A reliable method to study cue-, priming-, and stress-induced reinstatement of cocaine self-administration in mice

Abstract

Cocaine addiction is a relapsing psychiatric disorder with a high prevalence in developed countries. To date, the reinstatement model has been difficult to implement in mice. The design of an appropriate reinstatement model in mice is required in order to use genetically modified animals with the aim of clarifying the mechanisms involved in cocaine relapse. Our aim was to develop an appropriate model of reinstatement of cocaine-seeking behavior and to investigate the factors that can trigger this reinstatement by using an operant intravenous self-administration procedure in mice. Discrete cues, priming injection of cocaine, and exposure to stress were the stimuli used to reinstate cocaine-seeking behavior. Mice were trained to acquire intravenous self-administration of cocaine (1 mg/kg per infusion) on a fixed ratio 1 (FR1) schedule of reinforcement. After achieving the acquisition criteria, animals were led to extinguish the operant behavior. Subsequently, under extinction conditions, mice were tested after the administration of a cocaine priming injection (10 mg/kg i.p.), the presentation of a light cue associated with cocaine administration, or the exposure to a stressful situation (0.21 mA electric footshock). Under our experimental conditions the three stimuli successfully reinstated an extinguished cocaine-seeking behavior. Reexposure to cocaine effects by a priming injection was revealed as the strongest stimulus, capable of reinstating cocaine-seeking behavior. The effective reinstatement model that we have developed will become a useful tool for future understanding of the neurobiological basis of cocaine addiction and relapse, specifically, with the use of genetically modified mice.