Impaired recovery of brain muscarinic receptor sites following an adaptive down-regulation induced by repeated administration of diisopropyl fluorophosphate in aged rats

Abstract

Potential age-related differences in the recovery rate of brain cholinesterase activity (ChE) and muscarinic acetylcholine receptor binding sites (mAChRs) following reduction induced by repeated treatment with diisopropyl fluorophosphate (DFP) were evaluated in Sprague-Dawley rats. Male 3-and 24-month old rats were s.c. injected with DFP (doses in mg/kg: first 1.1, two of 0.7 and four of 0.35) on alternate days for 2 weeks and killed 48 hr and 7, 14, 21, 28 and 35 days after the last treatment. In the hippocampus and striatum, but not in the cerebral cortex, of control rats there was a significant age-related decline of ChE activity and maximal density of 3H-QNB binding sites (Bmax). The repeated administration of DGP during the first week caused a syndrome of cholinergic stimulation both in aged and young rats. The syndrome was more pronounced, in terms of intensity and duration (for many hours after each injection), in aged than in young animals resulting in 40 and 12% mortality, respectively; during the second week the syndrome attenuated in the two age-groups. The percentage inhibition of brain ChE at the end of DFP treatment (about 70%) did not differ between young and surviving aged rats. The down-regulation of mAChRs (without changes in affinity) was present in the three brain regions of both young and aged rats (from 20 to 40%). Factorial analysis of variance (2 ages × 2 recoveries ANOVA) showed significant differences for age, recovery rate, and significant interaction between age and recovery rate, both for ChE and mAChRs in the three brain areas. For example, cortical ChE in young rats reached pretreatment levels within 3 weeks, while hippocampal and striatal ChE activity recovered within 4 weeks; at these intervals ChE activity in aged rats was still considerably reduced (except in the striatum). Cortical and striatal mAChRs in young rats almost normalized within 1 week and hippocampal mAChR binding sites normalized within 2 weeks; at these intervals Bmax in aged rats were markedly below control levels. The overall data indicate that the recovery rate to normal baseline levels of ChE activity and mAChRs, following the termination of repeated treatment with the antiChE agent, is impaired in brain of aged rats. The delay in recovery rate is particularly evident in the cerebral cortex.