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Influence of drugs acting on nitric oxide-dependent pathways on ethanol tolerance in rats

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Abstract

Rationale

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.

Objectives

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.

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References

  • Adams ML, Cicero TJ (1998) Alcohol intoxication and withdrawal: the role of nitric oxide. Alcohol 16:153–158

    Article  CAS  PubMed  Google Scholar 

  • Adams ML, Meyer ER, Sewing BN, Cicero TJ (1994) Effects of nitric oxide-related agents on alcohol narcosis. Alcohol Clin Exp Res 18:969–975

    CAS  PubMed  Google Scholar 

  • Amir S (1994) N-Methyl-d-aspartate receptor mediated signaling in the supraoptic nucleus involves activation of a nitric oxide-dependent pathway. Brain Res 645:330–334

    Article  CAS  PubMed  Google Scholar 

  • Arvola A, Sammalisto L, Wallgren H (1958) A test for level of alcohol intoxication in the rat. Q J Stud Alcohol 19:563–572

    CAS  Google Scholar 

  • Bocca L, Valenti S, Cuttica CM, Spaziante R, Giordano G, Giusti M (2000) Nitric oxide biphasically modulates GH secretion in cultured cells of GH-secreting human pituitary adenomas. Minerva Endocrinol 25:55–59

    CAS  PubMed  Google Scholar 

  • Bredt DS, Snyder SH (1989) Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum. Proc Natl Acad Sci USA 86:9030–9033

    CAS  PubMed  Google Scholar 

  • Bredt DS, Hwang PH, Snyder SH (1990) Localization of nitric oxide synthase indicating a neural role for nitric oxide. Nature 347:768–770

    CAS  PubMed  Google Scholar 

  • Bredt DS, Ferris CD, Snyder SH (1992) Nitric oxide synthase regulatory sites. Phosphorylation by cyclic AMP-dependent protein kinase, protein kinase C, and calcium/calmodulin protein kinase; identification of flavin and calmodulin binding sites. J Biol Chem 267:10976–10981

    CAS  PubMed  Google Scholar 

  • Calapai G, Mazzaglia G, Sautebin L, Constantino G, Marciano MC, Cuzzocrea S, Di Rosa M, Caputi AP (1996) Inhibition of nitric oxide formation reduces voluntary ethanol consumption in the rat. Psychopharmacology 125:398–401

    CAS  PubMed  Google Scholar 

  • Crabbe JC, Rigter H, Uijlen J, Strijbos C (1979) Rapid development of tolerance to the hypothermic effect of ethanol in mice. J Pharmacol Exp Ther 208:128–133

    CAS  PubMed  Google Scholar 

  • Dawson TM, Snyder SH (1994) Gases as biological messengers: nitric oxide and carbon monoxide in the brain. J Neurosci 14:5147–5159

    CAS  PubMed  Google Scholar 

  • Dawson TM, Sasaki M, Gonzalez-Zulueta M, Dawson VL (1998) Regulation of neuronal nitric oxide synthase and identification of novel nitric oxide signaling pathways. Prog Brain Res 118:3–11

    CAS  PubMed  Google Scholar 

  • Demontis MP, Varoni MV, Volpe AR, Emanueli C, Madedu P (1998) Role of nitric oxide synthase inhibition in the acute hypertensive response to intracerebroventricular cadmium. Br J Pharmacol 123:129–135

    CAS  PubMed  Google Scholar 

  • Dinnerman JL, Steiner JP, Dawson TM, Dawson V, Snyder SH (1994) Cyclic nucleotide dependent phosphorylation of neuronal nitric oxide synthase inhibits catalytic activity. Neuropharmacology 33:1245–1251

    Article  PubMed  Google Scholar 

  • East SJ, Garthwaite J (1991) NMDA receptor activation in rat hippocampus induces cyclic GMP formation through the l-arginine nitric oxide pathway. Neurosci Lett 123:17–19

    Google Scholar 

  • Ferreira VM, Valenzuela CF, Morato GS (1999) Role of nitric oxide-dependent pathways in ethanol-induced anxiolytic effects in rats. Alcohol Clin Exp Res 23:1898–1904

