Neuroscience and Behavior, Psychology Department, University of Nebraska at Omaha, Omaha, NE, USA.
Neuroscience and Behavior, Psychology Department, University of Nebraska at Omaha, Omaha, NE, USA.
Drug Alcohol Depend. 2024 Oct 1;263:112426. doi: 10.1016/j.drugalcdep.2024.112426. Epub 2024 Aug 25.
Overdose deaths remain high for opioid use disorder, emphasizing the need to pursue innovative therapeutics. Classic psychedelic drugs that engage many monoamine receptors mitigate opioid use. Here, we tested the hypothesis that the preferential serotonin 5-HTR agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI) could reduce the demand for fentanyl in a preclinical model of fentanyl self-administration.
Male and female Sprague-Dawley rats (n = 25-29) were implanted with indwelling jugular catheters and allowed to self-administer fentanyl (3.2μg/kg/infusion). Rats progressed to a novel low price twice within-session threshold procedure where rats sampled the lowest price twice before decreasing the dose of fentanyl by a ¼ log every 10minutes across 11 doses. Once stable, rats were pretreated with saline or DOI (0.01, 0.03, 1mg/kg). Fentanyl consumption was analyzed using an exponentiated demand function to extract the dependent variables, Q and α.
Male and female rats acquired fentanyl self-administration in the lowest price twice within-session threshold procedure. DOI dose-dependently altered fentanyl intake such that 5-HTR activation decreased Q in female rats but increased Q in male rats. For demand elasticity, DOI increased α in male rats but did not alter α in female rats. DOI did not alter inactive lever presses or latency.
DOI reduces consumption at minimally constrained costs but did not affect the reinforcement value of fentanyl in female rats. Alternatively, DOI significantly reduced the reinforcement value of fentanyl in male rats. Biological sex alters the therapeutic efficacy of DOI and 5-HTR activation sex-dependently alters opioid reinforcement.
阿片类药物使用障碍导致的药物过量死亡仍然居高不下，这强调了需要寻求创新的治疗方法。与多种单胺受体结合的经典迷幻药物可减轻阿片类药物的使用。在这里，我们测试了这样一个假设，即优先作用于 5-羟色胺 5-HTR 的激动剂 2,5-二甲氧基-4-碘苯丙胺（DOI）可以减少芬太尼在芬太尼自我给药的临床前模型中的需求。
雄性和雌性 Sprague-Dawley 大鼠（n = 25-29）植入了留置颈内导管，并允许自行注射芬太尼（3.2μg/kg/ 输注）。大鼠在一个新的低价格两次内会话阈值程序中进展，在该程序中，大鼠在减少芬太尼剂量之前，在 11 个剂量中每 10 分钟采样两次最低价格。一旦稳定，大鼠用生理盐水或 DOI（0.01、0.03、1mg/kg）预处理。使用指数需求函数分析芬太尼消耗，以提取依赖变量 Q 和 α。
雄性和雌性大鼠在最低价格两次内会话阈值程序中获得了芬太尼的自我给药。DOI 剂量依赖性地改变了芬太尼的摄入，使得 5-HTR 激活降低了雌性大鼠的 Q，但增加了雄性大鼠的 Q。对于需求弹性，DOI 增加了雄性大鼠的α，但没有改变雌性大鼠的α。DOI 不改变无效杆按压或潜伏期。
DOI 降低了消费，但不会影响女性大鼠芬太尼的强化价值。相反，DOI 显著降低了雄性大鼠芬太尼的强化价值。生物性别改变了 DOI 的治疗效果，5-HTR 激活性别依赖性地改变了阿片类药物的强化作用。
