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

Background: We have shown that the endogenous stimulation of cannabinoid type-1 (CB1) 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 CB1 receptor mutations and of CB1 receptor blockade on wheel-running performance. We then assessed the consequences of ventral tegmental area (VTA) CB1 receptor blockade on the wheel-running performances of wildtype (gamma-aminobutyric acid [GABA]-CB1+/+) and mutant (GABA-CB1-/-) mice for CB1 receptors in brain GABA neurons. Using in vivo electrophysiology, the consequences of wheel running on VTA dopamine (DA) neuronal activity were examined in GABA-CB1+/+ and GABA-CB1-/- mice. Results: Conditional deletion of CB1 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 CB1 receptor antagonists on running behavior were abolished in GABA-CB1-/- mice. The absence of CB1 receptors from GABAergic neurons led to a depression of VTA DA neuronal activity after acute/repeated wheel running. Conclusions: This study provides evidence that CB1 receptors on VTA GABAergic terminals exert a permissive control on rodent voluntary running performance. Furthermore, it is shown that CB1 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.