Medial nucleus accumbens dopamine receptors modulate motivation for wheel running in male mice.

Abnormal motivation for natural rewards is a hallmark of various psychiatric disorders, including behavioral addiction. The mesolimbic dopamine pathway has been identified as a critical modulator of motivated behavior primarily based on studies using food-reinforced operant tasks. However, the focus on food rewards in previous studies limits the generalizability of these findings to other natural rewards implicated in behavioral addiction. In this study, we investigated the reinforcing and high motivational properties of wheel running in rodents by developing a wheel running-reinforced operant conditioning procedure. This procedure allowed for the independent quantification of appetitive and consummatory behaviors as operant responses and running duration, respectively, facilitating an in-depth exploration of the role of dopamine signaling in the medial nucleus accumbens (mNAc) in wheel running motivation. The results indicated that the systemic inhibition of dopamine D₁ and D₂ receptors suppressed appetitive behavior, whereas inhibition of D₁ receptors reduced consummatory behavior. Similarly, inhibition of mNAc neural activity and blockade of D₁ and D₂ receptors within this region diminished appetitive behavior, with D₁ receptor inhibition uniquely impairing consummatory behavior. Fiber photometry recordings demonstrated that decreases in mNAc neural activity and increases in dopamine levels preceded appetitive behavior. Additionally, mNAc neural activity and dopamine levels were elevated following cues signaling the availability of wheel running. Furthermore, systemic D₁ receptor inhibition attenuated the reduction in mNAc neural activity observed during appetitive behavior. These findings suggest that increased dopamine release and the subsequent D₁ receptor-mediated suppression of mNAc neural activity underlie the motivated behavior for wheel running.