DOI
https://doi.org/10.25772/1HKD-0R04
Defense Date
2023
Document Type
Thesis
Degree Name
Master of Science
Department
Pharmacology & Toxicology
First Advisor
Kate Nicholson
Abstract
Rationale: Initially developed as an anesthetic, ketamine is now used to treat a variety of disorders, including treatment resistant depression (TRD). While ketamine appears to be a breakthrough therapy for TRD, it has many use-limiting side effects, including abuse liability, psychotomimetic effects, and sedation. Utilizing ketamine in combination with other medications, such as the monoaminergic antidepressant desipramine (DSP), opioid antagonist naltrexone (NTX), and the NMDA receptor partial agonist D-cycloserine (DCS) may reduce side-effects resulting from ketamine therapy.
Objectives: The goal of this project was to study ketamine’s adverse effects using locomotor activation in an open field as a behavioral correlate for dopamine elevation in the brain, a characteristic linked to abuse-related effects. The locomotor activating effects of ketamine in an open field were characterized in Sprague-Dawley (SD, control), Wistar (WIS, control) and Wistar Kyoto (WKY, stress-vulnerable) rats. Secondly, we examined the effects of ketamine when administered following pretreatment with DSP, DCS and NTX to determine their potential to attenuate ketamine’s locomotor activating effects.
Methods: The effects of ketamine (3 - 56 mg/kg, IP) on activity were determined in an open field during 30-min sessions in male WIS rats and both male and female SD and WKY rats. Distance traveled (meters) was recorded using overhead cameras interfaced with AnyMaze software. To evaluate the impact of pretreatment drugs on ketamine-induced locomotor activation, 10 and 30 mg/kg of ketamine were re- evaluated in combination with DSP (0.3- 3 mg/kg, IP), DCS (30-300 mg/kg, SC) and NTX (1-30 mg/kg, SC).
Results: Ketamine dose-dependently increased distance traveled at one or more doses in all three strains in male rats and across both sexes in the SD and WKY rats. In all comparisons, distance traveled by WKY rats was 3- to 4-fold lower than distances traveled by SD and WIS rats. Despite a significant main effect of strain, there was no interaction between strain and treatment supporting a similar increase in activity produced by ketamine in all three strains. A significant effect of sex was demonstrated by locomotor activation occurring at both 10 and 30 mg/kg in females, versus activity only increasing following 30 mg/kg in males. In the locomotor assay, DSP alone produced significant activity decreases in SD females, while DCS had no significant effect on activity in either sex. When administered in combination with ketamine, neither DSP nor DCS produced any alteration in the distance traveled following ketamine administration. NTX also produced a significant reduction in distance traveled in both SD and WKY female rats, but had no effect on male activity. When administered in combination with ketamine, 1 and 10 mg/kg NTX produced a trend for attenuation of ketamine’s activating effects in SD males and females; but, the decrease in activity was only significant in WKY females at 10 mg/kg NTX. However, this decrease was reversed by the higher NTX dose, 30 mg/kg.
Conclusions: Consistent with previous literature, ketamine induced locomotor activation in SD and WIS rats. WKY showed a similar response to ketamine, despite the dramatically different distances traveled. Furthermore, the effect of ketamine was more pronounced in female rats in both strains. Overall, the dose combinations with DSP and DCS did not significantly decrease ketamine's activating effects. NTX administered alone suppressed activity. This non-selective suppression of behavior likely accounted for the decreases in ketamine-induced locomotor stimulation that were observed following 1 and 10 mg/kg NTX. It is unclear what is causing the resurgence of locomotor activation following pretreatment with 30 mg/kg NTX, but it has been demonstrated in two different strains and in both sexes and warrants further investigation.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
8-14-2023