Effects of Sarin on Temperature and Activity of Rats as a Model for Gulf War Syndrome Neuroregulatory Functions Carole A. Conn,* Karol Dokladny,* Margaret G. Me ´nache,* Edward B. Barr,† Wieslaw Kozak,‡ Anna Kozak,‡ Maceij Wachulec,‡ Karin Rudolph,† Matthew J. Kluger,‡ and Rogene F. Henderson† *University of New Mexico, Albuquerque, New Mexico 87106; †Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108; and ‡Medical College of Georgia, Augusta, Georgia 30901 Received February 8, 2002; accepted July 23, 2002 Effects of Sarin on Temperature and Activity of Rats as a Model for Gulf War Syndrome Neuroregulatory Functions. Conn, C. A., Dokladny, K., Me ´nache, M. G., Barr, E. B., Kozak, W., Kozak, A., Wachulec, M., Rudolph, K., Kluger, M. J., and Henderson, R. F. (2002). Toxicol. Appl. Pharmacol. 184, 77– 81. Coexposure to subclinical levels of nerve gas and to heat stress may have induced some of the clinical symptoms of the Gulf War Syndrome. We tested the hypothesis that single or repeated sub- clinical exposure to sarin, particularly under conditions of heat stress, would impairregulation of body temperature and locomo- tor activity. Male F344 rats were housed at 25°C or under mild heat stress at 32°C and were exposed 1 h/day for 1, 5, or 10 days to 0, 0.2, or 0.4 mg/m 3 of sarin in a nose-only exposure system. Body temperature and activity were monitored continuously by telemetry during exposure and 1 month postexposure. Exposed rats showed no clinical symptoms of toxicity such as tremors, despite evidence of reduced red blood cell cholinesterase activity. Heat stress consistently elevated body temperature in unexposed animals, particularly during the dark period when animals are most active. Inhalation of sarin gas at the two subclinical levels did not affect body temperature acutely in a biologically meaningful manner after the first exposure nor after 5 or 10 repeated expo- sures, either at thermoneutral ambient temperature or during chronic heat stress. There were no consistent effects of sarin or housing temperature on activity. The data suggest that subclinical levels of sarin have minimal effects on temperature regulation and locomotor activity under these observation conditions. © 2002 Elsevier Science (USA) Key Words: subclinical exposure; telemetry; anticholinesterase; heat stress. Following active duty in the Persian Gulf between August 1990 and June 1991, some U.S. military personnel manifested symptoms designated as the Gulf War Syndrome. Expression of the syndrome differs among individuals but can include arthralgia, weakness, fatigue, headache, memory loss, and in- creased susceptibility to infections (IOM, 1995). Etiology of the syndrome is currently unknown, but it has been hypothe- sized that exposure to subclinical levels of nerve gas might cause subtle neuroimmune abnormalities that could manifest in the clinical symptoms of the syndrome (Haley et al., 1999). Similar clinical symptoms were noted in individuals living in the area surrounding Matsumoto City, Japan, following the acute sarin poisoning that occurred inside the city on June 27, 1994 (Nakajima et al., 1999). However, very little experimen- tal evidence is available on the physiological effects of single or repeated exposures to low levels of nerve gas. One mechanism by which organophosphate agents such as sarin gas exert their physiological effects is by irreversibly inhibiting the enzyme acetylcholinesterase (AChE), resulting in central accumulation of acetylcholine and overexcitation of cholinergic neurons. High levels of exposure result in seizures, which increase the release of glutamate and cause toxicity to surrounding cells (Solberg and Belkin, 1997). The control of body temperature is integrated in the central nervous system via cholinergic pathways, and acute exposure to organophos- phates can cause profound changes in body temperature lasting several days (Gordon, 1996). A smaller accumulation of ace- tylcholine because of a low-level exposure might also alter the capability for normal thermoregulation, but this hypothesis is currently untested. In addition to the inhibition of cholinester- ases, a range of noncholinesterase effects of organophosphates has been observed (Ray, 1998). As an example pertinent to this investigation, hippocampal slices exposed to low levels of sarin showed altered release of -amino butyric acid and glu- tamate neurotransmitters involved in thermoregulation (Rocha et al., 1998). Fatigue is a major symptom of the Gulf War Syndrome and also has been documented in female greenhouse workers ex- posed to organophosphorous pesticides (Bazylewicz-Walczak et al., 1999). Central fatigue resulting in lethargy is postulated to occur when neurotransmitter activity in the central nervous system is altered (Newsholme et al., 1992; Bailey et al., 1993), and the hypothesis has been put forward that alterations in GABAergic and cholinergic transmission are involved in fa- tigue syndromes (Corrigan et al., 1994). Both sarin and soman have decreased locomotor activity in rats when injected ip in doses large enough to inhibit AchE activity in the blood Toxicology and Applied Pharmacology 184, 77– 81 (2002) doi:10.1006/taap.2002.9496 77 0041-008X/02 $35.00 © 2002 Elsevier Science (USA) All rights reserved.