Species differences in diisopropylfluorophosphate-induced decreases in the number of brain nicotinic receptors.
DBA and C3H mice were injected chronically with 2.0 mg/kg diisopropylfluorophosphate (DFP) every other day for 2 or 4 weeks. Although acetylcholinesterase (AChE) activity and muscarinic receptor numbers ([3H] quinuclidinyl benzilate (QNB) binding) were decreased in DFP-treated DBA and C3H mice, the number of nicotinic receptors (L-[3H]nicotine and alpha-[125I]bungarotoxin (BTX) binding) was unchanged by chronic DFP treatment. Sprague-Dawley rats injected chronically with lower doses of DFP than were used in mice exhibited a greater reduction in AChE activity, as well as accompanying decreases in [3H]QNB and [3H]nicotine binding. Neither species exhibited changes in alpha-[125I]BTX following chronic DFP injection. The effects of chronic DFP treatment on sensitivity to DFP and to nicotine were also assessed in the two mouse strains using a battery of behavioral and physiological tests that included rotarod performance, Y-maze crossing and rearing activity, heart rate, and body temperature. No tolerance to DFP was observed in either mouse strain after 2 weeks of treatment. Following 4 weeks of treatment, DFP-treated DBA mice exhibited modest tolerance to the effect of DFP on body temperature. C3H mice did not survive the 4-week treatment. Some evidence for reduced sensitivity to nicotine's effects was detected in the DFP-treated DBA mice, but cross-tolerance to nicotine was not observed in the DFP-injected C3H mice. Because chronic DFP treatment did not evoke a change in the number of brain nicotinic receptors, the reduced sensitivity to some of nicotine's effects seen in DBA mice must be due to some factor other than receptor downregulation.
Van de Kamp
J L
JL
School of Pharmacy, University of Colorado, Boulder 80309.
Collins
A C
AC
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects*; D002038:Bungarotoxins / Q000378:metabolism; D003864:Depression, Chemical; D004361:Drug Tolerance; D006339:Heart Rate / Q000187:drug effects; D007531:Isoflurophate / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008811:Mice, Inbred DBA; D009538:Nicotine / Q000378:metabolism; D010095:Oxotremorine / Q000494:pharmacology; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D011978:Receptors, Nicotinic / Q000187:drug effects*; D013045:Species Specificity
D002038:Bungarotoxins; D011978:Receptors, Nicotinic; D007531:Isoflurophate; D010095:Oxotremorine; D011813:Quinuclidinyl Benzilate; D009538:Nicotine