The motivation to seek cocaine comes in part from a dysregulation of reward processing manifested in dysphoria, or affective withdrawal. Learning is a critical aspect of drug abuse; however, it remains unclear whether drug-associated cues can elicit the emotional withdrawal symptoms that promote cocaine use. Here we report that a cocaine-associated taste cue elicited a conditioned aversive state that was behaviorally and neurophysiologically quantifiable and predicted subsequent cocaine self-administration behavior. Specifically, brief intraoral infusions of a cocaine-predictive flavored saccharin solution elicited aversive orofacial responses that predicted early-session cocaine taking in rats. The expression of aversive taste reactivity also was associated with a shift in the predominant pattern of electrophysiological activity of nucleus accumbens (NAc) neurons from inhibitory to excitatory. The dynamic nature of this conditioned switch in affect and the neural code reveals a mechanism by which cues may exert control over drug self-administration.

In Experiment 1, water-deprived Sprague-Dawley rats were given 5 min access to saccharin. This tube retracted, an empty tube advanced, and the rats were given 1 hr to lick the empty tube on a fixed-ratio 10 lick contingency to self-administer saline or cocaine (0.33 mg/infusion) via an intravenous catheter. The results showed that rats avoided intake of saccharin after saccharin-cocaine pairings and that greater avoidance of the gustatory cue was associated with greater cocaine self-administration. In Experiment 2, a similar dose-response function was obtained with either the empty tube or a lever as the operant. In Experiment 3, avoidance of the saccharin cue and the propensity to self-administer cocaine were maintained after at least 1 month of abstinence. As such, this paradigm may be useful as a model of cue-induced craving and drug-induced devaluation of natural rewards.

In Experiment 1, water deprived rats were given 5 min access to saccharin followed by either the active or the yoked delivery of saline or cocaine (0.33 mg/infusion) via an intravenous catheter. Both cocaine groups avoided intake of the saccharin cue following saccharin-cocaine pairings, however, the rats in the yoked condition exhibited greater avoidance of the taste cue than did those that actively self-administered the same dose of the drug. Experiment 2 evaluated subsequent self-administration behavior on fixed and progressive ratio schedules of reinforcement. The results showed that prior yoked exposure to cocaine reduced subsequent drug taking behavior on a progressive ratio but not on a fixed ratio schedule. Finally, Experiment 3 used a choice test to determine the impact of yoked drug delivery on the relative preference for cocaine vs. water. The results showed that rats with a history of self-administering cocaine preferred to perform operant behaviors on the side of the chamber previously paired with cocaine, whereas the rats with a history of yoked delivery of cocaine avoided this side and, instead, preferred to perform operant behaviors on the opposite side of the chamber. These data show that, in most rats, the unpredictable, uncontrollable delivery of cocaine protects against the subsequent motivation for cocaine through an aversive mechanism.

Adaptive social behavior requires transmission and reception of salient social information. Impairment of this reciprocity is a cardinal symptom of autism. The amygdala is a critical mediator of social behavior and is implicated in social symptoms of autism. Here we found that a specific amygdala circuit, from the lateral nucleus to the medial nucleus (LA-MeA), is required for using social cues to learn about environmental cues that signal imminent threats. Disruption of the LA-MeA circuit impaired valuation of these environmental cues and subsequent ability to use this cue to guide behavior. Rats with impaired social guidance of behavior due to knockout of Nrxn1, an analog to autism-associated genes (NRXN), exhibited marked LA-MeA deficits. Chemogenetic activation of this circuit reversed these impaired social behaviors. These findings identify an amygdala circuit required to guide emotional responses to socially significant cues and identify a novel exploratory target for disorders associated with social impairments.