A rat model of operant negative reinforcement in opioid-dependent males and females.

RATIONALE AND OBJECTIVE: Avoidance of opioid withdrawal plays a key role in human opioid addiction. Here, we present a procedure for studying operant negative reinforcement in rats that was inspired by primate procedures where opioid-dependent subjects lever-press to prevent naloxone infusions. METHODS: In Experiment 1, we trained rats (n = 30, 15 females) to lever-press to escape and then avoid mild footshocks (0.13-0.27 mA) for 35 days (30 trials/d). Next, we catheterized them and implanted minipumps containing methadone (10 mg/kg/day) or saline. We then paired (4 times, single session) a light cue (20-s) with a naloxone infusion (20 µg/kg, i.v) that precipitated opioid withdrawal. Next, we trained the rats to escape naloxone injections for 10 days (30 trials/d). Each trial started with the onset of the opioid-withdrawal cue. After 20-s, the lever extended, and an infusion of naloxone (1 to 2.2 µg/kg/infusion) began; a lever-press during an 11-s window terminated the withdrawal-paired cue and the infusion. In Experiment 2, we trained rats (n = 34, 17 females) on the same procedure but decreased the footshock escape/avoidance training to 20 days. RESULTS: All rats learned to lever-press to escape or avoid mild footshocks. In both experiments, a subset, 56% (10/18) and 33% (8/24) of methadone-dependent rats learned to lever-press to escape naloxone infusions. CONCLUSIONS: We introduce an operant negative reinforcement procedure where a subset of opioid-dependent rats learned to lever-press to escape withdrawal-inducing naloxone infusions. The procedure can be used to study mechanisms of individual differences in opioid negative reinforcement-related behaviors in opioid-dependent rats.

Characterization of operant social interaction in rats: effects of access duration, effort, peer familiarity, housing conditions, and choice between social interaction vs. food or remifentanil.

RATIONALE AND OBJECTIVE: Social factors play a critical role in drug addiction. We recently showed that rats will abstain from methamphetamine, cocaine, heroin, and remifentanil self-administration when given a choice between the addictive drug and operant social interaction. Here, we further characterized operant social interaction by determining the effects of access duration, effort, peer familiarity, and housing conditions. We also determined choice between social interaction vs. palatable food or remifentanil. METHODS: We first trained single-housed male and female rats to lever-press for social interaction with a sex- and age-matched peer. Next, we determined effects of access duration (3.75 to 240 s), effort (increasing fixed-ratio schedule requirements or progressive ratio schedule), peer familiarity (familiar vs. unfamiliar), and housing conditions (single vs. paired housing) on social self-administration. We also determined choice between social interaction vs. palatable food pellets or intravenous remifentanil (0, 1, 10 µg/kg/infusion). RESULTS: Increasing access duration to a peer decreased social self-administration under fixed ratio but not progressive ratio schedule; the rats showed similar preference for short vs. long access duration. Social self-administration under different fixed ratio requirements was higher in single-housed than in paired-housed rats and higher for a familiar vs. unfamiliar partner in single-housed but not paired-housed rats. Response rates of food-sated rats under increasing fixed-ratio requirements were higher for palatable food than for social interaction. The rats strongly preferred palatable food over social interaction and showed dose-dependent preference for social interaction vs. remifentanil. CONCLUSIONS: We identified parameters influencing the reinforcing effects of operant social interaction and introduce a choice procedure sensitive to remifentanil self-administration dose.

Effects of Limited and Extended Pavlovian Training on Devaluation Sensitivity of Sign- and Goal-Tracking Rats.

Individual differences in Pavlovian approach predict differences in devaluation sensitivity. Recent studies indicate goal-tracking (GT) rats are sensitive to outcome devaluation while sign-tracking (ST) rats are not. With extended training in Pavlovian lever autoshaping (PLA), GT rats display more lever-directed behavior, typical of ST rats, suggesting they may become insensitive to devaluation with more Pavlovian training experience. Here, we use a within-subject satiety-induced outcome devaluation procedure to test devaluation sensitivity after limited and extended PLA training in GT and ST rats. We trained rats in PLA to determine GT and ST groups. Then, we sated rats on either the training pellets (devalued condition) or homecage chow (valued condition) prior to brief non-reinforced test sessions after limited (sessions 5/6) and extended (sessions 17/18) PLA training. GT rats decreased conditioned responding under devalued relative to valued conditions after both limited and extended training, demonstrating they are sensitive to satiety devaluation regardless of the amount of PLA training. While ST rats were insensitive to satiety devaluation after limited training, their lever directed behavior became devaluation sensitive after extended training. To determine whether sign-tracking rats also displayed sensitivity to illness-induced outcome devaluation after extended training, we trained a separate cohort of rats in extended PLA and devalued the outcome with lithium chloride injections after pellet consumption in the homecage. ST rats failed to decrease conditioned responding after illness-induced outcome devaluation, while Non-ST rats (GT and intermediates) were sensitive to illness-induced outcome devaluation after extended training. Together, our results confirm devaluation sensitivity is stable in GT rats across training and devaluation approaches. Extended training unmasks devaluation sensitivity in ST rats after satiety, but not illness-induced devaluation, suggesting ST rats respond appropriately by decreasing responding to cues during state-dependent but not inference-based devaluation. The differences in behavioral flexibility across tracking groups and devaluation paradigms have translational relevance for the understanding state- vs. inference-based reward devaluation as it pertains to drug addiction vulnerability.