Author ORCID Identifier

Defense Date


Document Type


Degree Name

Doctor of Philosophy



First Advisor

Joseph H. Porter

Second Advisor

A. Rory McQuiston

Third Advisor

Caroline O. Cobb

Fourth Advisor

Katherine L. Nicholson

Fifth Advisor

Mary E. Loos


In 2017, 7.1% of US adults were diagnosed with depression, and 50% of patients received medication to treat their depression. Depression can cause severe interruptions in an individual's cognitive functioning and behaviors like sleeping, eating, working, and socializing. Unfortunately, approximately 40% of patients do not respond to treatment with monoaminergic medications (e.g. Prozac) and therapeutic effects may be delayed 2-8 weeks. Due to these therapeutic shortcomings, faster acting and more efficacious treatments are needed. Recent preclinical findings indicate potential for glutamatergic drugs like (R,S)-ketamine and (2R,6R) hydroxynorketamine to produce more rapid and longer-acting therapeutic effects. The antidepressant effectiveness of (R,S)-ketamine for many patients is undisputed; however, the antidepressant efficacy of the ketamine metabolite (2R,6R)-hydroxynorketamine is disputed. Despite an incomplete understanding of the mechanism of action, the FDA approved (S) ketamine (esketamine, Ketanest, Spravato) for treatment-resistant depression in March 2019. Excitement for a better treatment, however, is lessened by reports indicating that some patients may experience severe side effects like reduced cognitive functioning a day or more after (S) ketamine treatment. In sum, some glutamatergic drugs like (R,S)-ketamine are effective in treating depression, but potential side-effects and abuse liability may limit their clinical use. This provides a strong impetus to further examine and compare the antidepressant efficacy and side effects of (R,S)-ketamine, the ketamine isomers (R)-ketamine, (S)-ketamine, and the ketamine metabolite (2R,6R)-hydroxynorketamine. The current study measured the effects of (R,S) ketamine, (R)-ketamine, (S)-ketamine, and (2R,6R)-hydroxynorketamine on C57bl/6 mice in three preclinical behavioral assays; differential-reinforcement-of-low-rate responding (DRL), drug discrimination, and spontaneous alternation in a Y-maze. These assays provide measures of antidepressant-like effects, discriminative stimulus effects, and cognitive effects of drugs, respectively. Results indicated that (R,S)-ketamine, (S)-ketamine, and (2R,6R) hydroxynorketamine produced significant antidepressant-like effects in the DRL task. No significant effect was found with (R)-ketamine in the DRL task. The lack of effect in the DRL task may be due to the slower metabolism of (R)-ketamine compared to (S)-ketamine and the 10 minute pretreatment time used in the present study. In the drug discrimination experiment, both isomers substituted for (R,S)-ketamine; the effective dose of (S)-ketamine was lower than (R) ketamine and this indicates greater potency in this experiment. (2R,6R)-Hydroxynorketamine did not substitute for (R,S)-ketamine at the tested doses. In the Y-maze experiment, (R,S)-ketamine and (S)-ketamine reduced spontaneous alternation 24-hours after injection. No effect on spontaneous alternation was observed with (R)-ketamine and (2R,6R)-hydroxynorketamine at the tested doses. The results from the Y-maze experiment indicate that (R)-ketamine and (2R,6R) hydroxynorketamine may have less effect on cognition than (R,S)-ketamine and (S)-ketamine. The present study reports novel findings regarding the antidepressant-like effects, subjective effects, and cognitive effects of (R,S)-ketamine, its isomers, and the metabolite (2R,6R) hydroxynorketamine. The results of the present study and many other preclinical studies suggest that clinical research is warranted for the (R)-ketamine (arketamine) isomer and the ketamine metabolite, (2R,6R)-hydroxynorketamine.


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