    CAS  PubMed  Google Scholar 

  • Field L, Dilts RV, Ravichandran R, Lenhert PG, Carnahan GE (1978) An unusually stable thionitrite from N-acethyl-dl-penicillamine, X-ray crystal and molecular structure of 2-(acetylamino)-2-carboxy-1,1-dimethylethyl thionitrite. J Chem Soc Comm 249–250

  • Förstermann U (1994) Biochemistry and molecular biology of nitric oxide synthases. Arzneimittelforschung 44:402–407

    PubMed  Google Scholar 

  • Garcia-Pascual A, Costa G, Labadia A, Jimenez E, Triguero D (1999) Differential mechanisms of urethral smooth muscle relaxation by several NO donors and nitric oxide. Naunyn Schmiedeberg's Arch Pharmacol 360:80–91

    Google Scholar 

  • Garthwaite J (1991) Glutamate, nitric oxide and cell-cell signaling in the nervous system. Trends Neurol Sci 14:60–67

    Article  CAS  Google Scholar 

  • Garthwaite J, Boulton CL (1995) Nitric oxide signaling in the central nervous system. Annu Rev Physiol 57:683–706

    CAS  PubMed  Google Scholar 

  • Garthwaite J, Charles SL, Chess-Williams R (1988) Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intracellular messenger in the brain. Nature 336:385–388

    Google Scholar 

  • Gonzales C, Cruz MA, Gallardo V, Miguel P, Carrasco G (1997) Relative potency of nitro vasodilators on human placental vessels from normal and preeclamptic pregnancies. Gynecol Obstet Invest 43:219–224

    PubMed  Google Scholar 

  • Gonzales MC, Llorente E (1998) Methylene blue inhibits stimulatory effect of sodium nitroprusside but not of 3-morpholino sydnonimine on prolactin secretion in freely moving male rats. Brain Res Bull 46:229–231

    Article  PubMed  Google Scholar 

  • Grser T, Rubanyi GM (1992) Different mechanism of hypoxic relaxation in canine coronary arteries and rat abdominal aortas. J Cardiovasc Pharmacol 20:S117–119

    PubMed  Google Scholar 

  • Itzhak Y, Martin JL (2000) Blockade of alcohol-induced locomotor sensitization and conditioned place preference in DBA mice by 7-nitroindazole. Brain Res 858:402–407

    CAS  PubMed  Google Scholar 

  • Kalant H (1996) Current state of knowledge about the mechanisms of alcohol tolerance. Addiction Biol 1:133–141

    CAS  Google Scholar 

  • Khanna JM, Kalant H, Shah G, Chau A (1992) Effect of (+) MK-801 and ketamine on rapid tolerance to ethanol. Brain Res Bull 28:311–314

    Google Scholar 

  • Khanna JM, Shah G, Weiner J, Wu PH, Kalant H (1993a) Effect of NMDA antagonists on rapid tolerance to ethanol. Eur J Pharmacol 230:23–31

    CAS  PubMed  Google Scholar 

  • Khanna JM, Morato GS, Shah G, Chau A, Kalant H (1993b) Inhibition of nitric oxide synthesis impairs rapid tolerance to ethanol. Brain Res Bull 32:43–47

    Google Scholar 

  • Khanna JM, Morato GS, Chau A, Shah G (1995a) d-Cycloserine enhances rapid tolerance to ethanol motor incoordination. Pharmacol Biochem Behav 52:609–614

    CAS  PubMed  Google Scholar 

  • Khanna JM, Morato GS, Chau A, Shah G (1995b) Influence of nitric oxide synthase inhibition on the development of rapid tolerance to ethanol. Brain Res Bull 37:599–604

    Article  CAS  PubMed  Google Scholar 

  • Khanna JM, Shah G, Chau A (1997) Effect of NMDA antagonists on rapid tolerance to ethanol under two different testing paradigms. Pharmacol Biochem Behav 57:693–697

    CAS  PubMed  Google Scholar 

  • Kiss JP (2000) Role of nitric oxide in the regulation of monoaminergic neurotransmission. Brain Res Bull 52:459–466

    Article  CAS  PubMed  Google Scholar 

  • Kolesnikov YA, Pick CG, Pasternak GW (1992) NG-nitro-l-arginine prevents morphine tolerance. Eur J Pharmacol 221:399–400

