The rewarding and cognitive effects of corticosterone in mice

Corticosterone is the main glucocorticoid in rodents. Its secretion follows a circadian rhythm and is increased in response to stress. Corticosterone is thought to possess rewarding effects. For example, enhanced corticosterone secretion is associated with the exposure to natural rewards such as food, sex and running, and it has been reported that corticosterone is implicated in drug-seeking behaviour. In addition, rats orally self-administer the steroid hormone and are motivated to nose-poke for stress-like levels of corticosterone, suggesting that the stress hormone has rewarding effects on its own, although this proposal is not supported by conditioned place preference studies. Corticosterone is also found to be critical for learning and memory performance, but it is unclear whether cognitive effects of the hormone are modulated by its rewarding properties. Elevated glucocorticoid levels have been reported to accompany certain psychiatric and cognitive disorders, but it is not clear whether this is an underlying cause or a consequence of these diseases. The two broad aims of the present thesis were to investigate potential rewarding properties of corticosterone in C57BL/6J male mice and to examine their long-term impacts on cognition. In the first experiment, mice were subjected to a prolonged two-bottle choice test to measure their preference for the stress hormone. Results indicated that mice were motivated to self-administer corticosterone at high doses and this was accompanied by enhanced dopamine turnover in the striatum, suggesting that the rewarding effects of corticosterone involve the mesolimbic dopamine pathway; the activity of which is enhanced by the majority of addictive drugs. Corticosterone self-administration did not impair recognition memory in most groups, but it did improve spatial memory. Importantly, corticosterone self-administration induced neuroplasticity changes in the hippocampus and frontal cortex, indicating the involvement of these memory processing areas in the development of corticosterone-seeking behaviour. These results suggest that corticosterone self-administration is associated with spatial memory improvement in mice. Therefore, the remainder of the studies aimed to use a stressful natural reward (voluntary wheel running) to extend our understanding of the role of corticosterone in stress-seeking behaviour and its memory-related effects. The preliminary results revealed that single or repeated 1-hour running sessions increased plasma corticosterone levels. Moreover, metyrapone (a corticosterone synthesis inhibitor) attenuated the running performance of trained mice. In another pilot study, repeated running sessions prevented the improvement of the spatial memory of mice but did not impair their recognition memory compared to non-exercising mice. The final study was undertaken to determine the influences of pharmacological blockade of glucocorticoid or dopamine D2 receptors on the running performance and the exercise-related effects on memory in mice. In contrast to metyrapone, mifepristone (a glucocorticoid receptor antagonist) did not decrease running distances of mice, but it did induce recognition memory impairment in non-exercising mice. These memory deficits were reversed by running, suggesting that exercise-evoked corticosterone increase is involved in the cognitive effects of wheel running. On the other hand, a dopamine D2 receptor antagonist (sulpiride) attenuated the running performance of mice and induced exercise-dependent opposite effects on memory. Overall, the results of this thesis support the hypothesis that corticosterone is rewarding in mice, and that these effects probably enhance certain aspects of cognition.