Ventral Tegmental Area Cannabinoid Type-1 Receptors Control Voluntary Exercise Performance

Background We have shown that the endogenous stimulation of cannabinoid type-1 (CB 1 ) receptors is a prerequisite for voluntary running in mice, but the precise mechanisms through which the endocannabinoid system exerts a tonic control on running performance remain unknown. Methods We analyzed the respective impacts of constitutive/conditional CB 1 receptor mutations and of CB 1 receptor blockade on wheel-running performance. We then assessed the consequences of ventral tegmental area (VTA) CB 1 receptor blockade on the wheel-running performances of wildtype (gamma-aminobutyric acid [GABA]- CB 1 +/+ ) and mutant (GABA- CB 1 –/– ) mice for CB 1 receptors in brain GABA neurons. Using in vivo electrophysiology, the consequences of wheel running on VTA dopamine (DA) neuronal activity were examined in GABA- CB 1 +/+ and GABA- CB 1 –/– mice. Results Conditional deletion of CB 1 receptors from brain GABA neurons, but not from several other neuronal populations or from astrocytes, decreased wheel-running performance in mice. The inhibitory consequences of either the systemic or the intra-VTA administration of CB 1 receptor antagonists on running behavior were abolished in GABA- CB 1 –/– mice. The absence of CB 1 receptors from GABAergic neurons led to a depression of VTA DA neuronal activity after acute/repeated wheel running. Conclusions This study provides evidence that CB 1 receptors on VTA GABAergic terminals exert a permissive control on rodent voluntary running performance. Furthermore, it is shown that CB 1 receptors located on GABAergic neurons impede negative consequences of voluntary exercise on VTA DA neuronal activity. These results position the endocannabinoid control of inhibitory transmission as a prerequisite for wheel-running performance in mice.