Elsevier

Biological Psychiatry

Volume 73, Issue 9, 1 May 2013, Pages 895-903
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2012.10.025Get rights and content

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.

Section snippets

Animals

All experiments complied with the French and European rules on animal experimentation. This study involved 2-month-old male C57BL/6N mice and 2- to 3-month-old male CB1 receptor mutant and wildtype animals, including constitutive CB1 receptor mutant mice (CB1–/–), conditional mutant mice lacking CB1 receptors from principal neurons (CaMK-CB1–/–), brain GABAergic neurons (GABA-CB1–/–), cortical glutamatergic neurons (Glu-CB1–/–), serotonergic neurons (TPH2-CB1–/–), dopamine D1

CB1 Receptors on Brain GABAergic Neurons Control Voluntary Running

Mutant mice lacking CB1 receptors from the whole body (CB1–/–) and their wildtype littermates (CB1+/+), bred as in Dubreucq et al. (14), were offered 3-hour daily access to running wheels for 2 weeks. This paradigm allowed observation of plateau levels of performance in both genotypes (Figure 1A). CB1–/– mice displayed low running activity, compared with CB1+/+ mice [F(1,35) = 8.22, p = .007], the amplitude of this difference increasing with the number of running sessions [F(13,455) = 3.23, p =

Discussion

Mutant mice lacking CB1 receptors have been reported to spend less time running and to run shorter distances than their wildtype littermates when housed with running wheels 14, 15. In these studies, however, the animals had unlimited access to the wheels, thus questioning the role of CB1 receptors during shorter running activities. To solve this issue, we used a paradigm in which mice had daily 3-hour access to exercise. This exercise duration was selected because it is sufficient to observe

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    Authors GM, FG, and FC contributed equally to this work

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