Influence of drugs acting on nitric oxide-dependent pathways on ethanol tolerance in rats.
BACKGROUND
Our previous studies have shown that the inhibition of nitric oxide (NO) synthesis with drugs administered either by systemic or ICV routes blocks the development of tolerance to some of the effects of ethanol.


OBJECTIVE
The aim of this study was to further investigate the role of NO-dependent pathways in tolerance to the incoordinating effect of ethanol through ICV administration of drugs that activate or interfere with NO-dependent pathways.


METHODS
Male Wistar rats were pretreated with IP ethanol (2.7 g/ kg) or saline before receiving ICV injections of the soluble guanylyl cyclase (sGC) inhibitors methylene blue (30 nmol), 6(phenylamino)-5,8-quinolinedione (LY83583, 10 nmol), 1H-(1,2,4)-oxodiazolo (4,3-a)quinoxalin-1-one (ODQ, 1 nmol), and 4H-8-bromo-1,2,4-oxadiazolo (3,4-d)benz(b)(1,4)oxazin-1-one (NS2028, 10 nmol), or the respective control solutions. The animals were tested on the tilt plane apparatus. Tolerance was assessed 24 h after the first ethanol injection, by administering ethanol to all animals and re-testing them on the tilt plane. The effects of the cyclic guanylate 3',5'-monophosphate (cGMP) analogue, 8-bromo-cGMP (40 nmol or 80 nmol) and of the NO donors S-nitroso-N-acetylpenicillamine (SNAP, 40 or 80 nmol) and sodium nitroprusside (SNP, 40 or 80 nmol) were also studied.


RESULTS
All sGC inhibitors significantly blocked rapid tolerance, whereas SNP (40 nmol) and 8-bromo-cGMP (80 nmol) increased the magnitude of ethanol tolerance (ANOVA+Tukey's test).


CONCLUSIONS
The present results suggest that activation or inhibition of NO-dependent pathways increases or blocks rapid tolerance, respectively. These results give additional support to the hypothesis that brain NO plays a role in the development of tolerance to ethanol, but it remains to be confirmed if the same basic cellular mechanisms are also applicable to tolerance to other behavioural and/or physiological effects of this drug.
Wazlawik
Elisabeth
E
Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Rua Ferreira Lima 82, 88015-420 Florianopolis, Santa Catarina, Brazil.
Morato
Gina Struffaldi
GS
D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D004361:Drug Tolerance / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000431:Ethanol / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors*; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D010069:Oxadiazoles / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D000634:Aminoquinolines; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D011810:Quinoxalines; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D000431:Ethanol; C041715:6-anilino-5,8-quinolinedione; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D006152:Cyclic GMP