Nicotinic mechanisms contribute to soman-induced symptoms and lethality
Introduction
The nerve gas soman (pinacolylmethylphosphonofluoridate) is an organophosphate that inactivates acetylcholinesterase (AChE). Organophosphate intoxication leads to extracellular accumulation of acetylcholine in the peripheral and central nervous system and causes a host of symptoms, which in both man and animals include respiratory dysfunction, heart failure, tremor, fasciculation, and epileptiform convulsions (Buccafusco and Aronstam, 1986, Nordgren et al., 1992, Morita et al., 1995).
The central nervous symptoms of soman intoxication have been attributed to an initial effect on muscarinic acetylcholine receptors with rapid recruitment of other neurotransmitter systems such as the glutamatergic and the monoaminergic (for review, see McDonough and Shih, 1997). Activation of nicotinic acetylcholine receptors has not been regarded as a prominent factor in soman intoxication, even though excessive activation of nicotinic receptors by nicotine may precipitate seizures (e.g. Damaj et al., 1999, Roshan-Milani et al., 2003). Experimental studies did not find any effect of the centrally acting, non-competitive nicotinic antagonist mecamylamine on convulsive activity after soman intoxication (Shih et al., 1999; for anti-nicotinic actions of mecamylamine, see Papke et al., 2001). A recent in vitro study on soman-induced epileptiform discharges in guinea pig hippocampal slices concluded that mecamylamine was without effect on such discharges (Harrison et al., 2004). A lack of effect of mecamylamine has been reported for other models of soman intoxication, including soman-induced firing of noradrenergic neurons in locus coeruleus (Ennis and Shipley, 1992) and soman-induced hypothermia (Clement, 1993).
However, Heyl et al. (1980) reported that adding mecamylamine, 2 mg/kg, to a pretreatment regimen consisting of pyridostigmine, 0.3 mg/kg, and atropine, 8 mg/kg, caused striking improvement in survival in soman-intoxicated rabbits. Further, Fleisher et al. (1970), studying another nerve gas, sarin, found that that addition of mecamylamine, 1 mg/kg, to a treatment regimen consisting of atropine, 16 mg/kg, and the AChE reactivator toxogonin, 7.5 mg/kg, improved survival in rats, but that mecamylamine was without effect unless toxogonin was included.
In previous studies the dose of mecamylamine was rarely an issue. In some studies the dose was ∼0.8 mg/kg (Harris and Stitcher, 1984, Lennox et al., 1985, Shih et al., 1999), in other it was 1–2.5 mg/kg (Heyl et al., 1980, Goldstein, 1991, Ennis and Shipley, 1992, Clement, 1993). However, Philippens and Olivier (1997) used 20 mg mecamylamine/kg to counteract effects of another AChE inhibitor, physostigmine, and in a later study Dekundy et al. (2003) used 10 mg mecamylamine/kg to improve symptoms caused by the AChE inhibitor methomyl.
The present investigation was undertaken to shed more light on the role of nicotinic receptor activation in soman intoxication. Mice were treated with mecamylamine prior to or subsequent to soman intoxication to see whether this nicotinic antagonist could influence symptoms or survival. To identify soman-induced symptoms that could stem from nicotinic activation mice received scopolamine prior to soman exposure to eliminate cholinergic symptoms caused by excessive muscarinic activation; the symptoms of these animals were compared to those seen in animals that received both scopolamine and mecamylamine. This approach identified several soman-induced symptoms that appeared to stem from nicotinic activation.
Section snippets
Animals and materials
Mice, 25–30 g female NMRI, were from B&M (Ry, Denmark). The animals had free access to food and tap water during housing and experiments. Soman was from TNO (Rijswijk, The Netherlands); mecamylamine and scopolamine were from Sigma (St. Louis, MO, USA); [3H]acetylcholine iodide (76 mCi/mmol) was from Perkin-Elmer Life Sciences (Boston, MA, USA).
Animal treatment protocol
Prior to experiments soman was diluted to 5 μg/ml saline, 0.9%, and mecamylamine and scopolamine were dissolved at 0.1, 0.4 or 4 mg/ml in 0.9% saline. In
Behavioral effects of mecamylamine and scopolamine
Within 10 min of the s.c. administration of mecamylamine, 20 mg/kg, mice had half-closed eyes (ptosis), became less active, and tended to sit in groups with a light degree of piloerection, leading to a ball-like posture. They could, however, easily be stimulated to walk about the cage and did not display ataxia.
Mice that received pretreatment with scopolamine, 0.5, 2 or 20 mg/kg, could not be distinguished from mice that received saline in terms of motor activity or social behavior. There was no
Nicotinic activation in soman poisoning
This study shows that nicotinic activation probably plays an important role in soman intoxication, since pretreatment with mecamylamine greatly prolonged survival after soman administration. The effect of mecamylamine was clearly dose-dependent, since a dose of 20 mg/kg afforded protection, whereas a dose of 2 mg/kg did not.
It was not possible to identify symptoms of soman intoxication that were caused by nicotinic activation by comparing saline-pretreated and mecamylamine-pretreated animals,
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