Defense Date


Document Type


Degree Name

Master of Science



First Advisor

Joseph H. Porter

Second Advisor

Katherine L. Nicholson

Third Advisor

Todd Hillhouse

Fourth Advisor

Timothy Donahue


Depression is one of the most debilitating disorders in the world. The currently available medications typically have a 2-4 week delay in their therapeutic effects and are ineffective for about 40% of patients. In 2000, a subanesthetic dose (0.5 mg/kg i.e.) of the dissociative anesthetic ketamine was reported to have both rapid and robust antidepressant effects in in treatment-resistant depressed patients. However, the mechanisms responsible for ketamine’s antidepressant effects remain unclear. In 2018, a clinical study reported that pretreatment with the nonselective opioid antagonist naltrexone attenuated the rapid antidepressant effect of ketamine in depressed patients. The current study investigated the potential role of the opioid system in ketamine’s antidepressant-like effects in two different preclinical behavioral assays. Mice were tested in the differential-reinforcement-of-low-rate responding (DRL) 72 sec task and tail suspension test (TST). Locomotor activity also was measured to determine if ketamine and/or naltrexone produced any changes in locomotor behavior that could influence the results in the DRL and TST assays. Ketamine and the nonselective opioid antagonist naltrexone were tested alone and in combination in C57BL/6 mice. The current study found that ketamine alone produced an acute antidepressant-like effect in the DRL 72 sec task at a dose of 32 mg/kg and TST at a dose of 10 mg/kg, and that this antidepressant-like effect was blocked by pretreatment of 2 mg/kg naltrexone in both behavioral assays. These results suggest that ketamine’s antidepressant effects may involve activation of the opioid system.


© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission