In vitro modulation of bovine caudate muscarinic receptor number by organophosphates and carbamates.

In vitro binding assays to measure muscarinic receptor number and affinity were carried out with isolated synaptic plasma membranes from bovine caudate nuclei. Diethyl-p-nitrophenyl phosphate (paraoxon; PX), dichlorvos (DDVP), and tetraethyl pyrophosphate (TEPP) were demonstrated to be weak noncompetitive receptor inactivators. PX, DDVP, and TEPP decreased the number of [3H]quinuclidinyl benzilate (QNB) binding sites by 16 to 31% and exhibited no significant effect on the affinity of central muscarinic receptors for QNB (KD congruent to 0.3 nM). QNB binding was inhibited by PX at 5 nM, DDVP at 50 nM, and TEPP at 50 nM, concentrations with no effect on acetylcholinesterase activity. Similar measurements with two carbamates, physostigmine and neostigmine (1 nM), showed no effect of neostigmine on QNB binding, while physostigmine both decreased the number of receptors and enhanced their affinity for QNB. The modulation of muscarinic receptors by 5 nM PX was abolished by carbodiimide modification of the membrane preparation. It is suggested that a decrease in the number of muscarinic cholinergic receptors in the brain may underlie some of the neurological and affective disorders observed after chronic exposure of humans to organophosphate insecticides.