Assessment of Ketamine and Its Enantiomers in an Organophosphate-Based Rat Model for Features of Gulf War Illness

• Main Authors: Jackie Zhu, Elisa Hawkins, Kristin Phillips, Laxmikant S. Deshpande
• Format: Article
• Language: English
• Published: MDPI AG 2020-06-01
• Series: International Journal of Environmental Research and Public Health
• Subjects: organophosphates; DFP; depression; <i>R</i>-ketamine; <i>S</i>-ketamine; Sprague-Dawley rats
• Online Access: https://www.mdpi.com/1660-4601/17/13/4710

Approximately 33% of U.S. soldiers from the first Gulf War suffer from a multi-system disorder known as the Gulf War Illness (GWI). GW veterans suffer from a cluster of symptoms that prominently include fatigue and can include mood-related symptoms<b>.</b> Compared to traditional antidepressants, ketamine (KET) produces a fast-onset and long-lasting antidepressant response, but assessments of KET for GWI-related depression are lacking. The etiology of GWI is multi-factorial and exposure to organophosphates (OP) during deployment is one of the factors underlying GWI development. Here, male Sprague-Dawley rats were repeatedly exposed to an OP DFP and three months later these rats, when assessed on a battery of rodent behavioral assays, displayed signs consistent with aspects of GWI characteristics. When treated with a sub-anesthetic dose of KET (3, 5, or 10 mg/kg, i.p.), DFP-treated rats exhibited a significant improvement in immobility time, open-arm exploration, and sucrose consumption as early as 1 h and much of these effects persisted at 24-h post-KET injection. KET’s stereoisomers, <i>R</i>-KET and <i>S</i>-KET, also exhibited such effects in DFP rats, with <i>R</i>-KET being the more potent isomer. Our studies provide a starting point for further assessment of KET for GWI depression.