Abstract

Anorexia nervosa (AN) is a life-threatening psychiatric illness characterized by severe caloric restriction, excessively low body weight, and extreme fear of weight gain. Up to 81% of individuals with AN exhibit high levels of physical activity which is associated with higher relapse, longer hospitalizations, and poorer outcomes. Mood and anxiety disorders, cognitive impairment, and alterations in reward processing are common in AN. Only about half of individuals with AN achieve full remission of symptoms and relapse is frequent. There is a pressing need for a better understanding of risk factors and underlying pathogenesis of AN. Activity-based anorexia (ABA) is an animal model of AN-like symptoms combining wheel access and food restriction resulting in increased running wheel activity, failure to increase food intake, and accelerated weight loss which can result in death if the animal is not removed from the experiment. While ABA has been used since the 1960s, only recently have researchers begun to explore the individual differences in response to ABA. The goal of this series was to establish the use of the model in our laboratory and to explore individual variability in ABA response by investigating behavioural and neurobiological differences between resilient and susceptible rats.
The experiments in Chapter 3 aimed to determine the ideal parameters to establish the use of the ABA model in our laboratory. ABA reliably developed in both male and female rats and female rats were particularly susceptible. Efforts to use behavioural measures of cognitive flexibility and anxiety- and depression-like behaviours during the ABA paradigm revealed that it is possible to do so without interfering with ABA development. In Chapter 4, we aimed to further characterize ABA susceptibility by assessing baseline anxiety- and depression-like behaviours, amphetamine-induced locomotor activity as an index of mesolimbic DA activity, and response to pharmacological treatment. In Chapter 5, we compared general neural activity between resilient and susceptible rats in several key brain areas using c-Fos immunohistochemistry. We followed up on these findings by assessing response inhibition, a facet of impulsivity that is dependent on prefrontal functioning. In Chapter 6, we examined the effect of ABA on later cocaine-taking behaviours and assessed for trait differences in response to cocaine. Overall, by comparing resilient and susceptible rats, we found important differences in baseline running wheel activity as well as in performance on the forced swim task. We also observed statistical trends for differences in neural activity in the prefrontal cortex and nucleus accumbens as well as differential responding to cocaine self-administration. These results highlight the importance of considering susceptibility to ABA to further our understanding of risk factors involved in the development, maintenance, and treatment response in AN.