    Article  CAS  PubMed  Google Scholar 

  • Lallemand F, De Witte P (1997) l-NNA decreases cortical vascularization, alcohol preference and withdrawal in alcoholic rats. Pharmacol Biochem Behav 58:753–761

    Article  CAS  PubMed  Google Scholar 

  • Lei SZ, Pan ZH, Aggarwal SK, Chen HS, Hartman J, Sucher NJ, Lipton SA (1992). Effect of nitric oxide production on the redox modulatory site of the NMDA receptor-channel complex. Neuron 8:1087–1099

    CAS  PubMed  Google Scholar 

  • Machado JD, Segura F, Brioso MA, Borges R (2000) Nitric oxide modulates a late step of exocytosis. J Biol Chem 275:20274–20279

    Article  CAS  PubMed  Google Scholar 

  • Manzoni O, Bockaert J (1993) Nitric oxide synthase activity endogenously modulates NMDA receptors. J Neurochem 61:368–370

    CAS  PubMed  Google Scholar 

  • Martins-Pinge MC, Araujo GC, Lopes OU (1999) Nitric oxide-dependent guanylyl cyclase participates in the glutamatergic neurotransmission within the rostral ventrolateral medulla of awake rats. Hypertension 34:748–751

    CAS  PubMed  Google Scholar 

  • Melis MR, Stancampiano R, Argiolas A (1995) Role of nitric oxide in penile erection and yawning induced by 5-HT1c receptor agonists in male rats. Naunyn Schmiedeberg's Arch Pharmacol 351:439–445

    Google Scholar 

  • Migaud M, Charlesworth P, Dempster M, Webster LC, Watabe AM, Makhinson M, He Y, Ramsay MF, Morris RGM, Morrison JH, O'Dell TJ, Grant SGN (1998) Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein. Nature 396:433–439

    Google Scholar 

  • Miyamoto Y, Noda Y, Komori Y, Sugihara H, Furukawa H, Nabeshima T (2000) Involvement of nitric oxide in phencyclidine-induced place aversion and preference in mice. Behav Brain Res 116:187–196

    Article  CAS  PubMed  Google Scholar 

  • Montague PR, Gancayco CD, Winn MJ, Marchase RB, Friedlander MJ (1994) Role of NO production in NMDA receptor-mediated neurotransmitter release in cerebral cortex. Science 263:973–977

    Google Scholar 

  • Morris R, Southam E, Gittins SR, De Vente J, Garthwaite J (1994) The NO-cGMP pathway in neonatal rat dorsal horn. Eur J Neurosci 6:876–879

    CAS  PubMed  Google Scholar 

  • Nakane M, Mitchell J, Forstermann U, Murad F (1991) Phosphorylation by calcium calmodulin-dependent protein kinase II and protein kinase C modulates the activity of nitric oxide synthase. Biochem Biophys Res Commun 180:1396–1402

    Google Scholar 

  • Palmer RM, Ferrige AG, Moncada S (1987) Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327:524–526

    CAS  PubMed  Google Scholar 

  • Prast H, Philippu A (2001) Nitric oxide as modulator of neuronal function. Prog Neur 64:51–68

    PubMed  Google Scholar 

  • Quintanilla ME, Tampier L (2000) Effect of naltrexone on acute tolerance to ethanol in UchB rats. Alcohol 21:245–249

    Article  CAS  PubMed  Google Scholar 

  • Rand MJ, Li CG (1995) Nitric oxide as a neurotransmitter in peripheral nerves: nature of transmitter and mechanism of transmission. Annu Rev Physiol 57:659–682

    Article  CAS  PubMed  Google Scholar 

  • Rezvani AH, Grady DR, Peek AE, Pucilowski O (1995) Inhibition of nitric oxide synthesis attenuates alcohol consumption in two strains of alcohol-preferring rats. Pharmacol Biochem Behav 50:265–270

    Article  CAS  PubMed  Google Scholar 

  • Shibuki K, Okada D (1991) Endogenous nitric oxide release required for long-term synaptic depression in the cerebellum. Nature 349:326–328

