Cannabis and exercise: Effects of Δ9-tetrahydrocannabinol on preference and motivation for wheel-running in mice
Introduction
Does cannabis consumption facilitate exercise? If so, does cannabis act on exercise motivation, exercise pleasure, and/or exercise performance? Recent years have seen an expanding number of online press reports from top newspapers (see e.g. Ducharme, 2019; Hesse, 2016; Miller, 2018) and an Outlook in Nature (Nguyen, 2019) that focused on these questions. This media interest is accounted for by a growing number of sportspeople interviews, initially thought to be only anecdotal, highlighting the expanding use of cannabis prior to or after exercise (most often long-distance running). The main reasons for cannabis use are the beliefs that it increases exercise pleasure and performance whilst alleviating after-exercise fatigue symptoms (Nguyen, 2019). Nowadays, the anecdotal reports on the relationship between cannabis and exercise have given way to true scientific interest. Studies based on self-reports in large individual samples confirm that cannabis use is primarily aimed at increasing exercise pleasure (and hence possibly precipitate the so-called “runner's high”), performance, motivation, and after-exercise recovery (Gillman et al., 2015; Huestis et al., 2011; Kennedy, 2017; Ware et al., 2018). However, how these beliefs range compared to each other was unknown until a recent study addressed this issue. The recent legalisation of cannabis use in several states of the United States of America has facilitated the largest survey (i.e. hundreds of aerobic and anaerobic exercise practitioners) on the beliefs underlying cannabis use before/after exercise (YorkWilliams et al., 2019). The results indicate that beliefs linked to exercise pleasure and after-exercise recovery actually surpass the belief that cannabis increases exercise motivation or exercise performance (YorkWilliams et al., 2019). The finding that exercise performance was not the main reason why cannabis was used prior to exercise is in keeping with the observation that cannabis negatively impacts such a performance in certain individuals (Gillman et al., 2015; Huestis et al., 2011; Kennedy, 2017; Ware et al., 2018). Moreover, because cannabis does not have an ergogenic effect on its own (Ware et al., 2018), it is widely accepted that the positive effects of cannabis on performance, if any, are indirect and are chiefly accounted for by relaxation, well-being, and analgesia (effects that underlie the forbidden use of cannabis use in sport competition by the World Anti-Doping Agency since 2004).
These findings question the extent to which the belief in the positive effects of cannabis before/after exercise reflect scientifically-proven properties of cannabis. One means of answering this question is through the use of animal models of exercise. However, because cannabis cannot be provided as such to laboratory animals, one prerequisite for the study of cannabis' impact on exercise is to identify the compounds through which cannabis bears its effects. Cannabis is made of hundreds of compounds (Andre et al., 2016) and it is assumed that its effects during/after exercise, including the adverse ones (Kennedy, 2017), are accounted for by the psychoactive properties of Δ9-tetrahydrocannabinol (THC; Wachtel et al., 2002). Rodent models of exercise chiefly include treadmill-running and wheel-running (swimming is a stress response in laboratory rodents: Porsolt et al., 1978). However, the former relies on a negative reinforcement process because rodents are forced to run to escape electric shocks or air puffs. Hence, wheel-running, by virtue of its volitional use, is the preferred model of exercise (Sherwin, 1998). Accordingly, most investigators place a running wheel in the rodent housing cage, thereby allowing free access to the wheel and on-line measures of running performance. As an illustration, mice housed with running wheels run several kilometres a day (see e.g. Dubreucq et al., 2010), further suggesting that wheel-running is a strong reward in laboratory rodents (see below).
Using home cage wheel-running, we and others have shown that the endocannabinoid system exerts a tonic control on wheel-running performance, as assessed by running distances or durations (Dubreucq et al., 2010; Keeney et al., 2008; Zhou and Shearman, 2004). This tonic control is mediated by CB1 receptors - the principal cannabinoid receptor in the brain - located in the ventral tegmental area (VTA; Dubreucq et al., 2013), the structure from which project reward-regulating mesocorticolimbic dopaminergic neurones. Because THC's psychoactive effects are accounted for by the stimulation of CB1 receptors (Huestis et al., 2001), it is expected that THC augments running performance. Actually, when acutely tested at doses devoid of intrinsic locomotor effects, THC lacked effects on running performance (Dubreucq et al., 2013). However, in keeping with the running paradigm used in this study, i.e. permanent housing with a wheel, thus allowing running with neither any constraint nor any other alternative than resting, this result does not document whether THC impacts (i) preference for running and/or (ii) running motivation. The T-maze test allows preference for a reward to be measured since the reward is located at the extremity of one of the arms of the maze. Therefore, animals have to first make the choice for a distant reward before exerting exploratory efforts to reach that reward. Several T-maze studies have used a running wheel, either provided alone (Hill, 1961) or in concurrence with a second reward placed at the other end of the maze (Correa et al., 2016), but none have explored (i) whether the endocannabinoid system controls running motivation, and if so, (ii) whether the latter is modified by THC administration. Although it has been claimed that the T-maze additionally provides information on reward motivation (Robinson et al., 2005), it is thought that the (exploratory) cost to access the reward in the T-maze is too low to efficiently provide such an information (unless a surmountable barrier is added: Salamone et al., 1994). As opposed to the T-maze, cued-reward instrumental tasks - where e.g. lever pressing is needed for reward access - provide indices ofthe primary reinforcing value of the reward under investigation; indeed, such procedures have confirmed that wheel-running is highly reinforcing (Belke and Garland Jr, 2007; Collier and Hirsch, 1971; Iversen, 1993). Measuring the maximal efforts exerted to reach the reward under progressive ratio (PR) reinforcement schedules provides selective indices of motivation for that reward (Hodos, 1961). Having developed a paradigm wherein wheel-running is conditioned by prior nose poking, we have shown that VTA CB1 receptors exert a tonic control over running motivation (Muguruza et al., 2019). However, whether acute THC administration affects running motivation in this paradigm remains an open question. Besides measuring motivation for a reward, operant conditioning procedures further permit craving-like behaviour for a reward to be measured by means of a cue-induced reinstatement of reward seeking in animals that have extinguished the cue-reward association (Shaham et al., 2003; Venniro et al., 2016). Indeed, we have further shown that wheel-running is a reward strong enough to promote seeking after such an extinction period (Muguruza et al., 2019). Again, whether THC affects the intensity of exercise seeking is an issue for which information is still lacking.
