Acute and long lasting central actions of organophosphorus agents

Abstract

This review concerns aspects of anticholinesterase (anti-ChE) research that differ from those of the classical studies of these agents; to clarify the focus of this review, let me first allude to three classical aspects of anti-ChE research. Animal research as well as records of purposeful or accidental administration of anti-ChE's of both organophosphorus (OP) or carbamate and related types were initiated more than 100 years ago (see Holmstedt, 1959, 1963; Koelle and Gilman, 1949; Karczmar, 1970a). Initially, peripheral, particularly neuromyal effects of these drugs were studied in depth, whereas their central actions that were described included essentially only their toxic effects, i.e., respiratory depression and convulsions (cf. Gilman, 1946; Krop and Kunkel, 1954). Behavioral and functional central actions of OP and carbamate drugs, while sporadically reported in the Thirties and Forties came into their own much later (Sjostrand, 1937; Izergina, 1949; cf. Karczmar, 1970b). The second characteristic aspect of the early studies of anti-ChE's is as follows: in conjunction with the discoveries of the Twenties through Forties concerning ChE's, acetylcholine (ACh) and cholinergic transmission and with the discovery of the action of physostigmine (Stedman et al., 1932) and OP drugs (see Bodansky, 1945) on ChE's it was felt that pharmacological effects of these drugs are due solely to ChE, particularly AChE, inhibition. Only in the Forties evidence militating against this concept was presented. The third classical concept, actually a corollary of the notion that OP and carbamate drugs act via their inhibition of ChE's, is that their action is short-lived or relatively short-lived as it depends on dissociation of the ChE-carbamate complex in the case of physostigmine and related drugs or on regeneration of ChE's in that of OP drugs, a process that may take at most days, or hours (Srinivasan et al., 1976). More recent studies suggest that it may be not so. Accordingly, this paper is intended as a brief summary of research concerning these three novel aspects of action of anti-ChE's: their central including behavioral and mental health effects; their actions that may not depend on ChE inhibition-which is also the subject of other papers of this issue; and, finally, their chronic and delayed actions. © 1984.