Regional adaptation of muscarinic receptors and choline uptake in brain following repeated administration of diisopropylfluorophosphate and atropine.
The specific [3H]QNB binding and high-affinity uptake of [14C]choline in 8 brain regions (cerebral cortex, hippocampus, hypothalamus, thalamus, striatum, midbrain, cerebellum and brainstem) after repeated administration of DFP and atropine to guinea-pigs were simultaneously measured. Following repeated DFP administration, AChE was markedly depressed in each brain region. In these animals, there was a significant decrease in specific [3H]QNB binding in the cerebral cortex, hippocampus and striatum, whereas the [3H]QNB binding in the rest of brain regions was unchanged. Scatchard analysis revealed a 36% decrease in the Bmax value for the striatal [3H]QNB binding without a change in the Kd value, suggesting a change in the receptor density. In contrast, repeated atropine administration produced a significant enhancement in the [3H]QNB binding only in the hippocampus and striatum. The Bmax value in the striatum increased by 21% without a change in the Kd value. In addition to the receptor alteration, high affinity uptake of [14C]choline in the hippocampus and striatum was significantly decreased by DFP treatment, while that in the striatum increased by atropine treatment. Thus the present study has demonstrated that a prolonged activation and blockade of central muscarinic receptors resulted in specific adaptation in both the receptor density and ACh availability at the synapses in the cerebral cortex, hippocampus and striatum.
D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D001285:Atropine / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002794:Choline / Q000378:metabolism*; D006168:Guinea Pigs; D007531:Isoflurophate / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000378:metabolism*; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*; D014018:Tissue Distribution
D011950:Receptors, Cholinergic; D011976:Receptors, Muscarinic; D007531:Isoflurophate; D011813:Quinuclidinyl Benzilate; D001285:Atropine; D000110:Acetylcholinesterase; D002794:Choline