Abstract:
The Nucleus Accumbens (NAc) is a critical brain region for the effects of psychostimulant drugs. Type-1 cannabinoid receptors (CB(1)), the main elements of the endocannabinoid system (ECS) in the brain, participate in these effects and modulate synaptic functions in the NAc. Besides their neuronal expression, CB(1) receptors are also present in astrocytes, where they contribute to the regulation of synaptic plasticity and behavior. However, the impact of astroglial CB(1) receptors on synaptic plasticity in the NAc and on psychostimulant-induced synaptic and behavioral effects is currently unknown. This study shows that the psychostimulant amphetamine impairs a form of astroglial CB(1) receptor-dependent synaptic plasticity in the NAc of male, but not female mice. Consistently, locomotor effects of amphetamine require astroglial CB(1) receptors in male, but not female mice. These results, by revealing unforeseen mechanisms underlying sex-dependent effects of amphetamine, pave the way to a better understanding of the diverse impact of psychostimulants in women and men.

Abstract:
Physical exercise, which can be addictogenic on its own, is considered a therapeutic alternative for drug craving. Exercise might thus share with drugs the ability to strengthen excitatory synapses onto ventral tegmental area (VTA) dopaminergic neurones, as assessed by the ratio of AMPA receptor (AMPAR)-mediated excitatory postsynaptic currents (EPSCs) to NMDA receptor (NMDAR)-mediated EPSCs. As did acute cocaine, amphetamine, or Delta(9) -tetrahydrocannabinol (THC) pretreatments, an acute 1-h wheel-running session increased the AMPAR/NMDAR ratio in VTA dopaminergic neurones. To dissect the respective influences of wheel-running seeking and performance, mice went through an operant protocol wherein wheel-running was conditioned by nose poking under fixed ratio schedules of reinforcement. Conditioned wheel-running increased the AMPAR/NMDAR ratio to a higher extent than free wheel-running, doing so although running performance was lower in the former paradigm than in the latter. Thus, the cue-reward association, rather than reward consumption, played a major role in this increase. The AMPAR/NMDAR ratio returned to baseline levels in mice that had extinguished the cued-running motivated task, but it increased after a cue-induced reinstatement session. The amplitude of this increase correlated with the intensity of exercise craving, as assessed by individual nose poke scores. Finally, cue-induced reinstatement of running seeking proved insensitive to acute cocaine or THC pretreatments. Our study reveals for the first time that the drive for exercise bears synaptic influences on VTA dopaminergic neurones which are reminiscent of drug actions. Whether these influences play a role in the therapeutic effects of exercise in human drug craving remains to be established.

Abstract:
Recent surveys have revealed close links between cannabis and exercise. Specifically, cannabis usage before and/or after exercise is an increasingly common habit primarily aimed at boosting exercise pleasure, motivation, and performance whilst facilitating post-exercise recovery. However, whether these beliefs reflect the true impact of cannabis on these aspects of exercise is unknown. This study has thus examined the effects of cannabis' main psychoactive ingredient, namely Delta(9)-tetrahydrocannabinol (THC), on (i) mouse wheel-running preference and performance and (ii) running motivation and seeking behaviour. Wheel-running preference and performance were investigated using a T-maze with free and locked wheels located at the extremity of either arm. Running motivation and seeking were assessed by a cued-running operant task wherein wheel-running was conditioned by nose poking. Moreover, because THC targets cannabinoid type 1 (CB1) receptors, i.e. receptors previously documented to control running motivation, this study also assessed the role of these receptors in running preference, performance, and craving-like behaviour. Whilst acute blockade or genetic deletion of CB1 receptors decreased running preference and performance in the T-maze, THC proved ineffective on either variable. The failure of THC to affect running variables in the T-maze extended to running motivation, as assessed by cued-running under a progressive ratio (PR) reinforcement schedule. This ineffectiveness of THC was not related to the treatment protocol because it successfully increased motivation for palatable food. Although craving-like behaviour, as indexed by a cue-induced reinstatement of running seeking, was found to depend on CB1 receptors, THC again proved ineffective. Neither running motivation nor running seeking were affected when CB1 receptors were further stimulated by increasing the levels of the endocannabinoid 2-arachidonoylglycerol. These results, which suggest that the drive for running is insensitive to the acute stimulation of CB1 receptors, raise the hypothesis that cannabis is devoid of effect on exercise motivation. Future investigation using chronic administration of THC, with and without other cannabis ingredients (e.g. cannabidiol), is however required before conclusions can be drawn.

