Ketamine Corrects a Deficit in Reversal Learning Caused by Chronic Intermittent Cold Stress in Female Rats

Abstract

BackgroundIndividuals with stress-related psychiatric disorders exhibit deficits in cognitive flexibility. We have shown that chronic intermittent cold stress induces deficits in reversal learning, a form of cognitive flexibility mediated in the orbitofrontal cortex, that was reversed by ketamine in male rats. Such effects have not been tested in females. In this study, we examined effects of chronic intermittent cold stress and ketamine on reversal learning in females.MethodsFemale Sprague-Dawley rats underwent 14 days of chronic intermittent cold and 3 days later received an injection of ketamine (10 mg/kg, i.p.). They were tested on reversal learning 24 hours post-injection. A separate cohort of female rats underwent 14 days of chronic intermittent cold. Three days later they received ketamine and were killed 2 hours post-injection for measurement of the synaptic marker PSD95 in orbitofrontal cortex.ResultsChronic intermittent cold induced a reversal learning deficit in females comparable with that seen in males, which was corrected by ketamine. Moreover, chronic intermittent cold increased PSD95 expression in orbitofrontal cortex, but this increase was not seen in rats receiving ketamine.ConclusionsChronic intermittent cold stress and ketamine altered reversal learning in female rats similar to effects seen in males. Further, chronic intermittent cold increased PSD95 in orbitofrontal cortex of female rats, indicative of synaptic dysregulation. This effect was attenuated after ketamine administration.

Cognitive Behavioral Therapy to Sustain the Antidepressant Effects of Ketamine in Treatment-Resistant Depression: A Randomized Clinical Trial

“…Preclinical work in rodents suggests that sensitivity to negative stimuli and distraction by negative feedback are decreased after ketamine treatment in a probabilistic reversal learning task [36]. Other studies have demonstrated the ability of ketamine to rapidly correct for stress-induced decreases in reversal learning [12, 13] and improve flexible control in processing affective material.…”

“…At the molecular level, ketamine has been shown to have complex metaplastic effects on hippocampal slice preparations [37]. Ketamine has also been shown to reverse stress-induced deficits in reversal learning [12], enhance extinction of fear conditioning [38], and enhance hippocampal long-term potentiation and facilitate extinction of avoidance behavior in drug-responsive Wistar-Kyoto rats (an animal model of endogenous depression [39]), with effects lasting at least 3 weeks [40]. Moreover, ketamine has been shown to have a rapid onset of marked effects on dendritic architecture and spine density and function in prefrontal cortical regions that persist for at least 1 week after a single administration [41] and may be extended with subchronic dosing [42].…”

Changes in synaptic markers after administration of ketamine or psychedelics: a systematic scoping review

“…In other studies, ketamine (10 mg/kg) did not change PSD-95 levels in the OFC and hippocampus, but it reduced PSD-95 phosphorylation on Thr-19 in hippocampal membranes, suggesting decreased GluA1 receptor internalization ( 102 , 103 ). Ketamine (10 mg/kg) also increased PSD-95 levels and mPFC post-synaptic density while decreasing PSD-95 levels and hippocampal post-synaptic density.…”

“…One study has examined ketamine with chronic intermittent cold stress (CIC). Ketamine (10 mg/kg) post-treatment reversed CIC-induced increases in PSD-95 levels in the OFC ( 103 ).…”