Development of a mouse model of ethanol addiction: naltrexone efficacy in reducing consumption but not craving
First Online: 09 February 2006 Received: 26 January 2005 Accepted: 22 October 2005 DOI:
Cite this article as: Fachin-Scheit, D., Frozino Ribeiro, A., Pigatto, G. et al. J Neural Transm (2006) 113: 1305. doi:10.1007/s00702-005-0416-z Summary.
The aim of the present study was validating pharmacologically a mouse model of alcohol addiction. Mice (n = 60) were offered ethanol (5% and 10%) and water in a free choice paradigm consisting of four phases: free choice (10 weeks), withdrawal (2 weeks), re-exposure (2 weeks) and quinine- adulteration (2 weeks). Control mice (n = 10) had access to water. They were housed individually with food
ad libitum. The animals’ behaviour was evaluated at the beginning of the treatment and during the withdrawal period. After the exposure to the model, mice received i.p. naltrexone (0.0; 0.125; 2.0 and 16.0 mg/kg) or saline. Mice were characterized as: addicted (n = 15, preference for ethanol without reducing intake when ethanol were adulterated with quinine); heavy drinker (n = 14, preference for ethanol but reduced intake when ethanol were adulterated); and light drinker (n = 16, no preference for ethanol). Naltrexone reduced ethanol intake in the heavy and light groups (p ≤ 0.01 and p ≤ 0.05, respectively, compared to saline-treated group) with no effect on water intake. It is discussed that naltrexone may be acting in the positive reinforcing properties of ethanol but does not seem to have anti-craving properties. It was concluded that the addicted mice had a compulsive behavior manifested by the continued ethanol intake even under aversive conditions and under naltrexone treatment suggesting that this model might be useful to study addiction. Keywords: Ethanol, naltrexone, alcoholism, addiction model, mice. References American Psychiatry Association 1994Diagnostic and statistical manual of mental disorders4 American Psychiatric Press Washington, DC Google Scholar Anton, RF, Moka, DH, Latham, PK, Waid, LR, Malcom, RJ, Dias, JK 1999 Naltrexone and cognitive behavioral therapy for the treatment of outpatient alcoholics: results of a placebo-controlled trial Am J Psychiatry 11 1758 1764 Google Scholar Anton, RF 1999 What is craving? Models and implications for treatment Alcohol Res Health 23 165 173 PubMed Google Scholar Boyle, AEL, Srewart, RB, Macenski, MJ, Spiga, R, Jonson, BA, Meisch, RA 1998 Effects of acute and chronic doses of naltrexone on ethanol self-administration in Rhesus monkeys Alcohol Clin Exp Res 22 359 366 PubMed CrossRef Google Scholar Carmen, B, Angeles, M, Ana, M, Maria, AJ 2004 Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review Addiction 99 811 828 CrossRef Google Scholar Carr, GD, Fibiger, HC, Phillips, AG 1989 Conditioned place preference as a measure of drug reward Liebman, JM Cooper, SJ eds. The neuropharmacological basis of reward Clarendon Press Oxford 264 319 Google Scholar Cole, JC, Littleton, JM, Little, HJ 2000 Acamprosate, but not naltrexone, inhibits conditioned abstinence behaviour associated with repeated ethanol administration and exposure to a plus-maze Psychopharmacology 147 403 411 PubMed CrossRef Google Scholar Cunningham, CL, Fidler, TL, Hill, KG 2000 Animal models of alcohol’s motivational effects Alcohol Res Health 24 85 92 PubMed Google Scholar Eravci, M, Kley, S, Pinna, G, Prengel, H, Brödel, O, Hiedra, L, Meinhold, H, Baumgartner, A 1999 Gene expression of glucose transporters and glycolytic enzymes in the CNS of rats behaviorally dependent on ethanol Mol Brain Res 65 103 111 PubMed CrossRef Google Scholar Ferraro, FM, III, Hill, KG, Kaczmarek, HJ, Coonfield, DL, Kiefer, SW 