, Volume 104, Issue 3, pp 367–376 | Cite as

Effect of naltrexone on alcohol consumption during chronic alcohol drinking and after a period of imposed abstinence in free-choice drinking rhesus monkeys

  • M. Kornet
  • C. Goosen
  • J. M. Van Ree
Original Investigations


Relapse into problematic alcohol drinking is a serious problem in the treatment of alcoholism. Free-choice drinking rhesus monkeys show relapse-like behaviour after imposed abstinence of alcohol, by immediately reinitiating ethanol intake at an increased level. The relapse-like behaviour of the monkeys seems not induced by physical withdrawal, but rather argues for a resistance to extinction of ethanol-reinforced behaviour. It has been suggested that endogenous opioids play a role in the positive reinforcing effect of ethanol. In this study, the effect of the opiate antagonist naltrexone was investigated in eight adult male rhesus monkeys(Macaca mulatta) who had about 1 year experience with alcohol drinking, under two conditions: 1) (expt 1) during continuous and concurrent supply of drinking water and two ethanol/water solutions (16% and 32% (v/v)), and 2) (expt 2) after 2 days of alcohol abstinence. In both experiments, each monkey received six doses of naltrexone (0.02, 0.06, 0.17, 0.5, 1.0, 1.5 mg · kg−1); each dose was paired with a placebo injection (im) in a cross-over design. Consumption was measured from 16.00 hours in the afternoon (30 min after injection) to 9.00 hours the next morning. In experiment 1 naltrexone reduced total net ethanol intake in a graded dose-dependent manner. The effect of naltrexone was apparent shortly after injection, and lasted until the following day. Consumption of drinking water was reduced only shortly after injection. In expt 2, reduction of net ethanol intake was largely restricted to the first few hours of reinitiation of alcohol drinking, i.e. the period in which the abstinence-induced increase was manifest. Consumption of drinking water was not affected by naltrexone. Naltrexone hardly influenced consumption of the non-preferred ethanol solution of 32%. It is postulated that the opioid modulation specifically interacted with positively reinforced behaviour. In expt 2 naltrexone reduced ethanol intake at a lower dose (0.17 mg · kg−1) compared to expt 1 (0.50 mg · kg−1), but net ethanol intakes however remained higher. It might be that alcohol abstinence resulted in altered opioid activity, leading to increased ethanol-seeking behaviour. The renewed presentation of ethanol solutions (also) might have stimulated reinitiation of alcohol drinking, representing conditioned incentive stimuli. The reported monkey model of relapse in alcohol drinking could be a useful tool to evaluate new hypotheses and experimental treatments with respect to human alcoholism.

Key words

Free-choice alcohol drinking Rhesus monkeys Alcohol abstinence Relapse Naltrexone 


