Locomotor and sensorimotor performance deficit in rats following exposure to pyridostigmine bromide, DEET, and permethrin, alone and in combination

Since their return from Persian Gulf War (PGW), many veterans have complain ed of symptoms including muscle and joint pain, ataxia, chronic fatigue, he adache, and difficulty with concentration. The causes of the symptoms remai n unknown. Because these veterans were exposed to a combination of chemical s including pyridostigmine bromide (PB), DEET, and permethrin, we investiga ted the effects of these agents, alone and in combination, on the sensorimo tor behavior and central cholinergic system of rats. Male Sprague-Dawley ra ts (200-250 gm) were treated with DEET (40 mg/kg, dermal) or permethrin (0. 13 mg/kg, dermal), alone and in combination with PB (1.3 mg/kg, oral, last 15 days only), for 45 days. Sensorimotor ability was assessed by a battery of behavioral tests that included beam-walk score, beam-walk time, incline plane performance, and forepaw grip on days 30 and 45 following the treatme nt. On day 45 the animals were sacrificed, and plasma and CNS cholinesteras e, and brain choline acetyl transferase, muscarinic and nicotinic acetylcho line receptors were evaluated. Animals treated with PB, alone or in combina tion with DEET and permethrin, showed a significant deficit in beam-walk sc ore as well as beam-walk time as compared with controls. Treatment with eit her DEET or permethrin, alone or in combination with each other, did not ha ve a significant effect on beam-walk score. All chemicals, alone or in comb ination, resulted in a significant impairment in incline plane testing on d ays 30 and 45 following treatment. Treatment with PB, DEET, or permethrin a lone did not have any inhibitory effect on plasma or brain cholinesterase a ctivities, except that PB alone caused moderate inhibition in midbrain acet ylcholinesterase (AChE) activity. Treatment with permethrin alone caused si gnificant increase in cortical and cerebellar AChE activity. A combination of DEET and permethrin or PB and DEET led to significant decrease in AChE a ctivity in brainstem and midbrain and brainstem, respectively. A significan t decrease in brainstem AChE activity was observed following combined expos ure to PB and permethrin. Coexposure with PB, DEET, and permethrin resulted in significant inhibition in AChE in brainstem and midbrain. No effect was observed on choline acetyl transferase activity in brainstem or cortex, ex cept combined exposure to PB, DEET, and permethrin caused a slight but sign ificant increase in cortical choline acetyltransferase activity. Treatment with PB, DEET, and permethrin alone caused a significant increase in ligand binding for m2 muscarinic acetylcholine receptor (mAChR) in the cortex. Co exposure to PB, DEET, and permethrin did not have any effect over that of P B-induced increase in ligand binding. There was no significant change in li gand binding for nicotinic acetylcholine receptor (nAChR) associated with t reatment with the chemical alone; a combination of PB and DEET or coexposur e with PB, DEET, and permethrin caused a significant increase in nAChR liga nd binding in the cortex. Thus, these results suggest that exposure to phys iologically relevant doses of PB, DEET, and permethrin, alone or in combina tion, leads to neurobehavioral deficits and region-specific alterations in AChE and acetylcholine receptors.