Anticholinesterase Effects on Number and Function of Brain Muscarinic Receptors and Central Cholinergic Activity: Drug Intervention.
Final rept. 31 Dec 84-30 Nov 85,
ISTITUTO DI RICERCHE FARMACOLOGICHE MARIO NEGRI MILAN (ITALY)
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The effects of acute and chronic treatments with the organophosphorous cholinesterase inhibitor DDVP dichlorvos 0,0-dimethyl 0-2,2-dichlorovinyl phospate, combined with drug treatments were studied on rat brain reginal cholinergic parameters acetlylcholine content, choline content, acetylcholinesterase, choline acetyltranserase, sodium dependent high affinity choline uptake, muscarinic receptor subtypes. Results show that the increase in brain regional acetylcholine induced by DDVP can, to some extent, be dissociated from the cholinesterase inhibition of the drug. DDVP appears to stimulate a positive feedback mechanism to shut down cholinergic nerve terminals and this is held to be at least partly responsible for the increase in acetylcholine. This results in an intraneural accumulations of the cholinergic neurotransmitter. Drugs that possibly interfere with the feedback may cause a shift in the proportion of intraneural acetlcholine, in favor of the former, in cholinesterase poisioned rats. In rats treated chronically with DDVP, AChE activity was reduced by more than 70 in the striatum, hippocampus and cortex. At the same time, ACh content in these regions was not altered. Marked tolerance to the ACh-accumulating action of DDVP and cross-tolerance to the increase produced by physostigmine were induced in the striatum but not in the hippocampus or cortex.