Garr Eric, Cheng Yifeng, Dong Andy, Janak Patricia H
Department of Psychological & Brain Sciences, Krieger School of Arts & Sciences, Johns Hopkins University, Baltimore, MD, 21218, USA.
Kavli Neuroscience Discovery Institute, Johns Hopkins University, Baltimore, MD, 21205, USA.
bioRxiv. 2025 Jun 5:2024.10.10.617707. doi: 10.1101/2024.10.10.617707.
It is commonly thought that drug addiction involves a transition to habitual control of action, where the choice to consume drugs becomes automatized and reflects a failure to deliberate over possible negative outcomes. Determining whether the pursuit of addictive drugs is habitual is hampered by a lack of behavior assessments suitable for use during a bout of actual drug seeking. Therefore, to understand how variable histories of drug reinforcement might affect goal-directed and habitual pursuit of drug, we trained rats to perform a multi-step decision-making task to earn oral fentanyl and sucrose rewards following extensive pretraining with either fentanyl or sucrose. Importantly, this task allowed for independent measurements of goal-directed and habitual choice characteristics during online pursuit of rewards, and habitual choice could be further categorized into perseverative and reward-guided components. Chronic fentanyl led to a bias for reward-guided habitual choice specifically in females, and a high degree of perseveration in both sexes. These behavioral changes after chronic fentanyl pretraining generalized across fentanyl and sucrose seeking. In contrast, acute fentanyl selectively increased perseveration in females, and blunted the gradual within-session improvement in goal-directed choice in both sexes. These results show that chronic fentanyl reinforcement promotes habits that generalize across drug and non-drug reward seeking, and that female rats are especially susceptible to habitual control induced by both chronic and acute fentanyl reinforcement.
人们普遍认为，药物成瘾涉及到行为控制向习惯化的转变，即服用药物的选择变得自动化，这反映出未能对可能的负面结果进行深思熟虑。由于缺乏适用于实际药物寻求过程中的行为评估方法，确定对成瘾药物的追求是否具有习惯性受到了阻碍。因此，为了了解不同的药物强化历史如何影响对药物的目标导向性和习惯性追求，我们训练大鼠在经过用芬太尼或蔗糖进行广泛预训练后，执行一项多步骤决策任务以获取口服芬太尼和蔗糖奖励。重要的是，这项任务允许在在线奖励追求过程中独立测量目标导向性和习惯性选择特征，并且习惯性选择可以进一步细分为坚持性和奖励引导性成分。慢性芬太尼导致了特别是在雌性大鼠中对奖励引导性习惯性选择的偏好，以及在两性中都出现了高度的坚持性。慢性芬太尼预训练后的这些行为变化在对芬太尼和蔗糖的寻求中都具有普遍性。相比之下，急性芬太尼选择性地增加了雌性大鼠的坚持性，并削弱了两性在目标导向性选择中会话内的逐渐改善。这些结果表明，慢性芬太尼强化促进了在药物和非药物奖励寻求中都具有普遍性的习惯，并且雌性大鼠对慢性和急性芬太尼强化诱导的习惯性控制尤其敏感。