The present study has thus examined the acute impact of THC administration on (i) preference for wheel-running and running performance in a T-maze wherein animals had the choice between two arms containing at their extremities either a free wheel or a locked wheel, and (ii) wheel-running motivation and craving-like behaviour, as assessed through a PR session and a cue-induced reinstatement of running seeking session respectively, using operant conditioning procedures. In the final series of experiments, we wondered whether the effects of THC on running motivation and seeking mimicked those elicited by an endogenous overstimulation of CB1 receptors. To this end, mice were pretreated with the monoacylglycerol lipase (MAGL) inhibitor JZL184 (Long et al., 2009a) (which increases the levels of the endocannabinoid 2-arachidonoylglycerol (2-AG), before being tested either under a PR reinforcement schedule or in a cue-induced reinstatement of running seeking session.
Section snippets
Animals
T-Maze experiments involved male C57BL/6N mice (Elevage Janvier, Le Genest-Saint-Isle, France) aged 8–12 weeks, and 8–14 week-old male constitutive CB1 receptor mutant (CB1 KO) mice and their wild-type (CB1 WT) littermates (Bellocchio et al., 2010; Dubreucq et al., 2013; Muguruza et al., 2019). Operant conditioning procedures used 8–12 week-old males from a C57BL/6N-derived mouse line bred in our animal facilities, namely the Cnr1flox/flox (CB1-floxed) line, and conditional mutants lacking
Effects of THC on wheel-running preference and performance in T-maze tests
We developed a choice procedure wherein two arms contained at their extremities either a free wheel or a locked wheel (Fig. 1A). This design allowed us to measure (i) the initial latency to reach the wheel and run, (ii) running preference (over a locked wheel), and (iii) running performance during 5-min tests. In contrast to operant conditioning procedures in which the role of CB1 receptors in the control of running motivation has been established (see above), their role in T-maze behaviours
Discussion
Self-reports suggest that cannabis usage prior to exercise is mainly aimed at increasing exercise pleasure whilst facilitating post-exercise recovery (Gillman et al., 2015; Huestis et al., 2011; Kennedy, 2017; Ware et al., 2018). In some cases, cannabis usage might also increase exercise motivation, and to a lesser extent, performance (YorkWilliams et al., 2019), although these effects might occur in a sport discipline-dependent manner (Lorente et al., 2005). This information, however, relies
Conclusion
This study is the first to examine the consequences of acute THC administration on running preference and performance in a T-maze task, and on running motivation in a cued-running instrumental task. Although running preference and motivation are tonically controlled by CB1 receptors, THC proved ineffective on these two variables. This ineffectiveness contrasted with the stimulating impact of THC on palatable feeding motivation. Lastly, THC also proved unable to affect cue-induced reinstatement
Ethical statement
Animal procedures, which complied with the French (Décret 2013-118) and European (2010/63/EU) rules on animal experimentation, were approved by the local Ethic Committee (Comité d'Ethique 50) with agreement numbers 33-063-69 and 22435 (F.C.) and A33-063-098 (animal facilities) provided under authority of the Préfecture de Gironde and the French Ministry of Agriculture.
Authors contribution
I.H., C.M., B.R., G.M., and F.C. contributed to the conception and design of the study, I.H., C.M., B.R., and F.C. participated in acquisition and analyses of the data, F.C. drafted the article, I.H., C.M., B.R., G.M., and F.C. revised the article and approved its final version.
Declaration of Competing Interest
The authors declare no conflicts of interest.
Acknowledgements
We thank Lucie Cabiro for technical help, Dr. Alex Fletcher-Jones for English correction and editing, and all the personnel from the Animal Facility and the Genotyping platform of the NeuroCentre Magendie. We also thank Virginie Morales and the other members of Marsicano's laboratory for their daily support and for useful discussions.This work was supported by the Agence Française de Lutte contre le Dopage (AFLD, to F.C.), l'Institut National de la Santé et de la Recherche Médicale (to G.M.),
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