-ratio 5 schedule, even at the largest doses examined, which produced behavioral sedation. The present results demonstrate that clonidine and other α-2 agonists do not function as reinforcers under limited-access conditions in nonopioid-dependent rats. Furthermore, fentanyl self-administration was not significantly altered by increasing fixed-proportion mixtures of clonidine or lofexidine under either behavioral economic demand or fentanyl versus food choice procedures. Overall, these results demonstrate that α-2 agonists do not modulate fentanyl reinforcement in nonopioid-dependent rats and suggest that other potential reasons need to be explored for α-2 agonist adulteration of illicitly manufactured fentanyl. SIGNIFICANCE STATEMENT: Illicitly manufactured fentanyl continues to be adulterated with α-2 agonists. The present results demonstrate that clonidine and lofexidine neither enhance nor attenuate fentanyl self-administration under either behavioral economic demand or drug-choice procedures. These results suggest other factors than reinforcement modulation should be examined regarding the premise for α-2 agonist adulteration of illicitly manufactured fentanyl.