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  1. Altshuler HL, Phillips PE, Feinhandler DA (1980) Alteration of ethanol self-administration by naltrexone. Life Sci 26:679–688Google Scholar
  2. Barnes DM (1988) Breaking the cycle of addiction. Science 241:1029–1030Google Scholar
  3. Barret L, Bourhis F, Buffet H, Danel V, Debru JL (1987) Determination ofβ-endorphin in alcoholic patients in the acute stage of intoxication: relation with naloxone therapy. Drug Alcohol Depend 19:71–78Google Scholar
  4. Burish TG, Maisto SA, Cooper AM, Sobell MB (1981) Effects of voluntary short-term abstinence from alcohol on subsequent drinking patterns of college students. J Stud Alcohol 42[11]:1013–1020Google Scholar
  5. Cloninger RC (1987) Neurogenetic adaptive mechanisms in alcoholism. Science 236:410–416Google Scholar
  6. Cornell CE, Rodin J, Weingarten H (1989) Stimulus-induced eating when satiated. Physiol Behav 45:695–704Google Scholar
  7. Czirr SA, Hubbell CL, Milano WC, Frank JM, Reid LD (1987) Selected opioids modify intake of sweetened ethanol solution among female rats. Alcohol 4:157–160Google Scholar
  8. De Witte P (1984) Naloxone reduces alcohol intake in a free-choice procedure even when both drinking bottles contain saccharin sodium or quinine substance. Neuropsychobiology 12:73–77Google Scholar
  9. Ellis FW, Pick HR (1972) Ethanol dependence in rhesus monkeys. Proceedings 3rd Conf. Exp Med Surg Primates, Lyon Part III Medical Primatology, pp 237–240Google Scholar
  10. Frenk H, Rogers GH (1979) The suppressant effects of naloxone on food and water intake in the rat. Behav Neural Biol 26:23–40Google Scholar
  11. Friedman HJ (1980) Assessment of physical dependence on and withdrawal from ethanol in animals. In: Rigter H, Crabbe JC (eds) Alcohol tolerance and dependence. Elsevier, Amsterdam, pp 93–122Google Scholar
  12. Friedman P (1988) GB-Stat. Dynamic Microsystems Inc, Silver Spring USAGoogle Scholar
  13. Genazzani AR, Nappi G, Facchinetti F, Mazzalla GL, Parrini D, Sinforiani E, Petraglia F, Savoldi F (1982) Central deficiency ofβ-endorphin in alcohol addicts. J Clin Endocrinol Metab 55[3]:583–586Google Scholar
  14. Gianoulakis C, Beliveau D, Angelogianni P, Meaney M, Thavundayil J, Tawar V, Dumas M (1989) Different pituitaryβ-endorphin and adrenal cortisol response to ethanol in individuals with high and low risk for future development of alcoholism. Life Sci 45:1097–1109Google Scholar
  15. Griffiths RR, Bigelow GE (1978) Commonalities in human and infrahuman drug selfadministration. In: Fishman J (ed) The bases of addiction. Dahlem Konferenzen, Berlin, pp 157–174Google Scholar
  16. Hand TH, Stinus L, Le Moal M (1989) Differential mechanisms in the acquisition and expression of heroin-induced place preference. Psychopharmacology 98:61–67Google Scholar
  17. Horwitz RI, Horwitz SM, Viscoli CM, Gottlieb LD, Kraus ML (1987) Craving and the social context: a new interaction model for enhancing recovery from alcoholism. J Chron Dis 40[12]:1135–1140Google Scholar
  18. Hubbell CL, Czirr SA, Hunter GA, Beaman CM, LeCann NC, Reid LD (1986) Consumption of ethanol solution is potentiated by morphine and attenuated by naloxone persistently across repeated daily administrations. Alcohol 3:39–54Google Scholar
  19. Hubbell CL, Czirr SA, Reid LD (1987) Persistence and specificity of small doses of morphine on intake of alcoholic beverages. Alcohol 4:149–156Google Scholar
  20. Jellinek EM (1955) The “craving” for alcohol. Qu J Stud Alcohol 16:35–38Google Scholar
  21. Kalant H (rapporteur), Engel JA, Goldberg L, Griffiths RR, Jaffe JH, Krasnegor NA, Mello NK, Mendelson JH, Thompson T, Van Ree JM (1978) Behavioral aspects of addiction. Group Report. In: Fishman J (ed) The bases of addiction. Dahlem Konferenzen, Berlin, pp 463–496Google Scholar
  22. Kirk RE (1968) Experimental design: procedures for the behavioral sciences. Brooks, Belmont, CaliforniaGoogle Scholar
  23. Koob GF, Weiss F (1990) Pharmacology of drug self-administration. Alcohol 7:193–197Google Scholar
  24. Kornet M, Goosen C, Van Ree JM (1990a) The effect of interrupted alcohol supply on spontaneous alcohol consumption by rhesus monkeys. Alcohol Alcohol 4:407–412Google Scholar
  25. Kornet M, Goosen C, Ribbens LG, Van Ree JM (1990b) Analysis of spontaneous alcohol drinking behaviour in rhesus monkeys. Physiol Behav 47:679–684Google Scholar
  26. Lewis JM, June HL (1990) Neurobehavioral studies of ethanol reward and activation. Alcohol 7:213–219Google Scholar
  27. Linseman MA (1989) Central vs. peripheral mediation of opioid effects on alcohol consumption in free-feeding rats. Pharmacol Biochem Behav 33:407–413Google Scholar
  28. Marlatt GA, George WH (1984) Relapse prevention: introduction and overview of the model. Br J Addict 79:261–273Google Scholar
  29. Mello NK, Mendelson JH (1980) Behavioral pharmacology of substance abuse: recent advances. Psychopharmacol Bull 16[1]:45–47Google Scholar
  30. Mendelson JH, Mello NK (1979) Biological concomitants of alcoholism. N Engl J Med 301:912–921Google Scholar
