Adaptive processes of the central and autonomic cholinergic neurotransmitter system: age-related differences

Potential age-related differences in the response of the ileum strip longitudinal and circular muscle to repeated treatment with diisopropyl fluorophosphate (DFP) were evaluated in Sprague-Dawley rats. The response was measured in terms of both biochemical parameters (acetylcholinesterase-AChE inhibition, muscarinic acetylcholine receptor binding sites-mAChRs, choline acetyltransferase-ChAT) and functional responsiveness (contractility of the isolated ileum stimulated by cholinergic agonists). The biochemical data were compared with those obtained for the cerebral cortex. Male 3- and 24-month old rats were s.c. injected with DFP on alternate days for 2 weeks (doses in mg/kg: first 1.1, two of 0.7 and four of 0.35). They were killed 48 hr and 7, 14, 21, 28 and 35 days after the last treatment. In the ileum strip of control rats there was a significant age-related decline of AChE, maximal density of 3H-QNB binding sites (Bmax) and ChAT. During the first week of DFP treatment the cholinergic syndrome was more pronounced in aged than in young rats, resulting in 35% and 10% mortality, respectively; subsequently the syndrome attenuated. At the end of DFP treatment ileal AChE were inhibited by about 30%; the down-regulation of mAChRs was about 50% in young and 35% in aged rats. No significant differences in the recovery rate of AChE were noted between young and aged rats (normalization within 7 days). On the contrary, mAChRs normalized within 5 weeks in young and 3 weeks in aged rats. This was probably due to more adaptive decline in the former group. There was a post-treatment increase of ChAT, transitory in young and persistent in aged rats. In spite of age-related marked loss of ileal mAChRs there were only little, although significant, changes in the contractile responsiveness of the isolated ileum to cholinergic agonists. Considerable DFP-induced down-regulation of mAChRs was not accompanied by changes in contractility stimulated by the agonists. The overall data indicate that age- and treatment-induced changes of AChE, mAChRs and ChAT in the ileum strip differ considerably from those observed in the cerebral cortex of the same rats.