Abstract:
Wheel running, especially in the homecage, has been widely used to study the neurobiology of exercise because animal tends to use it voluntarily. However, as for each reward, its consumption (in the present case, running performance) does not specifically provide information on its incentive value, i.e., the extent to which animals are motivated to run independently from their consumption of that reward. This is a major drawback, especially when focusing on the neurobiology governing the pathological imbalances between exercise and e.g., feeding (obesity, anorexia nervosa). Yet, few studies have shown that operant conditioning wherein wheel-running is used as a reinforcer that can be 'consumed' after nose-poking or lever-pressing allows to distinguish motivation from consumption. Thus, nose-poking or lever-pressing under a progressive ratio schedule of reinforcement in animals trained under fixed ratio reinforcement schedules provides, through the so-called breakpoint, an index of running motivation. As compared to wheel-running, numerous studies have used food as a reinforcer, which helped to uncover the neurobiology of feeding. However, to our knowledge, there is no paradigm allowing the assessment of the choice between running and feeding when presented in concurrence, with the possibility to measure a priori the motivation for each reward. Herein, we describe a protocol that first permits to measure the drive for each of these two rewards before it allows to measure the preference for one over the other in a reward choice setting. This paradigm could help to better characterize the neurobiology underlying pathological imbalances between physical activity and feeding, which is the core feature of eating disorders.

Abstract:
The lack of intrinsic motivation to engage in, and adhere to, physical exercise has major health consequences. However, the neurobiological bases of exercise motivation are still unknown. This study aimed at examining whether the endocannabinoid system (ECS) is involved in this process. To do so, we developed an operant conditioning paradigm wherein mice unlocked a running wheel with nose pokes. Using pharmacological tools and conditional mutants for cannabinoid type-1 (CB1) receptors, we provide evidence that CB1 receptors located on GABAergic neurons are both necessary and sufficient to positively control running motivation. Conversely, this receptor population proved dispensable for the modulation of running duration per rewarded sequence. Although the ECS mediated the motivation for another reward, namely palatable food, such a regulation was independent from CB1 receptors on GABAergic neurons. In addition, we report that the lack of CB1 receptors on GABAergic neurons decreases the preference for running over palatable food when mice were proposed an exclusive choice between the two rewards. Beyond providing a paradigm that enables motivation processes for exercise to be dissected either singly or in concurrence, this study is the first to our knowledge to identify a neurobiological mechanism that might contribute to sedentary behavior.

Abstract:
Anorexia nervosa (AN), mostly observed in female adolescents, is the most fatal mental illness. Its core is a motivational imbalance between exercise and feeding in favor of the former. The most privileged animal model of AN is the 'activity-based anorexia' (ABA) model wherein partly starved rodents housed with running wheels exercise at the expense of feeding. However, the ABA model bears face and construct validity limits, including its inability to specifically assess running motivation and feeding motivation. As infant/adolescent trauma is a precipitating factor in AN, this study first analyzed post-weaning isolation rearing (PWIR) impacts on body weights and wheel-running performances in female mice exposed to an ABA protocol. Next, we studied through operant conditioning protocols i) whether food restriction affects in a sex-dependent manner running motivation before ii) investigating how PWIR and sex affect running and feeding drives under ad libitum fed conditions and food restriction. Besides amplifying ABA-elicited body weight reductions, PWIR stimulated wheel-running activities in anticipation of feeding in female mice, suggesting increased running motivation. To confirm this hypothesis, we used a cued-reward motivated instrumental task wherein wheel-running was conditioned by prior nose poke responses. It was first observed that food restriction increased running motivation in male, but not female, mice. When fed grouped and PWIR mice were tested for their running and palatable feeding drives, all mice, excepted PWIR males, displayed increased nose poke responses for running over feeding. This was true when rewards were proposed alone or within a concurrent test. The increased preference for running over feeding in fed females did not extend to running performances (time, distance) during each rewarded sequence, confirming that motivation for, and performance during, running are independent entities. With food restriction, mice displayed a sex-independent increase in their preference for feeding over running in both group-housed and PWIR conditions. This study shows that the ABA model does not specifically capture running and feeding drives, i.e. components known to be affected in AN.