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

Exercise is rewarding, and long-distance runners have described a runner's high as a sudden pleasant feeling of euphoria, anxiolysis, sedation, and analgesia. A popular belief has been that endogenous endorphins mediate these beneficial effects. However, running exercise increases blood levels of both β-endorphin (an opioid) and anandamide (an endocannabinoid). Using a combination of pharmacologic, molecular genetic, and behavioral studies in mice, we demonstrate that cannabinoid receptors mediate acute anxiolysis and analgesia after running. We show that anxiolysis depends on intact cannabinoid receptor 1 (CB1) receptors on forebrain GABAergic neurons and pain reduction on activation of peripheral CB1 and CB2 receptors. We thus demonstrate that the endocannabinoid system is crucial for two main aspects of a runner's high. Sedation, in contrast, was not influenced by cannabinoid or opioid receptor blockage, and euphoria cannot be studied in mouse models.runner's high is described as an ephemeral pleasant phenomenon that may be experienced during long-term running. A popular belief has been that endorphins mediate a runner's high, although neurobiological mechanisms were unclear. In earlier experiments, two prominent systems (the opioid and endocannabinoid systems) were suggested to be involved in a runner's high (1-3). Running increases plasma levels of β-endorphin (an opioid) and anandamide (an endocannabinoid) in mice and men (4, 5). However, unlike the lipophilic anandamide, β-endorphin cannot cross the blood-brain barrier, rendering central effects of peripheral opioids unlikely. In an attempt to disentangle the biomechanism of a runner's high, we were using a combination of pharmacologic, molecular genetic, and behavioral studies in mice, and demonstrated for the first time to our knowledge that a runner's high depends on cannabinoid receptors in mice. Results and DiscussionIn a first step, mice (n = 32) were provided with running wheels for 3 d to start with and to habituate them to wheel running. Mice ran, on average, 5.4 km per day (Fig. 1A). After 2 d with blocked running wheels, half of the mice were assigned into a running (RUN) and the other half to a nonrunning (CON) group, considering matched running distances. Runners (n = 16) were again subjected to a brief period of wheel running (5 h) directly before behavioral testing (day 6) and ran, on average, 6.5 ± 0.7 km (Fig. 1A).When subsequently tested for anxiety-like behavior in the dark-light box test, runners exhibited significantly less anxiety by spending an increased time in the aversive bright area than controls (P = 0.002; Fig. 1B). Runners were also less active and displayed fewer exits from the dark compartment into the lit compartment (RUN, 10.3 ± 0.8 exits; CON, 12.6 ± 0.7 exits; P = 0.040). Next, mice were removed from the dark-light arena and subjected to the hot plate test to study pain sensitivity. Here, runners displayed an increased latency to lick hind paws or jump (first action), suggesting reduced thermal pain sensitivity (P = 0.0...

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“…, 4.9 km; P = 0.27; Fig. 3A); however, the difference was not statistically significant, in contrast to the study by Dubreucq and colleagues (8).…”

Section: Resultscontrasting

confidence: 56%

“…Earlier, it had been demonstrated that mice with a deletion of CB1 receptors on GABAergic neurons exhibit less wheel running activity when wheel running is restricted to 3 h per day (8). A possible reason is that these mice receive less emotional benefit from wheel running, and thus lose interest.…”

Section: Resultsmentioning

confidence: 99%

A runner’s high depends on cannabinoid receptors in mice

Fuß

Steinle

Bîndilă

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

176

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“…Again, proteins encoded by none of the previous suggested functional relevant or positional candidate genes were different between the strains. Also, in spite of the previously observed evidence that CB 1 receptors on VTA GABAergic terminals exert a permissive control on rodent voluntary running performance (Dubreucq et al, 2013) and the clearly differential wheel running response to dopaminergic-acting drugs in these inbred strains of mice (Knab et al, 2012) no strain differences were seen in the protein levels of the dopamine receptor 1 and endocannabinoid receptor 1. Specific Western blotting also did not reveal strain differences in the expression of the constituting Drd1 and Cr1 genes.…”

