phosphorylated enzyme then can undergo a second process, called aging, by loss of an alkyl group (dealkylation). The half-life for “aging” is about 5 hours after sarin exposure (Sidell and Borak, 1992). Only during this period prior to aging can treatment with oxime therapy (e.g., pralidoxime chloride) successfully remove sarin from the enzyme and thus block the aging process. After aging has occurred, the phosphorylated enzyme (now negatively charged) is resistant to cleavage or hydrolysis and can be considered irreversibly inhibited. Recovery of AChE function occurs only with synthesis of new enzyme. Inhibition of AChE prevents the breakdown of acetylcholine, which accumulates in central and peripheral nerve synapses, leading to the acute cholinergic syndrome.

Sarin also may exert its effects through other cholinergic mechanisms (unrelated to inhibition of AChE). A new line of research suggests that sarin (in picomolar concentrations) may interact directly with muscarinic ACh receptors (Rocha et al., 1998; Chebabo et al., 1999). Researchers uncovered this new mechanism by studying sarin’s ability to reduce evoked GABA (gamma-aminobutyric acid) release from hippocampal neurons. This effect of sarin is blocked by the muscarinic receptor antagonist atropine, but not by nicotinic receptor antagonists (Rocha et al., 1998). These findings suggest that sarin may interact with presynaptic muscarinic receptors, thereby reducing action potential-dependent release of GABA in the postsynaptic neuron (Chebabo et al., 1999). It is reasonable to consider that sarin acts as a muscarinic receptor antagonist inhibiting the evoked release of GABA. Reductions in the levels of GABA, which is an inhibitory neurotransmitter, may contribute to the convulsive properties of sarin.

Noncholinergic Mechanisms

For decades, researchers observed puzzling relationships between the extent of neurobehavioral toxicity and the degree of inhibition of AChE. For example, only sarin-induced tremor has a slight correlation with AChE inhibition in rat striatum, whereas chewing, hind-limb abduction, and convulsions have no clear correlation (Hoskins et al., 1986). Some sarin-treated rats with 90 percent inhibition of AChE in the striatum of the brain had no convulsions or hind-limb abduction, while rats with less enzyme inhibition exhibited both. From these findings, researchers have concluded that noncholinergic mechanisms may also contribute to toxicity induced by sarin and other organophosphates. The difficulty has been in disentangling which effects are mediated directly by sarin and which are secondary to its inhibition of AChE.

Several studies suggest that sarin may alter the level of neurotransmitters other than ACh. In most of these studies, however, the neurotransmitter effects are seen in brain regions where there are cholinergic synapses. Significant increases in catecholamines, measured histochemically, were found in the substantia nigra pars compacta and locus coeruleus of the brain following intramus-

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