Advertisement

Psychopharmacology

, Volume 98, Issue 2, pp 176–182 | Cite as

Inhibition of brain dopa-decarboxylase by RO 4-4602 infused ICV blocks alcohol drinking induced in rats by cyanamide

  • F. J. Miñano
  • R. D. Myers
Original Investigations

Abstract

Following the stereotaxic implantation of chronic cannulae for intracerebroventricular (ICV) infusion, rats were given an alcohol preference test to establish their preferred concentration in comparison with water. After alcohol was removed, 15 mg/kg cyanamide was then injected subcutaneously for 4 days in order to maximize volitional intake of single solutions of alcohol, which in these animals ranged from 7 to 15%. The l-dopa-decarboxylase inhibitor benserazide (Ro 4-4602) injected subcutaneously twice daily in doses of 50–100 mg/kg failed to alter the rats' alcohol consumption either in terms of g/kg or proportional values. However, when given ICV twice daily in concentrations of 10 ng–2.0 μg per 5.0 μl volume, benserazide attenuated the rats' alcohol drinking significantly. This reduction occurred in a dose-dependent manner in terms of both absolute and proportional intakes of alcohol. Pre-treatment of the animals with 1.0 μg benserazide given ICV, when alcohol was removed from the test situation, did not abolish the subsequent ingestion of alcohol but its peripheral administration (50 mg/kg) enhanced drinking. These results suggest that the interference with the metabolic pathway of dopamine or serotonin synthesis, possibly through the mechanism of reduced formation of aldehyde adducts in the brain, markedly alters the pattern of voluntary drinking in the rat. Alternatively, benserazide could act by its central inhibition of aldehyde dehydrogenase, which in turn would concomitantly elevate levels of acetaldehyde and thereby reduce alcohol drinking.