2002 Naltrexone modifies the palatability of basic tastes and alcohol in outbred male rats Alcohol 27 107 114 PubMed CrossRef Google Scholar Froehlich, JC, Harts, J, Lumeng, L, Li, TK 1990 Naloxone attenuates voluntary ethanol intake in rats selectively bred for high ethanol preference Pharmacol Biochem Behav 35 385 390 PubMed CrossRef Google Scholar Froehlich, JC, Zweifel, M, Harts, J, Lumeng, L, Li, TK 1991 Importance of delta opioid receptors in maintaining high alcohol drinking Psychopharmacology 103 467 472 PubMed CrossRef Google Scholar Froehlich, JC, Badia-Elder, NE, Zink, RW, McCullough, DE, Portoghese, PS 1998 Contribution of the opioid system to alcohol aversion and alcohol drinking behavior J Pharmacol Exp Ther 287 284 292 PubMed Google Scholar Froehlich, JC, O’Malley, S, Hyytiã, P, Davidson, D, Farren, C 2003 Preclinical and clinical studies on naltrexone: What have they taught each other? Alcohol Clin Exp Res 27 533 539 PubMed CrossRef Google Scholar Gatto, GJ, McBride, WJ, Murphy, JM, Lumeng, L, Li, TK 1994 Ethanol self-infusion into the ventral tegmental area by alcohol-preferring rats Alcohol 11 557 564 PubMed CrossRef Google Scholar Gonzales, RA, Weiss, F 1998 Supresión of etanol-reinforced behavior by naltrexone is associated with attenuation of the etanol-induced increase in dialysate dopamine levels in the nucleus accumbens J Neurosci 18 10663 10671 PubMed Google Scholar Götz, E, Wolf, U, Wolffgramm, J 1992 Reward by drug taking: operant place preference conditioning as a method to investigate the role of dopaminergic transmission Richter, D Elsner, N eds. Rhytmogenesis in neurons and networks Thieme Stuttgart 682 693 Google Scholar Götz, E, Wolffgramm, J 1993 Dopaminergic sensitivity and reward: experiments with operant place preference conditioning Elsner, N Heisenberg, M eds. Gene-brain-behaviour Thieme Stuttgart 702 715 Google Scholar Grahame, NJ, Rodd-Henricks, K, Li, TK, Lumeng, L 2000 Ethanol locomotor sensitization, but not tolerance correlates with selection for alcohol preference in high- and low-alcohol preferring mice Psychopharmacology 151 252 260 PubMed CrossRef Google Scholar Heyman, GM 2000 An economic approach to animal models of alcoholism Alcohol Res Health 24 132 140 PubMed Google Scholar Hubbell, CL, Reid, LD 1988 Opioids modulate rats’ intakes of alcoholic beverages Reid, LD eds. Opioids, bulimia, and alcohol abuse and alcoholism Springer New York 145 174 Google Scholar Hyytiã, H, Sinclair, JD 1993 Responding for oral ethanol after naloxone treatment by alcohol-preferring AA rats Alcohol Clin Exp Res 17 631 636 PubMed CrossRef Google Scholar Koob, G, Le Moal, M 1997 Drug abuse: hedonic homeostatic dysregulation Science 278 52 58 PubMed CrossRef Google Scholar Koob, GF, Le Moal, M 2001 Drug addiction, dysregulation of reward, and allostasis Neuropsychopharm 24 97 129 CrossRef Google Scholar Koob, GF 2000 Animal models of craving for ethanol Addiction 95 73 81 CrossRef Google Scholar Kornet, M, Goosen, C, Van Ree, JM 1991 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 PubMed CrossRef Google Scholar Krystal, JH 2001 Naltrexone in the treatment of alcohol dependence N Engl J Med 345 1734 1739 PubMed CrossRef Google Scholar Lê, AD, Poulos, CX, Quan, B, Chow, S 1993 The effects of selective blockade of delta and mu opiate receptors on ethanol consumption by C57BL/6 mice in a restricted access paradigm Brain Res 630 330 332 PubMed CrossRef Google Scholar Meisch, R 2001 Oral drug self-administration: an overview of laboratory animal studies Alcohol 24 117 128 PubMed CrossRef Google Scholar Middaugh, LD, Kelley, BM, Cuison, ER, Groseclose, CH 1999 Naltrexone effects on ethanol