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.