Influence of nitric oxide synthase inhibition on the development of rapid tolerance to ethanol.
We recently reported that the nitric oxide (NO) synthase inhibitor L-nitroarginine (L-NA) blocks the development of rapid tolerance to the motor incoordinating effect of ethanol in the tilt-plane test. To clarify the mechanism of L-NA blockade of tolerance, four additional experiments were carried out using the same test. The first demonstrated that L-NA prevented the development of rapid tolerance to ethanol when injected prior to ethanol either on both Days 1 and 2 or only on Day 1. In the second experiment, tolerance was blocked only when L-NA was injected before but not after behavioral testing on Day 1. In the third, L-NA blocked the enhancement of rapid tolerance to ethanol induced by D-cycloserine (CS), an agonist at the N-methyl-D-aspartate (NMDA) receptor. In the last experiment, L-NA pretreatment did not influence blood ethanol disappearance curves on Day 1, or ethanol concentrations in brain, tail blood or decapitated trunk blood on Day 2. These data argue against state-dependent learning as the basis of the L-NA effect, and confirm and extent our previous observation that NO plays a role in the development of rapid tolerance to ethanol.
Khanna
J M
JM
Department of Pharmacology, University of Toronto, Ontario, Canada.
Morato
G S
GS
Chau
A
A
Shah
G
G
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D003523:Cycloserine / Q000494:pharmacology; D004361:Drug Tolerance; D000431:Ethanol / Q000097:blood / Q000494:pharmacology*; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019001:Nitric Oxide Synthase; D019335:Nitroarginine; D004856:Postural Balance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D019335:Nitroarginine; D009569:Nitric Oxide; D000431:Ethanol; D016202:N-Methylaspartate; D001120:Arginine; D003523:Cycloserine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D019331:NG-Nitroarginine Methyl Ester