reward and discrimination in C57BL/6 mice Alcohol Clin Exp Res 23 456 464 PubMed CrossRef Google Scholar Middaugh, LD, Kelley, BM, Cuison, ER, Groseclose, CH 2000 Delta-opioid and 5-HT3 antagonist effects on ethanol reward and discrimination in C57BL/6 mice Alcohol Clin Exp Res 65 145 154 Google Scholar Middaugh, LD, Szumlinski, KK, Patten, YV, Marlowe, ALB, Kalivas, PW 2003 Chronic ethanol consumption by C57BL/6 mice promotes tolerance to its interoceptive cues and increases extracelular dopamine, an effect blocked by naltrexone Alcohol Clin Exp Res 27 1892 1900 PubMed CrossRef Google Scholar Middaugh, LD, Lee, AM, Bandy, AL 2000 Ethanol reward after chronic consumption and deprivation in C57BL/6J mice Alcohol Clin Exp Res 23 1172 1179 Google Scholar Monti, PM, Tidey, J, Czachowski, CL, Grant, KA, Rohsenow, DJ, Sayette, M, Maners, N, Pierre, P 2004 Building bridges: the transdisciplinary study of craving from the animal laboratory to the lamppost Alcohol Clin Exp Res 26 279 287 Google Scholar Monti, PM, Rohsenow, DJ, Hutchison, KE, Swift, RM, Mueller, TI, Colby, SM, Brown, RA, Gulliver, SB, Gordon, A, Abrams, DB 1999 Naltrexone’s effect on cue-elicited craving among alcoholics in treatment Alcohol Clin Exp Res 23 1386 1394 PubMed CrossRef Google Scholar O’Brien, CP 2005 Anticraving medications for relapse prevention: a possible new class of psychoactive medications Am J Psychiatry 162 1423 1431 PubMed CrossRef Google Scholar O’Malley, SS, Jaffe, AJ, Chang, G, Schottenfeld, RS, Meyer, RE, Rounsaville, B 1992 Naltrexone and coping skills therapy for alcohol dependence Arch Gen Psychiatry 49 881 887 PubMed Google Scholar O’Malley, SS, Krishnan-Sarin, S, Farren, C, Sinha, R, Kreek, MJ 2000 Naltrexone decreases craving and alcohol self-administration in alcohol-dependent subjects and activates the hypothalamo-pituitary-adrenocortical axis Psychopharmacology (Berl) 160 19 29 CrossRef Google Scholar Parkes, JH, Sinclair, JD 2000 Reduction of alcohol drinking and upregulation of opioid receptors by oral naltrexone in AA rats Alcohol 21 215 221 PubMed CrossRef Google Scholar Phillips, TJ 2002 Animal models for the genetic study of human alcohol phenotypes Alcohol Res Health 26 202 207 PubMed Google Scholar Phillips, TJ, Wenger, CD, Dorow, JD 1997 Naltrexone effects on ethanol drinking acquisition and on established ethanol consumption in C57BL/6J mice Alcohol Clin Exp Res 21 691 702 PubMed CrossRef Google Scholar Potgieter, AS, Deckers, F, Geerlings, P 1999 Craving and relapse measurement in alcoholism Alc Alcohol 34 254 260 Google Scholar Reid, LD, Hubbell, CL 1992 Opioids modulate rats’ propensities to take alcoholic beverages Naranjo, CA Sellers, EM eds. Novel pharmacological interventions for alcoholism Springer New York 121 134 Google Scholar Richter, CP, Campbell, K 1940 Alcohol taste thresholds and concentration of solution preferred by rats Science 91 507 508 Google Scholar Robinson, TE, Berridge, KC 1993 The neural basis of drug craving: an incentive-sensitization theory of addiction Brain Res Rev 18 247 291 PubMed CrossRef Google Scholar Robinson, TE, Berridge, KC 2001 The psychology and neurobiology of addiction: an incentive-sensitization view Addiction 96 103 114 PubMed CrossRef Google Scholar Samson, HH, Doyle, TF 1985 Oral ethanol self-administration in the rat: effect of naloxone Pharmacol Biochem Behav 22 91 99 PubMed CrossRef Google Scholar Samson, HH, Slawecki, CJ, Sharpe, AL, Chappell, A 1998 Appetitive and consummatory behaviors in the control of ethanol consumption: a measure of ethanol seeking behavior Alcohol Clin Exp Res 22 1783 1787 PubMed CrossRef Google Scholar Schwarz-Stevens, KS, Files, FJ, Samson, HH 1992 Effects of