Key words

Alcohol Drinking Ro 4-4602 Benserazide Brain l-dopa Cerebral ventricle Dopa-decarboxylase inhibition Ethanol CNS 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Balldin J, Alling C, Gottfries CG, Lindstedt G, Langstrom G (1985) Changes in dopamine receptor sensitivity in humans after heavy alcohol intake. Psychopharmacology 86:142–146Google Scholar
  2. Bartholini G, Pletscher A (1969) Effect of various decarboxylase inhibitors on the cerebral metabolism of dihydroxyphenylalanine. J Pharm Pharmacol 21:323–324Google Scholar
  3. Bartholini G, Pletscher A (1975) Decarboxylase inhibitors. Pharmacol Ther 1 (3):407–421Google Scholar
  4. Blum K, Eubanks JD, Wallace JE, Schwertner HA (1976) Suppression of ethanol withdrawal by dopamine. Experientia 32:493–495Google Scholar
  5. Cashaw JL, Geraghty CA, McLaughlin BR, Davis VE (1987) Effect of acute ethanol administration on brain levels of tetrahydropapaveroline in l-dopa-treated rats. J Neurosci Res 18:497–503Google Scholar
  6. Clow A, Stolerman IP, Murray RM, Sandler M (1983) Ethanol preference in rats: increased consumption after intraventricular administration of tetrahydropapaveroline. Neuropharmacology 2:563–565Google Scholar
  7. Collins MA, Kahn AJ (1982) Attraction to ethanol solutions in mice: induction by a tetrahydroisoquinoline derivative of l-dopa. Subst Alc Actions/Misuse 3 (5):299–302Google Scholar
  8. Collins MA, Custod JT, Rubenstein JA, Tabakoff B (1976) Studies on the effects of pyrogallol and the structurally related dopa decarboxylase inhibitor RO4-4602 on acetaldehyde metabolism. Ann NY Acad Sci 273:227–233Google Scholar
  9. Critcher EC, Hepler JR, Myers RD (1983) Induction of alcohol preference in the rat after aldehyde elevation in brain by ICV infusion of cyanamide. Alcohol: Clin Exp Res 7:246Google Scholar
  10. Critcher EC, Myers RD (1984) Evidence for the hippocampus as a site of action of tetrahydropapaveroline (THP)-or cyanamide-induced alcohol drinking. Alcohol 1:167Google Scholar
  11. Critcher EC, Myers RD (1987) Cyanamide given ICV or systemically to the rat alters subsequent alcohol drinking. Alcohol 4 (5):347–353Google Scholar
  12. Dar MS, Wooles WR (1984) The effect of acute ethanol on dopamine metabolism and other neurotransmitters in the hypothalamus and the corpus striatum of mice. J Neural Transm 60:283–294Google Scholar
  13. Deitrich RA, Troxell PA, Worth WS, Erwin VG (1976) Inhibition of aldehyde dehydrogenase in brain and liver by cyanamide. Biochem Pharmacol 25:2733–2737Google Scholar
  14. Eriksson T, Liljequist S, Carlsson A (1979) Ethanol-induced increase in the penetration of exogenously administered l-dopa through the blood-brain barrier. J Pharm Pharmacol 31:636–637Google Scholar
  15. Geller I, Hartmann RJ, and Messiha FS (1981) Blockade of 5-HTP reduction of ethanol drinking with the decarboxylase inhibitor, RO 4-4602. Pharmacol Biochem Behav 15(6) 871–874Google Scholar
  16. Huttunen P, Myers RD (1987) Anatomical localization in hippocampus of tetrahydro-B-carboline-induced alcohol drinking in the rat. Alcohol 4(3):181–187Google Scholar
  17. Imperato A, Di Chiara G (1986) Preferential stimulation of dopamine release in the nucleus accumbens of freely moving rats by ethanol. J Pharmacol Exp Ther 239:219–228Google Scholar
  18. Jurio AV (1983) The effect of some decarboxylase inhibitors on striatal tyramines in the mouse. Neuropharmacology 22:71–73Google Scholar
  19. Kiianmaa K, Andersson K, Fuxe K (1979) On the role of ascending dopamine systems in the control of voluntary ethanol intake and ethanol intoxication. Pharmacol Biochem Behav 10(4):603–608Google Scholar
  20. Kikta DC, Threatte RM, Barney CC, Fregly MJ, Greenleaf JE (1981) Peripheral conversion of l-5-hydroxytryptophan to serotonin induces drinking in rats. Pharmacol Biochem Behav 14:889–893Google Scholar
  21. Levy AD, Ellison G (1985) Amphetamine-induced enhancement of ethanol consumption: role of central catecholamines. Psychopharmacology 86:233–236Google Scholar
  22. Melchior CL, Myers RD (1976) Genetic differences in ethanol drinking of the rat following injection of 6-OHDA, 5,6-DHT or 5,7-DHT into the cerebral ventricles. Pharmacol Biochem Behav 5(1):63–72Google Scholar
  23. Messiha FS (1978) Voluntary drinking of ethanol by the rat: biogenic amines and possible underlying mechanism. Pharmacol Biochem Behav 9:379–384Google Scholar
  24. Miñano FJ, Myers RD (1988) Central and peripheral dopa decarboxylase inhibition: effects on alcohol drinking in the rat. Alcoholism Clin Exp Res 12 (12):304Google Scholar
  25. Myers RD (1971) General laboratory procedures. In: Myers RD (ed) Methods in psychobiology, vol 1. Academic Press, London, pp 27–65Google Scholar
  26. Myers RD (1971) Methods for chemical stimulation of the brain. In: Myers RD (ed) Methods in psychobiology, vol 1. Academic Press, London, pp 247–280Google Scholar
  27. Myers RD (1978) Psychopharmacology of alcohol. Ann Rev Pharmacol Toxicol 18:125–144Google Scholar
  28. Myers RD (1985a) Alkaloid metabolites and addicitive drinking of alcohol. In: Chang NC, Chao HM (eds) NIAAA Res Monogr 17. pp 268–284Google Scholar
  29. Myers RD (1985b) Multiple metabolite theory, alcohol drinking and the alcogene. In: Collins MA (ed) Aldehyde adducts in alcoholism. Liss, New York, pp 201–220Google Scholar
  30. Myers RD, Melchior CL (1977) Alcohol drinking: abnormal intake caused by tetrahydropapaveroline in brain. Science 196:554–556Google Scholar
  31. Myers RD, McCaleb ML, Ruwe WD (1982) Alcohol drinking induced in the monkey by tetrahydropapaveroline (THP) infused into the cerebral ventricle. Pharmacol Biochem Behav 16:995–1000Google Scholar
  32. Myers WD, Ng KT, Marzuki S, Myers RD, Singer G (1984) Alteration of alcohol drinking in the rat by peripherally self-administered acetaldehyde. Alcohol 1:229–236Google Scholar
  33. Petersen DR, Hjelle JJ (1982) Metabolic interactions of aldehyde dehydrogenase with therapeutic and toxic agents. Prog Clin Biol Res 114:103–120Google Scholar
  34. Pfeffer AO, Samson HH (1985) Oral ethanol reinforcement in the rat: effects of acute amphetamine. Alcohol 2:693–697Google Scholar
  35. Pfeffer AO, Samson HH (1988) Haloperidol and apomorphine effects on ethanol reinforcement in free feeding rat. Pharmacol Biochem Behav 29:343–350Google Scholar
  36. Reggiania A, Barbaccia ML, Spano PF, Trabucchi M (1980) Dopamine metabolism and receptor function after acute and chronic ethanol. J Neurochem 35:34–37Google Scholar
  37. Rommelspacher H, Buchau C, Weiss J (1987) Harman induces preference for ethanol in rats: is the effect specific for ethanol? Pharmacol Biochem Behav 26 (4):749–755Google Scholar
  38. Signs AS, Schechter MD (1988) The role of dopamine and serotonin receptors in the mediation of the ethanol interoceptive cue. Pharmacol Biochem Behav 30:55–64Google Scholar
  39. Sinclair JD, Gribble PA (1985) Cyanamide injections during alcohol deprivation increase alcohol drinking. Alcohol 2:627–630Google Scholar
  40. Sinclair JD, Lindros KO (1981) Suppression of alcohol drinking with brain aldehyde dehydrogenase inhibition. Pharmacol Biochem Behav 14:377–383Google Scholar
  41. Spivak KJ, Amit Z (1987) The role of acetaldehyde-metabolizing enzymes in the mediation of ethanol consumption: an investigation using a simulated drinking bout. Alcohol Alcohol 1:361–365Google Scholar
  42. Stein L (1980) The chemistry of reward. In: Routtenberg A (ed) Biology of reinforecment: facets of brain stimulation reward. Academic Press. New York, pp 109–130Google Scholar
  43. Threatte RM, Fregly MJ, Connor TM, Kikta DC (1981) l-5-Hydroxytryptophan-induced drinking in rats: possible mechanisms for induction. Pharmacol Biochem Behav 14 (3) 385–391Google Scholar
  44. Weiner H, Simpson CW, Thurman JA, Myers RD (1978) Disulfiram alters dopamine metabolism at sites in rat's forebrain as detected by push-pull perfusions. Brain Res Bull 3 (5) 541–548Google Scholar

Copyright information

© Springer-Verlag 1989

Authors and Affiliations

  • F. J. Miñano
    • 1
  • R. D. Myers
    • 1
  1. 1.Departments of Pharmacology and Psychiatric MedicineEast Carolina University School of MedicineGreenvilleUSA

Personalised recommendations