Effects of Interacting Stressors on Mood: Modulation by Ketamine



Melanson, Brett

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University of Guelph


Introduction. There is evidence in support of a link between metabolic and mood disorders. Impaired glucose metabolism may play a role in the development of core depressive symptoms like lowered mood and anhedonia, possibly by interacting with other stressors to enhance their effects on the hypothalamic-pituitary-adrenal axis and the immune system. As well, recent evidence indicates that the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist ketamine alleviates core symptoms of depression, even in those who do not respond to conventional antidepressant medications. Hence, the current dissertation explored the impact of interacting stressors on depressive-like behaviour and physiological responses, and possible modulation by ketamine. Methods. A series of studies were performed in male Sprague-Dawley rats to determine whether ketamine could modulate the impact of interacting hypoglycemic (2-deoxy-D-glucose; 2-DG) and psychophysical (forced swimming stress; FSS) stressors on animal correlates of depressive-like behaviour and biological reactivity of the HPA axis and immune system. In addition, this thesis investigated whether ketamine and conditioning factors (i.e., drug-environment interactions) possibly linked to ketamine’s effects could play a role in the antidepressant-like profile of this drug. Results. It was found that: 1) hypoglycemic stress accelerated the depressive-like behavioural response to repeated psychophysical stress, induced a state of consummatory anhedonia, and amplified biological reactivity of the HPA axis and immune system to acute swim stress well after exposure to the combined stressors; 2) ketamine reversed the impact of interacting hypoglycemic and psychophysical stressors on depressive-like behaviour and physiology, and produced an anti-immobility effect that occurred well after exposure to the drug; and 3) exposure to a context paired with ketamine, but not the common antidepressant medications bupropion or escitalopram, reduced immobility during FSS, which is typically interpreted as an antidepressant-like response in rodents. Conclusion. The work presented in this dissertation provides novel insight about the interaction between different stressor types on depressive-like behaviours and physiological responses, as well as biological and conditioning factors that may play a role in the antidepressant action of ketamine. Importantly, the animal work reported in this thesis emphasizes the importance of considering dietary factors in the development of depressive illness, and provides key information by which the antidepressant response to a single infusion of ketamine may be enhanced following repeated administration of the drug during treatment.



Forced swimming stress, Ketamine, Blood glucose, Saccharin preference, Immobility, Glucoprivation, Hypoglycemia, 2-deoxy-D-glucose, Conditioning, Antidepressant, Corticosterone, TNF-alpha, Inflammation, Stress, HPA axis, Psychedelic


Melanson, B., Lapointe, T., & Leri, F. (2021). Impact of impaired glucose metabolism on responses to a psychophysical stressor: modulation by ketamine. Psychopharmacology (Berl) 238:1005�??1015. https://doi.org/10.1007/s00213-020-05748-w
Melanson, B., & Leri, F. (2021). Effect of ketamine on the physiological responses to combined hypoglycemic and psychophysical stress. IBRO Neuroscience Reports, 11, 81�??87. https://doi.org/10.1016/j.ibneur.2021.08.002
Melanson, B., Wolter, M., Leatham, Z., Lapointe, T., Kennedy, S., & Leri, F. (2021). Conditioned anti-immobility by ketamine: a comparison to bupropion and escitalopram. Manuscript submitted for publication.