In behavioral addiction, addicts repeat certain behaviors, such as internet gaming and gambling, despite negative consequences. No cure has been established due to the lack of animal models to explore its neuronal mechanisms. Here, by focusing on voluntary wheel-running in rodents, we have developed a novel operant conditioning task as a model of behavioral addiction, in which male C57BL/6J mice (> 7 weeks old) were allowed for wheel-running after certain numbers of nose pokes. In this task, the magnitude of motivation for wheel-running is quantifiable by evaluating the number of nose pokes.
We first measured dopamine (DA) release using fiber photometry with GRAB-DA sensors and found that DA was increased in the nucleus accumbens (NAc) immediately after nose-poking. Systemic administration of antagonists for DA D1 receptor (SCH23390; 0.025–0.1 mg/kg), D2 receptor (raclopride; 0.1–0.6 mg/kg), or an agonist for adenosine A2A receptor (CGS21680; 0.05-0.1 mg/kg) dose-dependently decreased the number of nose pokes. Intra-NAc infusion of these drugs (SCH23390; 0.05 µg/side, raclopride; 0.3 µg/side, CGS21680; 1 ng/side) also reduced the number of nose pokes. Additionally, systemic administration of serotonin (5-HT)2A receptor antagonist (volinanserin; 0.01–0.1 mg/kg) or 5-HT2C receptor antagonist (SB242084; 0.3–1.0 mg/kg) dose-dependently decreased the number of nose pokes. These results suggest that neurotransmission via D1, D2, and A2A receptors in the NAc and 5-HT2A and 2C receptors are involved in the motivation for wheel-running.