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.
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 Δ9‐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.
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