Defense Date

2022

Document Type

Thesis

Degree Name

Master of Science

Department

Pharmacology & Toxicology

First Advisor

Dr. Katherine Nicholson

Second Advisor

Dr. David Walentiny

Third Advisor

Dr. Joseph Porter

Abstract

Major Depressive Disorder (MDD) affects approximately 280 million people worldwide. The standard of care for pharmacological treatment of MDD has been monoaminergic antidepressants (MAA). However, MAAs have serious clinical limitations including a relatively slow onset of action and up to 40% of patients failing to respond and being diagnosed as “treatment resistant”. Ketamine, an N-methyl-D-aspartate antagonist, was originally approved for use as an injectable anesthetic. In addition, ketamine has been shown to rapidly improve depressive symptoms in patients with treatment resistant depression. In 2019, (S)-ketamine was approved as a nasal spray (Spravato®) for patients with MDD and treatment-resistant depression in conjunction with their previously prescribed MAAs. However, ketamine has limitations of its own, such as producing sedation and dissociative effects as well as having known abuse liability. The goal of the current study was to identify potential drug combinations that optimize ketamine’s therapeutic use by decreasing its abuse-related behavioral effects. To address this goal, we tested the effects of ketamine alone and in combination with desipramine (a tricyclic antidepressant), D-cycloserine (a partial agonist at the NMDA receptor glycine-site) or naltrexone (opioid receptor competitive antagonist) in two behavioral assays in adult Sprague Dawley rats. The effects of our drug treatments on open field behavior was used to assess locomotor activation which has been linked to dopamine release in the brain. The ability of our test compounds to alter ketamine’s reinforcing effects was evaluated using intravenous (IV) ketamine self-administration. Effects on activity in an open field following ketamine administered alone were consistent with both published literature and previous work in this laboratory. This included locomotor activation at intermediate doses of ketamine (10 and 30 mg/kg) with a sex-dependent difference in sensitivity to these activating effects at the 10 mg/kg dose. Ketamine readily maintained IV self-administration with 0.3 and 0.56 mg/kg/infusion serving as positive reinforcers of behavior. Intermediate and high doses of desipramine (1 and 3 mg/kg) were found to decrease locomotor activity alone but did not alter ketamine’s locomotor activating effects. The high desipramine dose also reduced total ketamine intake in the self-administration procedure. D-cycloserine produced no effects on locomotor activity when administered alone nor any significant effect on ketamine self-administration. Naltrexone alone decreased locomotor activity at 10 and 30 mg/kg. This non-selective suppression of behavior likely accounted for moderate decreases in ketamine-induced locomotor stimulation and self-administration that was observed. While data are too preliminary to rule out any of our three test compounds at this time, given its lack of disruption of behavior in the open field, potential to enhance antidepressant effects, and suggestion of modest decreases in ketamine self-administration, D-cycloserine remains the test drug of greatest interest.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

7-12-2022

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