CARBACHOL-INDUCED ACCUMULATION OF INOSITOL PHOSPHATES AND ITS MODULATION BY EXCITATORY AMINO-ACIDS IN CORTICAL SLICES OF YOUNG AND AGED RATS WITH DOWN-REGULATION OF MUSCARINIC M-1 RECEPTORS

The effects of a subacute intoxication with diisopropyl fluorophosphat e (DPF) on total muscarinic acetylcholine receptor sites (mAChRs) and M-1 AChRs were evaluated in the cerebral cortex of young (2-4 months) and aged (22-24 months) Fischer 344 rats. Since M-1 AChRs are coupled to the metabolism of phosphoinositides, carbachol-induced accumulation of inositol phosphates (IP) and its inhibition by glutamate and NMDA was also measured in the cortical slices. DFP treatment caused about 7 5% inhibition of cholinesterase and 35% down-regulation of mAChRs (mea sured as [H-3]quinuclidinyl benzylate binding) in both young and aged rats. The down-regulation of M-1-ACHRs (measured as [H-3]pirenzepine b inding) was more pronounced in aged (30%) than in young (17%) DFP-trea ted rats. There was a significant increase in carbachol-induced IP acc umulation in aged, with respect to young, untreated rats. DFP treatmen t caused a considerable decrease in such IP accumulation in aged but n ot in young rats. Glutamate and NMDA antagonized carbachol-induced IP accumulation in untreated young and aged rats (and the effects of NMDA were reversed by carboxy-piperazinyl-propyl phosphonic acid). In DFP- treated rats such antagonism was somewhat less pronounced. The data ap pear of interest in relation to the use of anticholinesterase compound s in the therapy of senile dementia of Alzheimer's type. They suggest that beside their primary action (increasing brain ACh levels) such co mpounds also act on post-receptor mechanisms and on the interactions b etween cholinergic and glutamatergic neurotransmitter systems.