Evidence for the involvement of presynaptic cholinergic functions in tolerance to diisopropylfluorophosphate.
Rats were treated with diisopropylfluorophosphate (DFP) acutely or daily for 14 days. The involvement of various presynaptic and postsynaptic functions of the cholinergic system in the development of tolerance to DFP was studied. Receptor density and affinity of both muscarinic and nicotinic receptors, high-affinity choline uptake, and [K+]-evoked release of acetylcholine (ACh) by atropine were not changed after acute administration of 2 mg/kg DFP. Both muscarinic and nicotinic receptors were down-regulated to the same extent (40-50%) after subacute administration of DFP (1 mg/kg) without changes in their affinities. Binding sites of muscarinic receptors were maximally decreased after 7 days of DFP administration. Thereafter, they remained constant throughout 14 days of administration. One hour after the last injection of 2 mg/kg DFP to subacutely treated rats, the maximum velocity of high-affinity choline uptake was significantly decreased in the striatum (33%) and hippocampus (53%) without changes in Km values. Twenty-four hours after the last injection of DFP, only a higher dose of DFP (2 mg/kg) significantly inhibited choline uptake. Potassium-evoked release of ACh by slices of striatum was not different between acutely and subacutely treated rats. However, the release of ACh by slices of striatum and hippocampus was significantly increased by atropine in subacutely treated rats. It is suggested that along with the down-regulation of the postsynaptic receptors, subsensitivity of presynaptic functions of the cholinergic synapse also develops during subacute administration of DFP.
Lim
D K
DK
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson 39216-4505.
Hoskins
B
B
Ho
I K
IK
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D002794:Choline / Q000378:metabolism; D004361:Drug Tolerance; D066298:In Vitro Techniques; D007531:Isoflurophate / Q000633:toxicity*; D007700:Kinetics; D008297:Male; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011950:Receptors, Cholinergic / Q000187:drug effects* / Q000502:physiology; D011976:Receptors, Muscarinic / Q000032:analysis; D011978:Receptors, Nicotinic / Q000032:analysis
D011950:Receptors, Cholinergic; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D007531:Isoflurophate; D002794:Choline; D000109:Acetylcholine; D011188:Potassium