Adenosine A2A receptor activation in the nucleus accumbens decreases motivation for wheel running in male mice.

RATIONALE: Wheel running is a highly motivated behavior in rodents and is often used as a natural reinforcer. The adenosine A2A receptor is abundantly expressed in the nucleus accumbens (NAc) and plays a key role in the regulation of motivation and reward-related behaviors. However, its involvement in motivation for wheel running remains unclear.

OBJECTIVES

This study aimed to investigate how systemic and intra-NAc pharmacological manipulation of A2A receptors affects motivation for wheel running in mice.

METHODS

We examined the effects of systemic administration of the A2A receptor antagonist istradefylline and the A2A receptor agonist CGS21680 on voluntary wheel-running activity and general locomotor activity. We also assessed the effects of these drugs on operant conditioning tasks in which wheel-running served as a reward. Furthermore, we infused CGS21680 directly into the NAc to examine site-specific effects.

RESULTS

Systemic istradefylline administration increased voluntary wheel-running activity and general locomotion. In contrast, CGS21680 decreased voluntary wheel-running without affecting locomotion. In the operant task, systemic CGS21680 significantly reduced the operant response, a measure of appetitive behavior, without altering running duration, which reflects consummatory behavior. Similarly, intra-NAc infusion of CGS21680 suppressed appetitive behavior.

CONCLUSIONS

These findings demonstrate that, in male mice, A2A receptor activation selectively suppressed the appetitive component of wheel-running motivation, whereas A2A receptor blockade did not. Together, our results highlight the crucial role of NAc A2A receptors in regulating motivation for wheel running and suggest the potential therapeutic application of A2A receptor agonists for treating maladaptive behavioral over-engagement.