Prolonged Inhibition of Motor Activity following Repeated Exposure to Low Levels of Chemical Warfare Agent Vx

While neurobehavioral effects of acute exposure to toxic levels of chemical warfare nerve agents (CWNA) have been characterized (e.g. [8]), much less is known about the effects of repeated exposure to non-convulsive levels of CWNA. In Exp. 1, male mice that received repeated exposure (1/day x 5 days/wk x 2 wk) to 0.4 LD50 of the nerve agent VX had much lower activity in the home cage, relative to saline treated mice, with activity levels gradually reaching that of control by 6 weeks post-exposure. In Exp. 2, repeated exposure to 0.2 LD50 and 0.4 LD50 VX in male and female mice reduced activity in a novel open-field test 10 days following the last VX exposure. These findings indicate long-term performance deficits following exposure to non-convulsive levels of VX. INTRODUCTION Chemical warfare nerve agents (CWNA) are highly toxic organophosphorus (OP) chemicals that irreversibly inhibit many serine esterases, including acetylcholine esterase (AChE) in the central and peripheral nervous system. Prolonged inhibition of AChE increases acetylcholine (ACh) at neuronal synapses and at the neuromuscular junction, and can cause acute toxicity. Toxic symptoms include convulsions, tremors, and bronchial constriction, which can then lead to asphyxiation and death [21]. In addition, symptoms of sleep disturbances, psychomotor retardation, and intellectual impairment have been reported following OP exposure. Pathological changes, including neuronal necrosis and axonal degeneration, are present in the hippocampus of rats surviving acute soman, with most behavioral and neuropathological effects of CWNA observed only in animals that display seizures [13,14,20]. While acute effects of CWNA on cognition and behavior are well characterized, much less is known about the effects of repeated exposure to sub-toxic levels of CWNA, including VX (O-ethyl S[2(diisopropylamino)ethyl]methylphosphonothioate). Most of the available literature on repeated exposure to low levels of organophosphorus compounds (OP) in humans is based on findings of repeated exposure to pesticides, some of which may elicit similar pathology but are typically much less toxic than CWNA. Repeated pesticide exposure has been linked with increased anxiety, depression, and fatigue, as well as impaired psychomotor function [10,16], and subtle cognitive deficits [15]. Incidents such as the release of sarin in the Tokyo subways [18] and the destruction of an ammunition depot containing sarin and cyclosarin potentially exposing civilians and soldiers to low level of CWNA (reviewed in [12]), have Report Documentation Page Form Approved OMB No. 0704-0188 Public reporting burden for the collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing the collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden, to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to a penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. 1. REPORT DATE 01 OCT 2005 2. REPORT TYPE N/A 3. DATES COVERED 4. TITLE AND SUBTITLE Prolonged Inhibition Of Motor Activity Following Repeated Exposure To Low Levels Of Chemical Warfare Agent VX 5a. CONTRACT NUMBER