Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
Neuropsychopharmacology. 2024 Dec;49(13):2011-2021. doi: 10.1038/s41386-024-01939-7. Epub 2024 Aug 5.
Substance use disorders are defined by persistent drug consumption despite adverse consequences. Accordingly, we developed two fentanyl-vs-shock avoidance/escape choice procedures in which male and female rats responded under a fixed-ratio (FR)1:FR1 concurrent schedule of shock avoidance/escape and IV fentanyl under either mutually exclusive or non-exclusive choice conditions. Initial experiments using a discrete-trial procedure determined behavioral allocation between mutually exclusive shock avoidance/escape and different fentanyl doses (0.32-18 μg/kg/infusion; Experiment 1). Shock intensity (0.1-0.7 mA) and shock avoidance/escape response requirement (FR1-16) were also manipulated (Experiment 2). Next, we used a free-operant procedure in which shock avoidance/escape and fentanyl were continuously available under non-exclusive conditions, and response-shock (R-S) interval (30-1000 s) was manipulated (Experiment 3). Finally, we tested the hypothesis that extended-access fentanyl self-administration would produce fentanyl dependence, establish fentanyl withdrawal as an endogenous negative reinforcer, and increase fentanyl choice in both procedures (Experiments 4 and 5). The shock avoidance/escape contingency decreased fentanyl self-administration, and rats consistently chose shock avoidance/escape over fentanyl in both choice conditions. Decreasing shock intensity or increasing shock avoidance/escape response requirement failed to increase fentanyl choice, suggesting that fentanyl and shock avoidance/escape are independent economic commodities. Increasing the R-S interval increased fentanyl choice but failed to increase shock delivery. Extended fentanyl access engendered high fentanyl intake and opioid withdrawal signs but failed to increase fentanyl choice under either choice condition. These results suggest that neither positive fentanyl reinforcement nor negative reinforcement by fentanyl withdrawal is sufficient to reduce shock avoidance/escape-maintained responding and increase foot shock as an adverse consequence.
物质使用障碍是指尽管存在不良后果，但仍持续使用药物。因此，我们开发了两种芬太尼与回避/逃避选择程序，雄性和雌性大鼠在回避/逃避和 IV 芬太尼的固定比率（FR）1:FR1 同时程序下进行反应，在相互排斥或非排斥选择条件下。使用离散试验程序的初步实验确定了相互排斥的回避/逃避和不同芬太尼剂量（0.32-18 μg/kg/输注；实验 1）之间的行为分配。还操纵了电击强度（0.1-0.7 mA）和回避/逃避反应要求（FR1-16）（实验 2）。接下来，我们使用自由操作程序，在非排斥条件下连续提供回避/逃避和芬太尼，操纵反应-电击（R-S）间隔（30-1000 s）（实验 3）。最后，我们检验了以下假设：延长的芬太尼自我给药会产生芬太尼依赖，将芬太尼戒断作为内源性负强化物，并增加两种程序中的芬太尼选择（实验 4 和 5）。回避/逃避条件减少了芬太尼的自我给药，并且在两种选择条件下，大鼠一致地选择回避/逃避而不是芬太尼。降低电击强度或增加回避/逃避反应要求都未能增加芬太尼的选择，这表明芬太尼和回避/逃避是独立的经济商品。增加 R-S 间隔增加了芬太尼的选择，但未能增加电击的输送。延长的芬太尼获取会导致芬太尼摄入量增加和阿片类戒断迹象，但在两种选择条件下均未能增加芬太尼的选择。这些结果表明，芬太尼的正强化或戒断引起的负强化都不足以减少回避/逃避维持的反应并增加作为不良后果的足部电击。