  31. Myers RD, Privette TH (1989) A neuroanatomical substrate for alcohol drinking: identification of tetrahydropapaveroline (THP)-reactive sited in the rat brain. Brain Res Bull 22:899–911Google Scholar
  32. Myers RD, Stoltman WP, Martin GE (1972) Effects of ethanol dependence induced artificially in the rhesus monkeys on the subsequent preference for ethyl alcohol. Physiol Behav 9:43–48Google Scholar
  33. Patel VA, Pohorecky LA (1989) Acute and chronic ethanol treatment onβ-endorphin and catecholamine levels. Alcohol 6:59–63Google Scholar
  34. Prunell M, Boada J, Feria M, Benitez MA (1987) Antagonism of the stimulant and depressant effects of ethanol in rats by naloxone. Psychopharmacology 92:215–218Google Scholar
  35. Reid LD, Czirr SA, Bensinger CC, Hubbell CL, Volanth AJ (1987) Morphine and diprenorphine together potentiate intake of alcoholic beverages. Alcohol 4:161–168Google Scholar
  36. Samson HH, Doyle TF (1985) Oral ethanol self-administration in the rat: effect of naloxone. Pharmacol Biochem Behav 22:91–99Google Scholar
  37. Samson HH, Tolliver GA, Schwarz-Stevens K (1990) Oral ethanol self-administration: a behavioral pharmacological approach to CNS control mechanisms. Alcohol 7:187–191Google Scholar
  38. Sandi C, Borrell J, Guaza C (1988) Naloxone decreases ethanol consumption within a free-choice paradigm in rats. Pharmacol Biochem Behav 29:39–43Google Scholar
  39. Sandi C, Borrell J, Guaza C (1989)β-endorphin administration interferes with the acquisition and initial maintenance of ethanol preference in the rat. Physiol Behav 45:87–92Google Scholar
  40. Siegel S (1956) In: Harlow HF (ed) Nonparametric statistics for the behavioural sciences. McGraw-Hill Kogakusha Ltd, TokyoGoogle Scholar
  41. Sinclair JD (1971) The alcohol-deprivation effect in monkeys. Psychon Sci 25[1]:21–22Google Scholar
  42. Sinclair JD, Adkins J, Walker S (1973) Morphine-induced suppression of voluntary alcohol drinking in rats. Nature 246:425–427Google Scholar
  43. Stein I, Belluzi JD (1987) Reward transmitters and drugs of abuse. In: Engel J, Oreland L, Ingvar DH, Pernow B, Rössner S, Pellborn LA (eds) Brain reward systems and abuse. Raven Press, New York, pp 19–34Google Scholar
  44. Stewart J, Vezina P (1988) A comparison of the effects of intra-accumbens injections of amphetamine and morphine on reinstatement of heroin intravenous self-administration behavior. Brain Res 457:287–294Google Scholar
  45. Stewart J, de Wit H, Eikelboom R (1984) Role of unconditioned and conditioned drug effects in the self-administration of opiates and stimulants. Psychol Rev 91:252–268Google Scholar
  46. Sweep CGJ, Van Ree JM, Wiegant VM (1988) Characterization ofβ-endorphin-immunoreactivity in limbic brain structures of rats self-administering heroin or cocaine. Neuropeptides 12:229–236Google Scholar
  47. Sweep CGJ, Wiegant VM, De Vry J, Van Ree JM (1989)β-Endorphin in brain limbic structures as neurochemical correlate of psychic dependence on drugs. Life Sci 44:1133–1140Google Scholar
  48. Tabakoff B, Hoffman PL (1987) Interactions of ethanol with opiate receptors: implications for the mechanisms of action of ethanol. In: Engel J, Oreland L, Ingvar DH, Pernow B, Rössner S, Pellborn LA (eds) Brain reward systems and abuse. Raven Press, New York, pp 99–107Google Scholar
  49. Topel H (1985) Biochemical basis of alcoholism: statements and hypotheses of present research. Alcohol 2:711–788Google Scholar
  50. Van Ree JM (1987) Reward and abuse: opiates and neuropeptides. In: Engel J, Oreland L, Ingvar DH, Pernow B, Rössner S, Pellborn LA (eds) Brain reward systems and abuse. Raven Press, New York pp 75–78Google Scholar
  51. Volpicelli JR, Davis MA, Olgin Je (1986) Naltrexone blocks the post-shock increase of ethanol consumption. Life Sci 38:841–847Google Scholar
  52. Volpicelli JR, O'Brien CP, Alterman AI, Hayashida M (1990) Naltrexone and the treatment of alcohol dependence: initial observations. In: Reid LD (ed) Opioids, bulimia and alcohol abuse and alcoholism. Springer, Berlin Heidelberg New York, pp 195–214Google Scholar
  53. White NM (1989) Reward or reinforcement: what's the difference? Neurosci Biobehav Rev 13:181–186Google Scholar
  54. Winger G (1988) Effects of ethanol withdrawal on ethanol-reinforced reponding in rhesus monkeys. Drug Alcohol Depend 22:235–240Google Scholar
  55. Wise RA, Bozarth MA (1987) A psychomotor stimulant theory of addiction. Psychol Rev 94[4]:469–492Google Scholar
  56. Woods JH et al. (1971) The reinforcing property of ethanol. In: Roach MK et al. (eds), Biological aspects of alcohol. University of Texas Press, Austin, p 371Google Scholar

Copyright information

© Springer-Verlag 1991

Authors and Affiliations

  • M. Kornet
    • 1
  • C. Goosen
    • 1
  • J. M. Van Ree
    • 2
  1. 1.Department of EthologyInstitute for Radiology and Immunology (ITRI) TNO, Primate CenterRijswijkThe Netherlands
  2. 2.Department of Pharmacology, Rudolf Magnus InstituteUniversity of UtrechtUtrechtThe Netherlands

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