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

Jackie Zhu,Elisa Hawkins,Kristin Phillips,Laxmikant S. Deshpande

doi:10.3390/ijerph17134710

Abstract

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. 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, R-KET and S-KET, also exhibited such effects in DFP rats, with R-KET being the more potent isomer. Our studies provide a starting point for further assessment of KET for GWI depression.

Highlights

One-third of nearly 700,000 U.S soldiers deployed during the first Gulf War (GW)suffer from a chronic multi-system disorder known as Gulf War Illness (GWI)
GWI is defined as the presence of a spectrum of chronic symptoms in GW service members that persist for 6 months or longer in at least two of six categories: development of fatigue, mood and cognitive changes, musculoskeletal changes, gastrointestinal symptoms, respiratory, and neurological disorders [2]
We have developed a rat model that recapitulates some aspects of GWI related neurological signs such as the mood and memory dysfunction that are reported by GW veterans

Summary

Introduction

One-third of nearly 700,000 U.S soldiers deployed during the first Gulf War (GW). Suffer from a chronic multi-system disorder known as Gulf War Illness (GWI). GWI is defined as the presence of a spectrum of chronic symptoms in GW service members that persist for 6 months or longer in at least two of six categories: development of fatigue, mood and cognitive changes, musculoskeletal changes, gastrointestinal symptoms, respiratory, and neurological disorders [2]. GWI have reported cognitive dysfunction and increases in mood disorders including anxiety and depression [3]. There are multiple factors to which the development of GWI could be potentially attributed, some of which may serve as confounders in assessing the role of others as causes of GWI. Deployment complexities led to soldiers being exposed to a variety of pharmaceuticals, chemicals, and environmental

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Conclusion