Cocaine reinstates extinguished food responding in male cynomolgus monkeys with a history of self-administering cocaine under a concurrent drug versus food choice paradigm.

The rate-dependency principle postulates that "stimulants" tend to increase low baseline rates of response and decrease high baseline responses. One exception to this principle is that stimulants do not typically increase responses that has been extinguished. However, drug self-administration studies showed that stimulant pretreatments reinstated extinguished drug-maintained responses. The goal of this study was to determine the effects of noncontingent cocaine on extinguished food-maintained responding in 3 male cynomolgus monkeys with extensive cocaine self-administration experience. Monkeys had a >4-year history of self-administering cocaine under a concurrent cocaine versus food schedule of reinforcement. For this study, only the discriminative stimulus (SD) signaling a fixed-ratio 30 schedule of food reinforcement was studied, and the previous cocaine-associated SD was not illuminated (inactive). In experiment 1, the effect of noncontingent food (1-5 pellets) and cocaine (0.03-0.3 mg/kg i.v.) on extinguished food-maintained responses was studied. In all 3 monkeys, 5 pellets and at least 1 cocaine dose significantly increased extinguished responding; the effects of cocaine were larger than those of food. In experiment 2, the behavioral mechanisms mediating these cocaine-induced increases in extinguished responses were studied. Following administration of 0.3 mg/kg cocaine, with no SD illuminated, responses occurred on both the previously active (food) and inactive (cocaine) manipulanda. When cocaine was given and both SDs were illuminated, more responses occurred on the inactive (cocaine) versus previously active (food) switch. These findings suggest that a cocaine self-administration history can influence the direct behavioral effects of cocaine. Increases in previously extinguished nondrug-reinforced behaviors could have clinical implications related to relapse. SIGNIFICANCE STATEMENT: Following long-term cocaine self-administration in the context of a nondrug alternative, noncontingent cocaine administration reinstated previously extinguished responses maintained by delivery of food pellets, suggesting that reinstatement studies may not be measuring relapse of "drug-seeking." Importantly, the effects of self-administered cocaine on the brain and behavior cannot be determined in the absence of systematically studying ongoing behavior.