    Article  CAS  PubMed  Google Scholar 

  • Smolenski A, Burckhardt AM, Eigenthaler M, Butt E, Gambaryan S, Lohmann S, Walter U (1998) Functional analysis of cGMP-dependent protein kinases I and II as mediators of NO/cGMP effects. Naunyn-Schmiedeberg's Arch Pharmacol 358:134–139

    Google Scholar 

  • Southam E, Garthwaite J (1991) Comparative effects of some nitric oxide donors on cyclic GMP levels in rat cerebellar slices. Neurosci Lett 130:107–111

    CAS  PubMed  Google Scholar 

  • Southam E, Garthwaite J (1993) The nitric oxide-cyclic GMP signaling pathway in rat brain. Neuropharmacology 32:1267–1277

    Google Scholar 

  • Spanagel R, Siegmund S, Cowen M, Schroff K-C, Schumann G, Fiserova M, Sillaber I, Wellek S, Singer M, Putzke J (2002) The neuronal nitric oxide synthase gene is critically involved in neurobehavioral effects of alcohol. J Neurosci 22:8676–8683

    CAS  PubMed  Google Scholar 

  • Stoner MC, Kellum JM (2001) Both serotonin and nitric-oxide donor cause chloride secretion in rat colonocytes by stimulating cGMP. Surgery 130:236–241

    Article  CAS  PubMed  Google Scholar 

  • Uzbay IT, Oglesby MW (2001) Nitric oxide and substance dependence. Neurosci Biobehav Rev 25:43–52

    Article  PubMed  Google Scholar 

  • Uzbay IT, Erden BF, Tapanygit EE, Kayaalp SO (1997) Nitric oxide synthase inhibition attenuates signs of ethanol withdrawal in rats. Life Sci 61:2197–2209

    Article  CAS  PubMed  Google Scholar 

  • Uzbay IT, Usanmaz SE, Tapanygit EE, Aynacioglu S, Akarsu ES (1998) Dopaminergic and serotonergic alterations in the rat brain during ethanol withdrawal: association with behavioral signs. Drug Alcohol Depend 53:39–47

    Article  CAS  PubMed  Google Scholar 

  • Vassiljev V, Kalda A, Pokk P, Vali M, Zharkovsky A (1998) The effects of the nitric oxide synthase inhibitor 7-nitroindazole on ethanol pharmacokinetics in rats after acute and chronic ethanol administration. Alcohol Alcohol 33:609–615

    PubMed  Google Scholar 

  • Wang X, Robinson PJ (1997) Cyclic GMP-dependent protein kinase and cellular signaling in the nervous system. J Neurochem 68:443–456

    CAS  PubMed  Google Scholar 

  • Wazlawik E, Morato GS (2002) Effects of intracerebroventricular administration of 7-nitroindazole on tolerance to ethanol. Brain Res Bull 57:165–170

    Article  CAS  PubMed  Google Scholar 

  • Wu PH, Mihic SJ, Liu JF, Lê AD, Kalant H (1993) Blockade of chronic tolerance to ethanol by the NMDA antagonist, (+)-MK-801. Eur J Pharmacol 231:157–164

    Article  CAS  PubMed  Google Scholar 

  • Zhang XQ, Kwek K, Read MA, Donoghue JF, Walters WA (2001) Effects of nitro vasodilators on the human fetal-placental circulation in vitro. Placenta 22:337–346

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr. J. Assreuy for providing SNAP, Dr. J.B. Calixto for providing ODQ, Dr. C.F. Valenzuela and Dr. M. Carli for their helpful comments. The authors are in debt to Dr. G.A Rae for critical reading the final version of the manuscript. G.S. Morato is a researcher fellow of CNPq - Brazil (Proc 52 0654/96-0).

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  1. Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Rua Ferreira Lima 82, 88015-420, Florianopolis, SC, Brasil

    Elisabeth Wazlawik & Gina Struffaldi Morato

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  1. Elisabeth Wazlawik
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  2. Gina Struffaldi Morato
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Correspondence to Gina Struffaldi Morato.

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Wazlawik, E., Morato, G.S. Influence of drugs acting on nitric oxide-dependent pathways on ethanol tolerance in rats. Psychopharmacology 170, 343–350 (2003). https://doi.org/10.1007/s00213-003-1555-2

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