Correlation between cholinesterase inhibition and reduction in muscarinic receptors and choline uptake by repeated diisopropylfluorophosphate administration: antagonism by physostigmine and atropine.

Muscarinic receptors, [14C]choline uptake and acetylcholinesterase (AChE) activity in central and peripheral tissues of guinea-pigs treated repeatedly with diisopropylfluorophosphate (DFP) were simultaneously determined. After repeated DFP (1 mg/kg) administration, there was a significant decrease in specific [3H] quinuclidinyl benzilate binding only in the striatum, ileal longitudinal muscle and urinary bladder among various tissues examined. Scatchard analysis revealed that the administration of DFP at 0.5, 1 and 2 mg/kg which depressed the tissue AChE by 50 to 90%, caused a dose-dependent decrease (20-50%) in striatal and ileal [3H]quinuclidinyl benzilate binding sites without a change in the dissociation constant. The lower dose (0.2 mg/kg) of DFP depressed significantly the AChE in both tissues by 30% but failed to alter their [3H]quinuclidinyl benzilate binding sites. High affinity uptake of [14C]choline in the striatum and ileal longitudinal muscle was significantly decreased by repeated administration of DFP at 0.5 and 1 mg/kg but not 0.2 mg/kg. The DFP-induced loss of striatal and ileal muscarinic receptors was effectively antagonized by a concomitant administration of physostigmine (0.5 mg/kg) and atropine (5 mg/kg). Also, these drugs antagonized the DFP-induced decrease in the striatal [14C]choline uptake. Thus, the present study has demonstrated that repeated DFP administration causes a specific decrease in muscarinic receptors and [14C]choline uptake in the striatum and ileal longitudinal muscle of guinea pigs which is closely associated with a considerable (more than 50%) depression of the tissue AChE. In addition, these adaptive changes by DFP were effectively antagonized by physostigmine and atropine.