Effect of a single dose of an acetylcholinesterase inhibitor on oxotremorine- and nicotine-induced hypothermia in mice.
Downregulation of cholinergic receptors is a consequence of subchronic exposure to an organophosphate anticholinesterase. The purpose of this investigation was to determine if there was a downregulation of the cholinergic receptors in mice following administration of a single dose of soman (pinacolyl methylphosphonofluoridate) or physostigmine. The change in the temporal response (mean minimum temperature and area under the curve) of core temperature following administration of either a muscarinic or nicotinic agonist such as oxotremorine (156 micrograms/kg, IP) or nicotine hydrogen tartrate (15 mg/kg, SC) was used as an indicator of downregulation of muscarinic or nicotinic receptors, respectively. Twenty-four h following soman (100 micrograms/kg, SC) administration, there was a significant decrease (p less than 0.05) in oxotremorine- but not nicotine-induced hypothermia. The significant differences in the mean minimum temperature and AUC were still present 4 days after exposure to the soman. Neither lower doses of the organophosphate anticholinesterase, soman (50 and 70 micrograms/kg), nor the carbamate anticholinesterase, physostigmine (500 micrograms/kg), produced a significant change in either oxotremorine- or nicotine-induced hypothermia. The results of this study suggest that receptor downregulation observed after subchronic administration of soman is also evident following administration of a single, sublethal dose of an organophosphate anticholinesterase, soman, but not after administration of a carbamate anticholinesterase, physostigmine. The in vivo assessment of the muscarinic receptor using oxotremorine hypothermia may be a sensitive indicator of the functionality of the drug-receptor coupling and indicate a physiological consequence of receptor downregulation.
Clement
J G
JG
Biomedical Defence Section, Defence Research Establishment Suffield, Ralston, Alberta, Canada.
D000818:Animals; D001831:Body Temperature / Q000187:drug effects*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D004361:Drug Tolerance; D008297:Male; D051379:Mice; D009538:Nicotine / Q000494:pharmacology*; D010095:Oxotremorine / Q000494:pharmacology*; D010830:Physostigmine / Q000494:pharmacology; D011976:Receptors, Muscarinic / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000187:drug effects; D012999:Soman / Q000494:pharmacology
D002800:Cholinesterase Inhibitors; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D010095:Oxotremorine; D009538:Nicotine; D012999:Soman; D010830:Physostigmine