morphine and naloxone on ethanol- and sucrose-reinforced responding in nondeprived rats Alcohol Clin Exp Res 16 822 832 PubMed CrossRef Google Scholar Shippenberg, TS, Koob, GF, et al. 2002 Recent advances in animal models of drug addiction Davis, KL eds. Neuropsychopharmacology: the fifth generation of progress: an official publication of the American College of Neuropsychopharmacology Lippincott Williams & Wilkins Philadelphia 1381 1397 Google Scholar Sinclair, JD, Senter, RJ 1967 Increased preference for ethanol in rats following alcohol deprivation Psychonom Sci 8 11 12 Google Scholar Spanagel, R, Hölter, SM 1999 Long-term alcohol self-administration with repeated alcohol deprivation phases: an animal model of alcoholism? Alc Alcohol 34 231 243 Google Scholar Spanagel, R, Hölter, SM 2000 Pharmacological validation of new animal model alcoholism J Neural Transm 107 669 680 PubMed CrossRef Google Scholar Spanagel, R, Zieglgänsberger, W 1997 Anti-craving compounds for ethanol: new pharmacological tools to study addictive processes Trends Pharmacol Sci 18 54 59 PubMed CrossRef Google Scholar Spanagel, R 2000 Recent animal models of alcoholism Alcohol Res Health 24 124 131 PubMed Google Scholar Spanagel, R 2003 Alcohol addicition research: from animal models to clinics Best Pract Res Clin Gastroenterol 17 507 518 PubMed CrossRef Google Scholar Spanagel, R, Montkowski, A, Allinham, K, Stöhr, T, Shoaib, M, Holsboer, F, Landgraf, R 1995 Anxiety: a potencial predictor of vulnerability to the initiation of ethanol self-administration in rats Psychopharmacology 122 369 373 PubMed CrossRef Google Scholar
Srisurapanont M, Jarusuraisin N (2005) Opioid antagonists for alcohol dependence (Cochrane Review). In: The Cochrane Library, Issue 2. Update Software, Oxford
Tabakoff, B, Hoffman, HL 2000 Animal models in alcohol research Alcohol Res Health 24 77 84 PubMed Google Scholar Tiffany, ST, Carter, BL 1998 Is craving the source of compulsive drug use? J Psychopharmacol 12 23 30 PubMed Google Scholar Volpicelli, JR, Alterman, AI, Hayashida, M, O’Brien, CP 1992 Naltrexone in the treatment of alcohol dependence Arch Gen Psychiatry 49 876 880 PubMed Google Scholar Weinstein, A, Feldtkeller, B, Malizia, A, Wilson, S, Bailey, J, Nutt, DJ 1998 Integrating the cognitive and physiological aspects of craving J Psychopharmacol 12 31 38 PubMed Google Scholar Weiss, F, Porrino, LJ 2002 Behavioral neurobiology of alcohol addiction: recent advances and challenges J Neurosci 22 3332 3337 PubMed Google Scholar Weiss, F 2000 Neuroadaptative changes in neurotransmitter systems mediating ethanol-induced behaviors Rev NIAAA’s Neurosci Behav Res Portfolio 34 261 314 Google Scholar Weiss, F, Mitchner, M, Bloom, FE, Koob, GF 1990 Free-choice responding for ethanol versus water in alcohol preferring (H) and unselected Wistar rats in differentially modified by naloxone, bromocriptine, and methysergide Psychopharmacology 101 178 186 PubMed CrossRef Google Scholar Williams, KL, Woods, JH 1998 Oral ethanol-reinforced responding in Rhesus monkeys: effects of opioid antagonists selective for the µ-, κ- or δ-receptor Alcohol Clin Exp Res 22 1634 1639 PubMed CrossRef Google Scholar Wolffgramm, J, Heyne, A 1995 From controlled drug intake to loss of control: the irreversible development of drug addiction in the rat Rev Behav Brain Res 70 77 94 CrossRef Google Scholar Wolffgramm, J, Galli, G, Thimm, F, Heyne, A 2000 Animal models of addiction: models for therapeutic strategies? J Neural Transm 107 649 668 PubMed CrossRef Google Scholar Wolffgramm, J 1990 Free choice ethanol intake of laboratory rats under different social conditions Psychopharmacology 101 233 239 PubMed CrossRef Google Scholar