Psychopharmacology

, Volume 107, Issue 2–3, pp 447–452 | Cite as

Suppression of alcohol and saccharin preference in rats by a novel Ca2+ channel inhibitor, Goe 5438

  • Olgierd Pucilowski
  • Amir H. Rezvani
  • David S. Janowsky
Original Investigations

Abstract

The effect of the novel 1,4-dihydronaphthyridine Ca2+ channel inhibitor Goe 5438 (CI-951) on voluntary ethanol consumption was examined in selectively bred alcohol-preferring (P) rats in a free choice two bottle preference test versus water. Intraperitoneally injected Goe 5438 dose-dependently (5, 10 or 20 µmol/kg, twice daily) inhibited ethanol and increased water intake over the 24 h period (injection day). The drug decreased ethanol preference, originally above 90%, by 6%, 19% and 45% at respective doses, on the injection day. That inhibitory effect of the highest dose of Goe 5438 on ethanol preference remained significant also on days 2 and 3 after injections (−51% and −18%, respectively). Goe 5438, in the highest dose, also tended to decrease granulated chow consumption during the injection day only. To further test whether the inhibition of ethanol preference is secondary to decrease in reinforcing properties of ethanol and not due to interference with satiety mechanisms, we compared the effect of two higher doses (10 and 20 µmol/kg, intraperitoneally, twice daily) of Goe 5438 on spontaneous preference for a non-caloric 0.04% saccharin solution in Sprague-Dawley rats. We observed a dose-dependent suppression of preference (by 44% and 58%, respectively) during the injection day, but not the subsequent 24 h period. However, Goe 5438 also significantly alleviated food pellet intake on the injection day. In conclusion, Goe 5438 produces potent and long-lasting inhibition of voluntary ethanol consumption, which may be secondary to attenuation of reinforcing properties of ethanol. Additionally, this particular Ca2+ channel inhibitor appears to have mild anorectic properties which may be conducive to acute suppression of alcohol intake.

Key words

Goe 5438 Ethanol Preference Ca2+ channel inhibitors Saccharin consumption Food intake Drinking behavior 

