Skip to main content
Log in

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

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

Abstract

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.

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

  • Altshuler HL, Phillips PE, Feinhandler DA (1980) Alteration of ethanol self-administration by naltrexone. Life Sci 26:679–688

    Google Scholar 

  • Barnes DM (1988) Breaking the cycle of addiction. Science 241:1029–1030

    Google Scholar 

  • 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 19:71–78

    Google Scholar 

  • 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]:1013–1020

    Google Scholar 

  • Cloninger RC (1987) Neurogenetic adaptive mechanisms in alcoholism. Science 236:410–416

    Google Scholar 

  • Cornell CE, Rodin J, Weingarten H (1989) Stimulus-induced eating when satiated. Physiol Behav 45:695–704

    Google Scholar 

  • Czirr SA, Hubbell CL, Milano WC, Frank JM, Reid LD (1987) Selected opioids modify intake of sweetened ethanol solution among female rats. Alcohol 4:157–160

    Google Scholar 

  • 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 12:73–77

    Google Scholar 

  • Ellis FW, Pick HR (1972) Ethanol dependence in rhesus monkeys. Proceedings 3rd Conf. Exp Med Surg Primates, Lyon Part III Medical Primatology, pp 237–240

  • Frenk H, Rogers GH (1979) The suppressant effects of naloxone on food and water intake in the rat. Behav Neural Biol 26:23–40

    Google Scholar 

  • 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 93–122

    Google Scholar 

  • Friedman P (1988) GB-Stat. Dynamic Microsystems Inc, Silver Spring USA

    Google Scholar 

  • 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]:583–586

    Google Scholar 

  • 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 45:1097–1109

    Google Scholar 

  • Griffiths RR, Bigelow GE (1978) Commonalities in human and infrahuman drug selfadministration. In: Fishman J (ed) The bases of addiction. Dahlem Konferenzen, Berlin, pp 157–174

    Google Scholar 

  • Hand TH, Stinus L, Le Moal M (1989) Differential mechanisms in the acquisition and expression of heroin-induced place preference. Psychopharmacology 98:61–67

    Google Scholar 

  • 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]:1135–1140

    Google Scholar 

  • 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 3:39–54

    Google Scholar 

  • Hubbell CL, Czirr SA, Reid LD (1987) Persistence and specificity of small doses of morphine on intake of alcoholic beverages. Alcohol 4:149–156

    Google Scholar 

  • Jellinek EM (1955) The “craving” for alcohol. Qu J Stud Alcohol 16:35–38

    Google Scholar 

  • 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 463–496

    Google Scholar 

  • Kirk RE (1968) Experimental design: procedures for the behavioral sciences. Brooks, Belmont, California

    Google Scholar 

  • Koob GF, Weiss F (1990) Pharmacology of drug self-administration. Alcohol 7:193–197

    Google Scholar 

  • Kornet M, Goosen C, Van Ree JM (1990a) The effect of interrupted alcohol supply on spontaneous alcohol consumption by rhesus monkeys. Alcohol Alcohol 4:407–412

    Google Scholar 

  • Kornet M, Goosen C, Ribbens LG, Van Ree JM (1990b) Analysis of spontaneous alcohol drinking behaviour in rhesus monkeys. Physiol Behav 47:679–684

    Google Scholar 

  • Lewis JM, June HL (1990) Neurobehavioral studies of ethanol reward and activation. Alcohol 7:213–219

    Google Scholar 

  • Linseman MA (1989) Central vs. peripheral mediation of opioid effects on alcohol consumption in free-feeding rats. Pharmacol Biochem Behav 33:407–413

    Google Scholar 

  • Marlatt GA, George WH (1984) Relapse prevention: introduction and overview of the model. Br J Addict 79:261–273

    Google Scholar 

  • Mello NK, Mendelson JH (1980) Behavioral pharmacology of substance abuse: recent advances. Psychopharmacol Bull 16[1]:45–47

