Hochstetler Mason, Dodge Anastasia, Chakraborty Songjukta, Jeffers Ann, Mitra Swarup
Department of Pharmacology and Physiology, Oklahoma State University Center for Health Sciences, Tulsa, OK, United States.
Department of Pharmacology and Physiology, Oklahoma State University Center for Health Sciences, Tulsa, OK, United States.
Pharmacol Biochem Behav. 2025 Sep;254:174052. doi: 10.1016/j.pbb.2025.174052. Epub 2025 Jun 10.
The current opioid use disorder crisis has been further complicated by the adulteration of the drug supply with the veterinary sedative xylazine. Xylazine is not approved for human use and is associated with numerous adverse effects when consumed. While most existing research has examined the consequences of fentanyl-xylazine co-administration, to date, no studies have explored the behavioral and withdrawal effects of heroin-xylazine co-administration. In the current study, we used a contingent model of heroin-xylazine (0.02 and 0.15 mg/kg/infusion) co-administration to demonstrate that in male rats, heroin consumption and motivation are attenuated when xylazine is co-administered with heroin. However, co-administration with xylazine potentiated cue-induced drug-seeking behavior following 10 days of extinction. In a separate cohort, we evaluated the impact of our selected xylazine dose on locomotion and found that it did not induce sedation, implicating that the behavioral effects produced were not confounded by locomotor suppression. We also assessed naloxone-precipitated withdrawal (1 mg/kg, s.c) and observed a reduction in total somatic withdrawal signs in the heroin-xylazine group, an effect not seen in the heroin-only group. Surprisingly, these reduced somatic signs did not extend to all behavioral modalities and diverged based on the type of somatic signs. These findings suggest that xylazine may function as a satiety-enhancing agent when co-administered with heroin, as evidenced by the suppression of self-administration. However, xylazine's effect on precipitating cue-induced reinstatement reveals the synergistic potential of its adulteration during relapse.
当前的阿片类药物使用障碍危机因兽用镇静剂赛拉嗪掺入毒品供应而进一步复杂化。赛拉嗪未被批准用于人类，服用时会产生许多不良反应。虽然大多数现有研究都考察了芬太尼 - 赛拉嗪联合给药的后果，但迄今为止，尚无研究探讨海洛因 - 赛拉嗪联合给药的行为和戒断效应。在本研究中，我们使用了海洛因 - 赛拉嗪（0.02和0.15毫克/千克/输注）联合给药的偶然模型，以证明在雄性大鼠中，当赛拉嗪与海洛因联合给药时，海洛因的摄入量和动机减弱。然而，在消退10天后，与赛拉嗪联合给药增强了线索诱导的觅药行为。在另一组实验中，我们评估了所选赛拉嗪剂量对运动的影响，发现它不会引起镇静作用，这意味着所产生的行为效应不是由运动抑制所混淆的。我们还评估了纳洛酮诱发的戒断反应（1毫克/千克，皮下注射），并观察到海洛因 - 赛拉嗪组的总体躯体戒断症状有所减少，而仅使用海洛因的组则未出现这种效果。令人惊讶的是，这些减少的躯体症状并未扩展到所有行为模式，而是根据躯体症状的类型有所不同。这些发现表明，赛拉嗪与海洛因联合给药时可能起到饱腹感增强剂的作用，自我给药的抑制就证明了这一点。然而，赛拉嗪对诱发线索诱导的复吸的影响揭示了其在复发期间掺入毒品的协同潜力。
