Ample evidence shows that the setting can control drug choices in both humans and animals. Here we reveal in rats that a major mechanism of this control involves a regulation of the drug influence on other competing options at the time of choice. Briefly, rats were offered a choice between a drug dose (cocaine or heroin) and a brief access to water sweetened with saccharin in two different settings. In one setting, choosing under the influence was not possible and rats largely preferred saccharin over either cocaine or heroin. In contrast, when the same rats were shifted to a setting where choosing under the influence was possible, they chose the drug either nonexclusively or exclusively depending on whether the drug enhanced or suppressed sweet reward, respectively. Thus, when rats were under the orexigenic influence of heroin at the time of choice, they more frequently chose saccharin in alternation with heroin. In contrast, when rats were under the anorexic influence of cocaine, they stopped choosing saccharin and continued taking cocaine exclusively. These settingand drug-specific changes in preference were rapid and reversible, and could be induced by passively administering cocaine or heroin before choice. Finally, rats behaved as if they were oblivious to the drug influence on their choices. This behavior could explain why rats are vulnerable to harm themselves, sometimes to the point of death, in settings where choices are made under the drug influence, notably if this influence excludes other important options or, conversely, enhances harmful ones.

The concept of compulsive cocaine-seeking habits is difficult to reconcile with other evidence showing that humans and even rats remain able to shift their choice away from the drug and toward an alternative nondrug reward, when available. This paradox could dissolve if preference for the nondrug option reflected in fact inflexible habitual decision-making (i.e., fixed in a habitual control mode, with no return to a goal-directed control mode). Previous research in rats has shown that prior drug use can favor habit formation, but whether the resulting habits are inflexible or not is largely unknown. Here we addressed this question by manipulating the value of water in rats that chose between water and cocaine in a discrete-trials procedure. Rats preferred water when thirsty and maintained this preference despite water devaluation by satiation. Only with repeated daily testing under water satiation did they progressively reverse their preference toward cocaine. Additional evidence showed that this progressive reversal of preference reflected in fact new interoceptive discrimination learning. Overall, this study suggests that rats seem to be stuck in a habitual decision-making mode, unable to return to a goal-directed mode upon experiencing a change in options value. It also reveals that inflexible decision-making does not necessarily promote drug choice, but can also under some circumstances favor abstinence.

People with cocaine addiction retain some degree of prefrontal cortex (PFC) inhibitory control of cocaine craving, a brain capacity that may underlie the efficacy of cognitive behavioral therapy for addiction. Similar findings were recently found in rats after extended access to and escalation of cocaine self-administration. Rats' inhibitory control of cocaine seeking was flexible, sufficiently strong to suppress cocaine-primed reinstatement and depended, at least in part, on neuronal activity within the prelimbic (PL) PFC. Here, we used a large-scale and high-resolution Fos mapping approach to identify, beyond the PL PFC, how top-down and/or bottom-up PFC-subcortical circuits are recruited during inhibition of cocaine seeking. Overall, we found that effective inhibitory control of cocaine seeking is associated with the coordinated recruitment of different top-down cortical-striatal circuits originating from different PFC territories, and of different bottom-up dopamine (DA) and serotonin (5-HT) midbrain subsystems that normally modulate activity in these circuits. This integrated brain response suggests that rats concomitantly engage and experience intricate cognitive and affective processes when they have to inhibit intense cocaine seeking. Thus, even after extended drug use, rats can be successfully trained to engage whole-brain inhibitory control mechanisms to suppress cocaine seeking.