An Exploration of the Wheel-Induced Feeding- Suppression

Anorexia nervosa is an enigmatic human condition typified by food-restriction that is often accompanied by extensive exercise. This has been modeled in rats in the wheel-induced feeding-suppression (WIFS) model. In this model, animals are given access to a running-wheel, which induces a volitional drop in food-consumption. Short periods of wheel access have induced a feeding-suppression which is effectively reversed by chlorpromazine administration (Adams et al., 2009). Recent attempts at replicating Adams et al.’s (2009) feeding-suppression have, however, been unsuccessful (Peckham et al., 2013). These attempts raised questions as to whether or not the existing methodology is most effective at suppressing food-consumption in rats. A reliable WIFS model using short terms of wheel-access is important if drugs are to be tested in this paradigm. The first part of this thesis focused on which factors are most important for a WIFS to be seen and to use these findings to develop a model that can easily incorporate drug administration.\nExperiment 1 tested if rats’ body weights or their amount of running could predict the size of the WIFS. Experiment 1 explored the changes in food-consumption of 64 rats by providing 4 days of 24 h wheel-access followed by 4 days of 3 h wheel-access several days later. Neither body weight nor wheel-turns were predictive of the WIFS following 24 h or 3 h wheel-access. Experiment 2 sought to explore the effects of prior wheel-exposure duration on future wheel experiences. This experiment was a partial replication of Experiment 1; but with half of the rats (n =17) receiving 3 h wheel-access before 24 h wheel-access. It was found that the feeding-suppression was not evident in wheel naïve rats on the first day they received 3 h of wheel-access but was evident with 3 h access in rats with prior 24 h wheel experience. It was also found that the eventual feeding-suppression was larger with 24 h than 3 h of wheel-access. Experiment 3 tested whether or not the time of day (morning or afternoon) that wheel-access is given was important to the WIFS which occurs over the subsequent 24 h and largely at night. This experiment provided 34 rats with 3 h wheel-access every third day for 4 wheel exposures. Time of wheel-access was found to affect running but not the feeding-suppression which was evident on each of the days following wheel-access. Experiments 1 to 3 led to the development of a paradigm used in Part 2.\nPart 2 of this thesis explored the endocannabinoid system’s (ECS) effects on the WIFS. Anorexia-like behaviours have been shown to directly affect the ECS. These changes in the ECS have been suggested as a sign of an underactive ECS in both humans (Gérard et al., 2011) and rats (Casteels et al., 2014). Interestingly, when cannabinoids are introduced to animals with wheel-access, food-consumption becomes elevated. This has been seen in a study using ∆9-tetrahydrocannabinol (THC), the main psychoactive ingredient in marijuana, where rats’ weight-loss was attenuated by the drug (Verty et al., 2011). It has also been suggested that URB597, a drug that increases levels of anandamide (an endogenous cannabinoid comparable to THC), similarly ‘restored’ food-consumption (Peckham et al., 2013). Two experiments were conducted to independently examine these drugs in a new WIFS model. Experiment 4a focused on URB597 (0, 0.17, 0.5, and 1.0 mg/kg) whereas Experiment 4b focused on ∆9-tetrahydrocannabinol (THC; 0, 0.125, and 0.25 mg/kg) – both administered immediately after locked or unlocked wheel-access. This new procedure was effective in reliably inducing a WIFS but neither drug was able to prevent the feeding-suppression: suggesting cannabinoids might not play an important role in the WIFS.

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