    Google Scholar 

  • Mendelson JH, Mello NK (1979) Biological concomitants of alcoholism. N Engl J Med 301:912–921

    Google Scholar 

  • Myers RD, Privette TH (1989) A neuroanatomical substrate for alcohol drinking: identification of tetrahydropapaveroline (THP)-reactive sited in the rat brain. Brain Res Bull 22:899–911

    Google Scholar 

  • 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 9:43–48

    Google Scholar 

  • Patel VA, Pohorecky LA (1989) Acute and chronic ethanol treatment onβ-endorphin and catecholamine levels. Alcohol 6:59–63

    Google Scholar 

  • Prunell M, Boada J, Feria M, Benitez MA (1987) Antagonism of the stimulant and depressant effects of ethanol in rats by naloxone. Psychopharmacology 92:215–218

    Google Scholar 

  • Reid LD, Czirr SA, Bensinger CC, Hubbell CL, Volanth AJ (1987) Morphine and diprenorphine together potentiate intake of alcoholic beverages. Alcohol 4:161–168

    Google Scholar 

  • Samson HH, Doyle TF (1985) Oral ethanol self-administration in the rat: effect of naloxone. Pharmacol Biochem Behav 22:91–99

    Google Scholar 

  • Samson HH, Tolliver GA, Schwarz-Stevens K (1990) Oral ethanol self-administration: a behavioral pharmacological approach to CNS control mechanisms. Alcohol 7:187–191

    Google Scholar 

  • Sandi C, Borrell J, Guaza C (1988) Naloxone decreases ethanol consumption within a free-choice paradigm in rats. Pharmacol Biochem Behav 29:39–43

    Google Scholar 

  • 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 45:87–92

    Google Scholar 

  • Siegel S (1956) In: Harlow HF (ed) Nonparametric statistics for the behavioural sciences. McGraw-Hill Kogakusha Ltd, Tokyo

    Google Scholar 

  • Sinclair JD (1971) The alcohol-deprivation effect in monkeys. Psychon Sci 25[1]:21–22

    Google Scholar 

  • Sinclair JD, Adkins J, Walker S (1973) Morphine-induced suppression of voluntary alcohol drinking in rats. Nature 246:425–427

    Google Scholar 

  • 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 19–34

    Google Scholar 

  • 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 457:287–294

    Google Scholar 

  • 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 91:252–268

    Google Scholar 

  • Sweep CGJ, Van Ree JM, Wiegant VM (1988) Characterization ofβ-endorphin-immunoreactivity in limbic brain structures of rats self-administering heroin or cocaine. Neuropeptides 12:229–236

    Google Scholar 

  • 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 44:1133–1140

    Google Scholar 

  • 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 99–107

    Google Scholar 

  • Topel H (1985) Biochemical basis of alcoholism: statements and hypotheses of present research. Alcohol 2:711–788

    Google Scholar 

  • 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 75–78

    Google Scholar 

  • Volpicelli JR, Davis MA, Olgin Je (1986) Naltrexone blocks the post-shock increase of ethanol consumption. Life Sci 38:841–847

    Google Scholar 

  • 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 195–214

    Google Scholar 

  • White NM (1989) Reward or reinforcement: what's the difference? Neurosci Biobehav Rev 13:181–186

    Google Scholar 

  • Winger G (1988) Effects of ethanol withdrawal on ethanol-reinforced reponding in rhesus monkeys. Drug Alcohol Depend 22:235–240

    Google Scholar 

  • Wise RA, Bozarth MA (1987) A psychomotor stimulant theory of addiction. Psychol Rev 94[4]:469–492

    Google Scholar 

  • 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 371

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kornet, M., Goosen, C. & Van Ree, J.M. Effect of naltrexone on alcohol consumption during chronic alcohol drinking and after a period of imposed abstinence in free-choice drinking rhesus monkeys. Psychopharmacology 104, 367–376 (1991). https://doi.org/10.1007/BF02246038

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02246038

Key words

Navigation