Section: Candidate Genesmentioning

confidence: 80%

Genetics of Regular Exercise and Sedentary Behaviors

et al. 2014

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Studies on the determinants of physical activity have traditionally focused on social factors and environmental barriers, but recent research has shown the additional importance of biological factors, including genetic variation. Here we review the major tenets of this research to arrive at three major conclusions: First, individual differences in physical activity traits are significantly influenced by genetic factors, but genetic contribution varies strongly over age, with heritability of leisure time exercise behavior ranging from 27% to 84% and heritability of sedentary behaviors ranging from 9% to 48%. Second, candidate gene approaches based on animal or human QTLs or on biological relevance (e.g., dopaminergic or cannabinoid activity in the brain, or exercise performance influencing muscle physiology) have not yet yielded the necessary evidence to specify the genetic mechanisms underlying the heritability of physical activity traits. Third, there is significant genetic modulation of the beneficial effects of daily physical activity patterns on strength and endurance improvements and on health-related parameters like body mass index. Further increases in our understanding of the genetic determinants of sedentary and exercise behaviors as well as the genetic modulation of their effects on fitness and health will be key to meaningful future intervention on these behaviors.

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“…The endocannabinoid system, mainly through type 1 cannabinoid receptors (CB1) located on glutamatergic (glutamatergic CB1) and GABAergic neurons (GABAergic CB1), control both excitatory and inhibitory neurotransmission, thereby modulating dopaminergic-dependent behaviors (Melis and Pistis, 2012;Dubreucq et al, 2013), including cocaine seeking (De Vries and Schoffelmeer, 2005). Full pharmacological antagonism of CB1 decreases the influence of conditioned factors on cocaine seeking and on extracellular Glu and DA in the NAc (Caillé and Parsons, 2006;Cheer et al, 2007;Oleson and Cheer, 2012;De Vries et al, 2001;Xi et al, 2006), as well as expression of cocaine-induced behavioral sensitization in a context-specific manner (Gerdeman et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Differential Control of Cocaine Self-Administration by GABAergic and Glutamatergic CB1 Cannabinoid Receptors

Martín‐García

Bourgoin

Cathala

et al. 2015

Neuropsychopharmacol

Self Cite

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The type 1 cannabinoid receptor (CB1) modulates numerous neurobehavioral processes and is therefore explored as a target for the treatment of several mental and neurological diseases. However, previous studies have investigated CB1 by targeting it globally, regardless of its two main neuronal localizations on glutamatergic and GABAergic neurons. In the context of cocaine addiction this lack of selectivity is critical since glutamatergic and GABAergic neuronal transmission is involved in different aspects of the disease. To determine whether CB1 exerts different control on cocaine seeking according to its two main neuronal localizations, we used mutant mice with deleted CB1 in cortical glutamatergic neurons (Glu-CB1) or in forebrain GABAergic neurons (GABA-CB1). In Glu-CB1, gene deletion concerns the dorsal telencephalon, including neocortex, paleocortex, archicortex, hippocampal formation and the cortical portions of the amygdala. In GABA-CB1, it concerns several cortical and non-cortical areas including the dorsal striatum, nucleus accumbens, thalamic, and hypothalamic nuclei. We tested complementary components of cocaine self-administration, separating the influence of primary and conditioned effects. Mechanisms underlying each phenotype were explored using in vivo microdialysis and ex vivo electrophysiology. We show that CB1 expression in forebrain GABAergic neurons controls mouse sensitivity to cocaine, while CB1 expression in cortical glutamatergic neurons controls associative learning processes. In accordance, in the nucleus accumbens, GABA-CB1 receptors control cocaine-induced dopamine release and Glu-CB1 receptors control AMPAR/NMDAR ratio; a marker of synaptic plasticity. Our findings demonstrate a critical distinction of the altered balance of Glu-CB1 and GABA-CB1 activity that could participate in the vulnerability to cocaine abuse and addiction. Moreover, these novel insights advance our understanding of CB1 neuropathophysiology.

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

Cited by 87 publications

References 58 publications

A runner’s high depends on cannabinoid receptors in mice

A runner’s high depends on cannabinoid receptors in mice

Genetics of Regular Exercise and Sedentary Behaviors

Differential Control of Cocaine Self-Administration by GABAergic and Glutamatergic CB1 Cannabinoid Receptors

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