Antidepressant-Like Effects of Ketamine on Fear Conditioning and Extinction

Abstract

The experience of chronic stress plays an important role in the pathogenesis of major depressive disorder. Prolonged stress induces a state of chronically elevated glucocorticoid exposure in the brain, which is neurotoxic and can lead to the dysfunction of glutamatergic signaling. Since memory is highly dependent upon glutamatergic neurotransmission, patients with depression commonly display alterations in memory processing that bias the recollection of past events towards negative emotional information. Negative cognitive biases are believed to support the development and maintenance of depression, emphasizing the need for antidepressant treatments that can effectively combat these insidious symptoms. Memory for negative emotional events can be studied in animals using fear conditioning and extinction paradigms. Fear conditioning trains an animal to associate a neutral cue with an emotionally aversive experience, while extinction learning challenges this association by forming a new memory that identifies the cue as harmless. The aim of this dissertation was to investigate the antidepressant-like effects of ketamine on auditory fear conditioning and extinction in both healthy rats and those with chronic glucocorticoid exposure. The first experiment sought to dissociate the effects of ketamine on distinct stages of auditory fear conditioning and extinction by administering a subanesthetic dose of ketamine at one of three unique time points: before fear conditioning training, immediately after fear conditioning training, or before fear extinction training. Post-conditioning and pre- extinction ketamine attenuated the long-term expression of cue-elicited freezing, suggesting that the consolidation and recall of conditioned fear were impaired, respectively. Pre-conditioning ketamine did not disrupt the acquisition of fear conditioning, and none of the treatments examined affected the long-term expression of fear extinction. The second experiment aimed to build upon these findings by examining the effect of pre-extinction ketamine on conditioned fear and extinction behavior in a repeated exogenous corticosterone (CORT) animal model of depression. Repeated CORT treatment provoked a spontaneous recovery of conditioned freezing between extinction sessions and induced a reinstatement of freezing following a sub- conditioning retraining procedure. Ketamine prevented CORT-induced failures in long-term extinction expression, and also greatly reduced freezing during early phase extinction training. Collectively, the findings of this dissertation help establish ketamine as a powerful modulator of negatively-valenced memory and emotionally-driven behavior, and contribute to our understanding of its antidepressant-like qualities.