phosphate-induced delayed neuropathy [OPIDN]). Intermediate syndrome (intermediate in onset between the acute toxic effects following exposure to a ChE inhibitor and the delayed neuropathic actions associated with certain OP-type cholinesterase inhibition) is a toxic syndrome associated with muscle weakness. It typically occurs 24 hours after exposure and is characterized by weakness or paralysis involving neck flexors, cranial nerves, proximal limb muscles, and respiratory muscles (Leon et al., 1996). The intermediate syndrome usually resolves over time, and although it has been associated with exposure to a variety of ChE inhibitors, PB has not been implicated (Golomb, 1999). Clinically, OPIDN (see below and Chapter 5) is a delayed neuropathy, its symptoms becoming manifest some 2–3 weeks after exposure to certain organophosphate ChE inhibitors. A detailed description of the disorder has been given recently (Golomb, 1999). Like the intermediate syndrome, OPIDN has not been associated with exposure to PB.
PB administration also results in enhanced expression of AChE in skeletal muscle, evident even after the enzyme is no longer inhibited (Lintern et al., 1997a,b). Further, repeated administration of PB over a period of weeks produces a dose-related increase in the expression of beta-endorphin and beta-endorphin 30-31 (glycylglutamine), both of which are derived from the same precursor protein pro-opiomelanocortin (POMC); the endorphins are thought to lead to the augmented AChE (Amos and Smith, 1998). POMC levels are also increased by nerve section (Edwards et al., 1986), as well as by other neurotoxicants including iminodipropionitrile (IDPN), acrylamide, and organophosphates (Hughes et al., 1992, 1995; Amos and Smith, 1998). Thus, increased expression of POMC and the consequent increase in AChE levels are probably obligatory components of an injury response, regardless of whether the injury is physical or chemical.
Compared to other carbamates, particularly physostigmine, or to organophosphate cholinesterase inhibitors, PB has had limited investigation for its potential neurobehavioral effects. Based on its reported lack of access to the central nervous system (CNS), PB has historically been used as a negative control in behavioral studies of other ChE inhibitors or as an agent to selectively produce peripheral nervous system actions of ChE inhibitors. PB is a carbamate possessing a positively charged quaternary group that restricts its penetration of the blood–brain barrier (Xia et al., 1981). Doses of PB employed in these studies, often in the range of 200 μg/kg, failed to produce observable effects on the behavioral paradigm under examination (McMaster and Finger, 1989; Wolthius et al., 1995); thus, PB has traditionally been thought to be devoid of CNS action.
The use of PB as a preventive measure against the effects of chemical warfare agents, coupled with the emerging understanding of the importance of a cholinergic link in Alzheimer’s disease, has led to a reexamination of the action of PB, particularly of chronic dosing schedules, on behaviors in both humans and laboratory animals. Low doses of PB have been reported to have behavioral