Fentanyl reinforcement history has sex-specific effects on multi-step decision-making

Abstract

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.

Figure 1.

(A) Cumulative sum of fentanyl and water rewards as a function of session time as rats pressed a lever for liquid rewards under thirsty and non-thirsty conditions. Cumulative sums were normalized in the range of 0–1 and then interpolated. Right-most bar plot shows means over the first half of the session. (B) Left: Mean reward rates while rats pressed a lever on an FR5 schedule for either liquid fentanyl or sucrose after receiving IP injections of saline or naltrexone. Grey lines are individual rats. Middle: Cumulative fentanyl rewards earned across sessions. Inset shows the cumulative intake. Right: Cumulative sucrose rewards earned across sessions.

Figure 2.

Two-step task structure, experimental design, and performance statistics. (A) Left: Schematic of behavioral apparatus, consisting of one magazine for center fixation and two flanking nose-ports, and one magazine for reward and two retractable levers on the opposite side. Right: task structure consisted of an initial choice state where either the left or right nose-poke could be chosen, and each choice led to a common (0.8) or rare (0.2) lever transition probability. Each lever was associated with a high (0.8) or low (0.2) reward probability, which switched in blocks. (B) Illustration of experimental design. Two groups of rats were trained to earn either oral fentanyl or sucrose on the two-step task for many sessions, and then experienced alternating sessions of fentanyl and sucrose. Alternating sessions with the reward type not experienced during training took place in contexts with a different scent and floor texture. (C) Definition of symbols in panel A. During the alternating rewards phase, two variables changed between sessions: reward type and context. The training context refers to the context the rats were trained in, while the alternating context refers to an altered floor texture (indicated by grid pattern) and scent (indicated by yellow outline). (D) Mean rewards, trials, reward rate, and fentanyl intake per session. Data are taken from the final 6 sessions of the alternating rewards phase. Black data points are males and grey data points are females.

Figure 3.

Fentanyl enhances habit expression in female rats. (A) Stay probabilities plotted as a function of the previous trial outcome (1 = reward, 0 = omission), transition (1 = common, 0 = rare), training group (fentanyl vs. sucrose), instrumental reward (fentanyl vs. sucrose), and sex (male vs. female). MF and MB indices derived from the stay probabilities are also shown. Bars show means across rats, error bars show SEMs, and grey lines are individual rats. (B) Stay probabilities averaged over trial-level variables (i.e. outcome and transition) and plotted as a function of training group and instrumental reward (left). Data are broken down further by dividing the sucrose training group into males and females (right). Bars show means across rats, error bars show SEMs, and grey lines are individual rats. (C) Summary of main findings. Perseveration, defined as the mean stay probability, is plotted against MF bias, defined as MF – MB index. Fentanyl trained females (left) showed a high level of perseveration and a high MF bias during fentanyl and sucrose sessions. Sucrose trained females (right) showed a high level of perseveration specifically during fentanyl sessions, but not MF bias. Each data point is an individual rat.

Figure 4.

Within-session decrements in MB choice during fentanyl reinforcement. (A) Reward-guided MB indices, defined as the difference in the stay probabilities between reward-common and reward-rare trials, are shown as a function of session half separately for males and females trained with fentanyl (top) or sucrose (bottom). Lines are means across rats, and shaded bounds are SEMs. (B) Summary of main finding. Reward-guided MB indices are plotted as a function of instrumental reward and session half for all rats (left). The difference between reward-guided MB choice during the first and second halves of the sessions is plotted for individual rats during sucrose and fentanyl sessions. (C) Stay probabilities averaged across trial-level variables (i.e. outcome and transition) are plotted over sessions halves separately for instrumental reward, training group, and sex. (D) Summary of perseveration scores over time. Stay probabilities are plotted as a function of instrumental reward and session half for all rats (left). The difference between perseveration scores during the first and second halves of the sessions is plotted for individual rats during sucrose and fentanyl sessions.