Chronic, low-level exposure to the cholinesterase inhibitor DFP. I. Time course of neurochemical changes in the rat pontomesencephalic tegmentum

Rats were repeatedly administered with a low dose of diisopropyifluorosphos phate (DFP; 0.2 mg/kg/day, SC, for 9 or 21 days), an irreversible cholinest erase (ChE) inhibitor. Control rats received a daily injection of oil vehic le. Neurochemical changes occurring in the pontomesencephalic tegmentum (PM T), a brain stem region critically involved in behavioral state control, we re evaluated at various times of treatment and after DFP withdrawal. First, enzyme assay revealed a profile of ChE inhibition in the whole PMT which l ooked like that observed in the striatum; both the inhibition and recovery proceeded more slowly than they did in the plasma. Second, quantitative his tochemistry indicated that ChE activity in the mesopontine cholinergic nucl ei and the pontine reticular formation progressively decreased across the f irst days of DFP exposure, to reach an asymptotic level of inhibition after 6 days (74-82% inhibition). The inhibition was less pronounced in the locu s coeruleus (49%). Third, [H-3]QNB autoradiography showed that muscarinic r eceptor density was unchanged in any of the PMT areas selected. These resul ts are discussed regarding the question of regional variation in susceptibi lity to anti-ChE agents. To what extent behavioral state alterations occur concomitantly with ChE activity changes is assessed in the companion articl e. (C) 1999 Elsevier Science Inc.