Skip to main content
Log in

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

  • Original Investigations
  • Published:
Psychopharmacology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Adachi H, Shoji T (1986) Characteristics of the inhibition of ligand binding to serotonin receptors in rat brain membranes by verapamil. Jpn J Pharmacol 41:431–435

    PubMed  Google Scholar 

  • 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 123:161–165

    Article  PubMed  Google Scholar 

  • Daniell LC, Leslie SW (1986) Inhibition of fast phase calcium uptake and endogenous norepinephrine release in rat brain region synaptosomes by ethanol. Brain Res 377:18–28

    Article  PubMed  Google Scholar 

  • DiChiara G, Imperato A (1985) Ethanol preferentially stimulates dopamine release in the nucleus accumbens of freely moving rats. Eur J Pharmacol 115:131–132

    Article  PubMed  Google Scholar 

  • Didly JE, Leslie SW (1989) Ethanol inhibits NMDA-induced increases in free intracellular Ca2+ dissociated brain cells. Brain Res 499:383–387

    Article  PubMed  Google Scholar 

  • Dolin SJ, Little HJ (1989) Are changes in neuronal calcium channels involved in ethanol tolerance? J Pharmacol Exp Ther 250:985–991

    PubMed  Google Scholar 

  • Dolin SJ, Little HJ, Hudspith M, Pagonis C, Littleton JM (1987) Increased dihydropyridine calcium channels in rats brain may underlie ethanol physical dependence. Neuropharmacology 26:270–275

    Article  Google Scholar 

  • Dooley DJ, Mahlmann H, Brenner O, Osswald H (1987) Characterization of the dihyropyridine binding sites of rat neocortical synaptosomes and microvessels. J Neurochem 49:900–904

    PubMed  Google Scholar 

  • 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 74:181–193

    Article  PubMed  Google Scholar 

  • 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 75:195–200

    Article  PubMed  Google Scholar 

  • Fadda F, Mosca E, Colombo G, Gessa GL (1990) Alcohol preferring rats: genetic sensitivity to alcohol-induced stimulation of dopamine metabolism. Physiol Behav 47:727–729

    Google Scholar 

  • 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 15:314

    Google Scholar 

  • Gaggi R, Gianni AM (1990) Effects of calcium antagonists on biogenic amines in discrete brain areas. Eur J Pharmacol 181:187–197

    Article  PubMed  Google Scholar 

  • Gill K, Amit Z (1987) Effects of serotonin uptake blockade on food, water, and ethanol consumption. Alcohol Clin Exp Res 11:444–449

    PubMed  Google Scholar 

  • 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 52:1937–1940

    PubMed  Google Scholar 

  • Hofmann HP, Raschack M, Unger L (1989) (S)-Emopamil, a novel calcium and serotonin antagonist for the treatment of cerebrovascular disorders. Drug Res 39:304–308

    Google Scholar 

  • Hunt T, Amit Z (1987) Conditioned taste aversion induced by self-administered drugs: paradox revisited. Neurosci Biobehav Rev 11:107–130

    PubMed  Google Scholar 

  • 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 225:571–575

    PubMed  Google Scholar 

  • 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 171–191

  • Little HJ, Dolin SJ, Halsey MJ (1986) Calcium channel antagonists decrease the ethanol withdrawal syndrome. Life Sci 39:2059–2065

    Article  PubMed  Google Scholar 

  • McBride WJ, Murphy JM, Lumeng L, Li T-K (1989) Serotonin and ethanol preference. Recent Dev Alcohol 7:187–209

    PubMed  Google Scholar 

  • 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 133–198

    Google Scholar 

  • 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 10:97–103

    PubMed  Google Scholar 

  • 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]:R28

  • 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 6:165–168

    Article  PubMed  Google Scholar 

  • 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 6:341–345

    Google Scholar 

  • Rezvani AH, Janowsky DS (1990) Decreased alcohol consumption by verapamil in alcohol preferring rats. Prog Neuropsychopharmacol Biol Psychiat 14:623–631

    Article  Google Scholar 

  • Rezvani AH, Grady DR, Janowsky DS (1991a) Effect of calciumchannel blockers on alcohol consumption in alcohol-drinking monkeys. Alcohol Alcohol 26:161–167

    PubMed  Google Scholar 

  • 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)

  • Rezvani AH, Pucilowski O, Janowsky DS (1991c) Effects of different Ca++ channel antagonists on alcohol preference in alcohol preferring rats. Alcohol Clin Exp Res 15:314

    Google Scholar 

  • Ross DH (1977) Adaptive changes in Ca2+ membrane interactions following chronic ethanol exposure. Adv Exp Med Biol 85A:459–472

    PubMed  Google Scholar 

  • Tallarida RJ, Murray RB (1987) Manual of pharmacologic calculations with computer programs. Springer-Verlag, New York

    Google Scholar 

  • 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 225:78–80

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pucilowski, O., Rezvani, A.H. & Janowsky, D.S. Suppression of alcohol and saccharin preference in rats by a novel Ca2+ channel inhibitor, Goe 5438. Psychopharmacology 107, 447–452 (1992). https://doi.org/10.1007/BF02245174

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02245174

Key words

Navigation