Abstract
The endogenous opioid system has been implicated in mediating the reinforcing effects of ethanol (EtOH). Naltrexone (NTX), an opioid antagonist with concentration-dependent selectivity for the mu receptor, naltrindole (NTI), a selective delta receptor antagonist, and U50,488H, a selective kappa receptor agonist were examined in both alcohol-preferring (P) and nonselected (Long Evans (LE)) rats to determine whether they differentially affected the seeking and consumption of EtOH and sucrose. Using the sipper-tube model, rats reinforced with either 2 % sucrose or 10 % EtOH were injected with vehicle and either NTI (2.5, 5.0, or 10.0 mg/kg), U50 (2.5, 5.0, or 10.0 mg/kg), low-dose NTX (0.1, 0.3, or 1.0 mg/kg), or high-dose NTX (1.0, 3.0, or 10.0 mg/kg). Subsequent intakes (consummatory) or lever responses (seeking) were assessed. Overall, NTI, U50, and NTX attenuated intake and responding for sucrose and EtOH, with EtOH-reinforced P rats being the most sensitive to the effects of NTI on intake and seeking. U50 treatment decreased intake and seeking in both P and LE rats but did not selectively reduce EtOH intake or seeking in either line. P rats were more sensitive than LE rats to lower doses of NTX, and these doses more selectively attenuated responding for EtOH than sucrose. Higher doses of NTX suppressed intake and responding across both lines and reinforcers. These results suggest that drugs selective for the opioid receptors may be good pharmacotherapeutic targets, particularly in those with an underlying genetic predisposition for greater EtOH preference/intake.
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References
Anton RF, Orosxi G, O'Malley S, Couper D, Swift R, Pettinati J, Goldman D (2008) An evaluation of mu-opioid receptor (OPRM1) as a predictor of naltrexone response in the treatment of alcohol dependence: Results from the combined pharmacotherapies and behavioral interventions for alcohol dependence (COMBINE) study. Arch Gen Psychiatry 65:135–144
Bals-Kubik R, Herz A, Shippenberg TS (1989) Evidence that the aversive effects of opioid antagonists and κ-agonists are centrally mediated. Psychopharmacology (Berl) 98:203–206
Bals-Kubik R, Shippenberg TS, Herz A (1990) Involvement of central mu and delta opioid receptors in mediating the reinforcing effects of beta-endorphin in the rat. Eur J Pharmacol 175:63–69
Bouza C, Angeles M, Munoz A, Amate JM (2004) Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review. Addiction 99:811–828
Childers SR, Creese I, Snowman AM, Snyder SH (1979) Opiate receptor binding affected differentially by opiates and opioid peptides. Eur J Pharmacol 55:11–18
Ciccocioppo R, Martin-Fardon R, Weiss F (2002) Effect of selective blockade of mu(1) or delta opioid receptors on reinstatement of alcohol-seeking behavior by drug-associated stimuli in rats. Neuropsychopharmacology 27:391–399
Cosgrove KP, Carroll ME (2002) Effects of bremazocine on self-administration of smoked cocaine base and orally delivered ethanol, phencyclidine, saccharin, and food in rhesus monkeys: A behavioral economic analysis. J Pharmacol Exp Ther 301:993–1002
Croop RS, Faulkner EB, Labriola DF (1997) The safety profile of naltrexone in the treatment of alcoholism—results from a multicenter usage study. Arch Gen Psychiatry 54:1130–1135
Daniel M, Martin AD, Carter J (1992) Opiate receptor blockade by naltrexone and mood state after acute physical activity. Br J Sports Med 26:111–115
De Waele JP, Papachristou GC (1992) The alcohol-preferring C57BL/6 mice present an enhanced sensitivity of the hypothalamic beta-endorphin system to ethanol than the alcohol-avoiding DBA/2 mice. J Pharmacol Exp Ther 261:788–794
Di Chiara G, Imperato A (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci U S A 85:5274–5278
Doyon WM, Howard EC, Shippenberg TS, Gonzales RA (2006) Kappa-opioid receptor modulation of accumbal dopamine concentration during operant ethanol self-administration. Neuropharmacology 51:487–496
Franck J, Lindholm S, Raaschou P (1998) Modulation of volitional ethanol intake in the rat by central delta-opioid receptors. Alcohol Clin Exp Res 22:1185–1189
Froehlich JC, Zweifel M, Harts J, Lumeng L, Li T-K (1991) Importance of delta opioid receptors in maintaining high alcohol drinking. Psychopharmacology (Berl) 103:467–472
