Ventral tegmental area cannabinoid type-1 receptors control voluntary exercise performance

Biol Psychiatry. 2013 May 1;73(9):895-903. doi: 10.1016/j.biopsych.2012.10.025. Epub 2012 Dec 11.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dronabinol / pharmacology
  • Male
  • Mice
  • Mice, Knockout
  • Motor Activity / drug effects
  • Motor Activity / physiology*
  • Neurons / drug effects
  • Neurons / metabolism
  • Physical Conditioning, Animal / physiology*
  • Piperidines / pharmacology
  • Pyrazoles / pharmacology
  • Receptor, Cannabinoid, CB1 / genetics
  • Receptor, Cannabinoid, CB1 / metabolism*
  • Rimonabant
  • Ventral Tegmental Area / drug effects
  • Ventral Tegmental Area / metabolism*


  • Piperidines
  • Pyrazoles
  • Receptor, Cannabinoid, CB1
  • AM 251
  • Dronabinol
  • Rimonabant