NEURAL ACTIVITY CHANGES VIA DOPAMINE D1 RECEPTOR STIMULATION IN THE NUCLEUS ACCUMBENS MODULATE MOTIVATION FOR WHEEL RUNNING IN MICE

Abstract Background Excessive motivation for natural rewards leads to behavioral addiction (Olsen 2011). Several human brain imaging studies suggest that brain reward circuits play an important role in behavioral addiction. However, detailed neural mechanisms remain unclear due to the lack of appropriate animal models. Wheel running is rewarding for rodents, and they learn lever-pressing and nose-poking for wheel running (Muguruza et al., 2019). In addition, wheel running for rodents may have addiction-like characteristics (Hoffman et al., 1987; Medrano et al., 2020), which are also induced by addictive drugs. Several reports, including our previous study, have shown that neural activation and dopamine signaling in the nucleus accumbens (NAc) are associated with wheel running (Rhodes and Garland 2003; Zhang et al., 2022). However, the role of NAc neural activity and dopamine signaling in the motivation for wheel running remains unclear. Aims & Objectives Here, we developed an operant conditioning task reinforced by wheel running as a model of behavioral addiction that can separately quantify appetitive and consummatory components of motivation for wheel running, and examined the role of NAc neural activity and dopamine signaling. Method In the operant wheel running task, male C57BL/6J mice (> 7 weeks old) were first habituated to the chamber and allowed to run freely on the wheel for 60 min per day, and then trained on the fixed ratio (FR) 1 schedule, in which the wheel was unlocked for 1 min after the mice made a nose poke to the active nose poke port. The FR was increased to FR10. The number of nosepokes (NPs) and running duration were evaluated as appetitive and consummatory components of motivation for wheel running. In fiber photometry recordings, neural activity and dopamine levels in the NAc were monitored using jGCaMP8m and GRABDA2h, respectively. Results Systemic administration of a dopamine D1 receptor antagonist SCH23390 (0.025-0.1 mg/kg, i.p.) or a D2 receptor antagonist raclopride (0.1-0.6 mg/kg, i.p.) dose-dependently decreased the number of active NPs, whereas only D1 receptor blockade decreased running duration. Intra-NAc administration of a GABAA receptor agonist muscimol (0.01 & micro;g/side), SCH23390 (0.05 & micro;g/side) or raclopride (0.3 & micro;g/side) significantly decreased the number of NPs, whereas only D1 receptor blockade decreased running duration. Fiber photometry recordings of jGCaMP8m demonstrated that NAc neural activity was decreased before the first NPs and increased immediately after the last NPs, by which mice recognized the availability of wheel-running. Additionally, fiber photometry recordings of GRABDA2h in the NAc revealed that dopamine levels increased before the first NPs and immediately after the last NPs. Furthermore, systemic administration of SCH23390 (0.05 mg/kg, i.p.), but not raclopride (0.3 mg/kg, i.p.), significantly attenuated the decrease and increase in NAc neural activity before the first NPs and after the last NPs, respectively. Discussion & Conclusion These findings suggest that the increase in dopamine release and the subsequent changes in neural activities mediated by D1 receptors in the NAc are associated with the motivated behavior for wheel running. References 1.Olsen C. M. (2011). Natural rewards, neuroplasticity, and non-drug addictions. Neuropharmacology, 61(7), 1109–1122. 2.Muguruza, C., Redon, B., Fois, G. R., Hurel, I., Scocard, A., Nguyen, C., Stevens, C., Soria-Gomez, E., Varilh, M., Cannich, A., Daniault, J., Busquets-Garcia, A., Pelliccia, T., Caillé, S., Georges, F., Marsicano, G., & Chaouloff, F. (2019). The motivation for exercise over palatable food is dictated by cannabinoid type-1 receptors. JCI insight, 4(5), e126190. 3.Hoffmann, P., Thoré n, P., & Ely, D. (1987). Effect of voluntary exercise on open-field behavior and on aggression in the spontaneously hypertensive rat (SHR). Behavioral and neural biology, 47(3), 346–355. 4.Medrano, M. C., Hurel, I., Mesguich, E., Redon, B., Stevens, C., Georges, F., Melis, M., Marsicano, G., & Chaouloff, F. (2021). Exercise craving potentiates excitatory inputs to ventral tegmental area dopaminergic neurons. Addiction biology, 26(3), e12967. 5.Rhodes, J. S., & Garland, T. (2003). Differential sensitivity to acute administration of Ritalin, apomorphine, SCH 23390, but not raclopride in mice selectively bred for hyperactive wheel-running behavior. Psychopharmacology, 167(3), 242–250. 6.Zhang, T., Nishitani, N., Niitani, K., Nishida, R., Futami, Y., Deyama, S., & Kaneda, K. (2022). A spatiotemporal increase of neuronal activity accompanies the motivational effect of wheel running in mice. Behavioural brain research, 432, 113981.