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References

  1. Adachi H, Shoji T (1986) Characteristics of the inhibition of ligand binding to serotonin receptors in rat brain membranes by verapamil. Jpn J Pharmacol 41:431–435PubMedGoogle Scholar
  2. Brown NL, Sirugue O, Worcel M (1986) The effects of some slow channel blocking drugs on high affinity serotonin uptake by rat brain synaptosomes. Eur J Pharmacol 123:161–165CrossRefPubMedGoogle Scholar
  3. Daniell LC, Leslie SW (1986) Inhibition of fast phase calcium uptake and endogenous norepinephrine release in rat brain region synaptosomes by ethanol. Brain Res 377:18–28CrossRefPubMedGoogle Scholar
  4. DiChiara G, Imperato A (1985) Ethanol preferentially stimulates dopamine release in the nucleus accumbens of freely moving rats. Eur J Pharmacol 115:131–132CrossRefPubMedGoogle Scholar
  5. Didly JE, Leslie SW (1989) Ethanol inhibits NMDA-induced increases in free intracellular Ca2+ dissociated brain cells. Brain Res 499:383–387CrossRefPubMedGoogle Scholar
  6. Dolin SJ, Little HJ (1989) Are changes in neuronal calcium channels involved in ethanol tolerance? J Pharmacol Exp Ther 250:985–991PubMedGoogle Scholar
  7. Dolin SJ, Little HJ, Hudspith M, Pagonis C, Littleton JM (1987) Increased dihydropyridine calcium channels in rats brain may underlie ethanol physical dependence. Neuropharmacology 26:270–275CrossRefGoogle Scholar
  8. Dooley DJ, Mahlmann H, Brenner O, Osswald H (1987) Characterization of the dihyropyridine binding sites of rat neocortical synaptosomes and microvessels. J Neurochem 49:900–904PubMedGoogle Scholar
  9. Engel JA, Fahlke C, Hulthe P, Hard E, Johannessen K, Snape B, Svensson L (1988) Biochemical and behavioral evidence for an interaction between ethanol and calcium channel antagonists. J Neural Transm 74:181–193CrossRefPubMedGoogle Scholar
  10. Fadda F, Gessa GL, Mosca E, Stefanini E (1989) Different effects of the calcium antagonist nimodipine and flunarizine on dopamine metabolism in the rat brain. J Neural Transm 75:195–200CrossRefPubMedGoogle Scholar
  11. Fadda F, Mosca E, Colombo G, Gessa GL (1990) Alcohol preferring rats: genetic sensitivity to alcohol-induced stimulation of dopamine metabolism. Physiol Behav 47:727–729Google Scholar
  12. Fadda F, Colombo G, Marchei MF, Gessa GL (1991) Inhibition of ethanol intake by a calcium-channel blocker, isradipine, in ethanol-preferring rats. Alcohol Clin Exp Res 15:314Google Scholar
  13. Gaggi R, Gianni AM (1990) Effects of calcium antagonists on biogenic amines in discrete brain areas. Eur J Pharmacol 181:187–197CrossRefPubMedGoogle Scholar
  14. Gill K, Amit Z (1987) Effects of serotonin uptake blockade on food, water, and ethanol consumption. Alcohol Clin Exp Res 11:444–449PubMedGoogle Scholar
  15. Hoffman PL, Rabe CS, Moses F, Tabakoff B (1989) N-methyl-D-aspartate receptors and ethanol: inhibition of calcium flux and cyclic GMP production. J Neurochem 52:1937–1940PubMedGoogle Scholar
  16. Hofmann HP, Raschack M, Unger L (1989) (S)-Emopamil, a novel calcium and serotonin antagonist for the treatment of cerebrovascular disorders. Drug Res 39:304–308Google Scholar
  17. Hunt T, Amit Z (1987) Conditioned taste aversion induced by self-administered drugs: paradox revisited. Neurosci Biobehav Rev 11:107–130PubMedGoogle Scholar
  18. Leslie SW, Barr E, Chandler W, Farrar RP (1983) Inhibition of fast- and slow-phase depolarization-dependent synaptosomal calcium uptake by ethanol. J Pharmacol Exp Ther 225:571–575PubMedGoogle Scholar
  19. Li T-K, Lumeng L, McBride WJ, Waller WB (1981) Indiana selection studies on alcohol-related behaviors. In: McClearn GE, Deitrich RA, Irvin VG (eds) Development of animal models as pharmacogenetic tools. NIAAA Research Monograph-6. Rockville, pp 171–191Google Scholar
  20. Little HJ, Dolin SJ, Halsey MJ (1986) Calcium channel antagonists decrease the ethanol withdrawal syndrome. Life Sci 39:2059–2065CrossRefPubMedGoogle Scholar
  21. McBride WJ, Murphy JM, Lumeng L, Li T-K (1989) Serotonin and ethanol preference. Recent Dev Alcohol 7:187–209PubMedGoogle Scholar
  22. Mello NK (1983) A behavioral analysis of the reinforcing properties of alcohol and other drugs in man. In: Kissin B, Begleiter H (eds) The pathogenesis of alcoholism, biological factors, vol 7. Plenum Press, New York, pp 133–198Google Scholar
  23. Meyer FB, Anderson RE, Sundt TM Jr (1990) The novel dihydronaphthyridine Ca2+ channel blocker CI-951 improves CBF, brain pHi, and EEG recovery in focal cerebral ischemia. J Cereb Blood Flow Metab 10:97–103PubMedGoogle Scholar
  24. Osswald H, Weinheimer G, Dooley DJ, Preuner J, Kleinschroth J, Mannhardt K, Hartenstein J, Satzinger G (1986) Smooth muscle relaxing and membrane binding characteristic of a new naphthyridine derivative Goe 5438 (CI-951). Naunyn-Schmiedeberg's Arch Pharmacol 334 [suppl]:R28Google Scholar
  25. Pucilowski O, Krzascik P, Trzaskowska E, Kostowski W (1989) Different effect of diltiazem and nifedipine on some central actions of ethanol in the rat. Alcohol 6:165–168CrossRefPubMedGoogle Scholar
  26. Rezazadeh SM, Woodward JJ, Leslie SW (1980) Fura-2 measurement of cytostolic free calcium in rat brain cortical synaptosomes and the influence of ethanol. Alcohol 6:341–345Google Scholar
  27. Rezvani AH, Janowsky DS (1990) Decreased alcohol consumption by verapamil in alcohol preferring rats. Prog Neuropsychopharmacol Biol Psychiat 14:623–631CrossRefGoogle Scholar
  28. Rezvani AH, Grady DR, Janowsky DS (1991a) Effect of calciumchannel blockers on alcohol consumption in alcohol-drinking monkeys. Alcohol Alcohol 26:161–167PubMedGoogle Scholar
  29. Rezvani AH, Pucilowski O, O'Brien R, Janowsky DS (1991b) Attenuation of alcohol preference by (S)-emopamil, a novel Ca++, antagonist in the rat. NCARA 15th Annual Symposium on Alcoholism: The Search for the Sources. Raleigh, NC (abstract)Google Scholar
  30. Rezvani AH, Pucilowski O, Janowsky DS (1991c) Effects of different Ca++ channel antagonists on alcohol preference in alcohol preferring rats. Alcohol Clin Exp Res 15:314Google Scholar
  31. Ross DH (1977) Adaptive changes in Ca2+ membrane interactions following chronic ethanol exposure. Adv Exp Med Biol 85A:459–472PubMedGoogle Scholar
  32. Tallarida RJ, Murray RB (1987) Manual of pharmacologic calculations with computer programs. Springer-Verlag, New YorkGoogle Scholar
  33. Waller MB, McBride WJ, Gatto GJ, Li T-K (1984) Intragastric self-administration of ethanol by ethanol-preferring and -non-preferring lines of rats. Science 225:78–80Google Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • Olgierd Pucilowski
    • 1
  • Amir H. Rezvani
    • 1
  • David S. Janowsky
    • 1
  1. 1.Skipper Bowles Center for Alcohol Studies and Department of PsychiatryUniversity of North Carolina at Chapel Hill, School of MedicineChapel HillUSA

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