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. 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. 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. 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. Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.