Gianoulakis C (1990) Characterization of the effects of acute ethanol administration on the release of beta-endorphin peptides by the rat hypothalamus. Eur J Pharmacol 180:21–29
Goldman D, Oroszi G, Ducci F (2005) The genetics of addictions: Uncovering the genes. Nat Rev Genet 6:521–532
Gonzales RA, Weiss F (1998) Suppression of ethanol reinforced behavior by naltrexone is associated with attenuation of the ethanol induced increase in dialysate dopamine levels in the nucleus accumbens. J Neurosci 18:10663–10671
Grant JE (2005) Outcome study of kleptomania patients treated with naltrexone: a chart review. Clin Neuropharmacol 28:11–14
Heinala P, Alho H, Kiianmaa K, Lonnqvist J, Kuoppasalmi K, Sinclair JD (2001) Targeted use of naltrexone without prior detoxification in the treatment of alcohol dependence: a factorial double-blind, placebo-controlled trial. J Clin Psychopharmacol 21:287–292
Henderson AN, Czachowski CL (2012) Neuropeptide Y (NPY) in the central nucleus of the amygdala (CeA) does not affect ethanol-reinforced responding in binge-drinking, nondependent rats. Pharmacol Biochem Behav 101:8–13
Honkanen A, Vilamo L, Wegelius K, Sarviharju M, Hyytia P, Korpi ER (1996) Alcohol drinking is reduced by a mu 1- but not by a delta-opioid receptor antagonist in alcohol-preferring rats. Eur J Pharmacol 304:7–13
Hyytia P (1993) Involvement of mu-opioid receptors in alcohol drinking by alcohol-preferring AA rats. Pharmacol Biochem Behav 45:697–701
Hyytia P, Kiianmaa K (2001) Suppression of ethanol responding by centrally administered CTOP and naltrindole in AA and Wistar rats. Alcohol Clin Exp Res 25:25–33
Johnson SW, North RA (1992) Opioids excite dopamine neurons by hyperpolarization of local interneurons. J Neurosci 12:483–488
Kim SG, Stromberg MF, Kim MJ, Volpicelli JR, Park J-M (2000) The effect of antagonists selective for mu- and delta-opioid receptor subtypes on alcohol consumption in C57BL/6 mice. Alcohol 22:85–90
Kim SW, Grant JE, Adson DE, Shin YC (2001) Double-blind naltrexone and placebo comparison study in the treatment of pathological gambling. Biol Psychiatry 49:914–921
King AC, Volpicelli JR, Frazerk A, O'Brien CP (1997) Effect of naltrexone on subjective alcohol response in subjects at high and low risk for future alcohol dependence. Psychopharmacology (Berl) 129:15–22
Kranzler HR, Van Kirk J (2001) Efficacy of naltrexone and acamprosate for alcoholism treatment: a meta-analysis. Alcohol Clin Exp Res 25:1335–1341
Krishnan-Sarin S, Jing SL, Kurtz DL, Zweifel M, Portoghese PS, Li T-K, Froehlich JC (1995a) The delta opioid receptor antagonist naltrindole attenuates both alcohol and saccharin intake in rats selectively bred for alcohol preference. Psychopharmacology (Berl) 120:177–185
Krishnan-Sarin S, Portoghese PS, Li T-K, Froehlich JC (1995b) The delta 2-opioid receptor antagonist naltriben selectively attenuates alcohol intake in rats bred for alcohol preference. Pharmacol Biochem Behav 52:153–159
Krishnan-Sarin S, Wand GS, Li XW, Portoghese PS, Froehlich JC (1998) Effect of mu opioid receptor blockade on alcohol intake in rats bred for high alcohol drinking. Pharmacol Biochem Behav 59:627–635
Krishnan-Sarin S, Krystal JH, Shi J, Pittman B, O'Malley SS (2007) Family history of alcoholism influences naltrexone-induced reducation in alcohol drinking. Biol Psychiatry 62:694–697
Le 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
Lindholm S, Werme M, Brene S, Franck J (2001) The selective κ-opioid receptor agonist U50,488H attenuates voluntary ethanol intake in the rat. Behav Brain Res 120:137–146
Logrip ML, Janak PH, Ron D (2008) Dynorphin is a downstream effector of striatal BDNF regulation of ethanol intake. FASEB J 22:2393–2404
Logrip ML, Janak PH, Ron D (2009) Blockade of ethanol reward by the kappa opioid receptor agonist U50,488H. Alcohol 43:359–365
Lord JA, Waterfield AA, Hughes J, Kosterlitz HW (1977) Endogenous opioid peptides: multiple agonists and receptors. Nature 267:495–499
Marinelli PW, Funk D, Harding S, Li Z, Juzytsch W, Le AD (2009) Roles of opioid receptor subtypes in mediating alcohol-seeking induced by discrete cues and context. Eur J Neurosci 30:671–678
Marrazzi MA, Bacon JP, Kinzie J, Luby ED (1995) Naltrexone use in the treatment of anorexia nervosa and bulimia nervosa. Int Clin Psychopharmacol 10:163–172
McLaughlin JP, Marton-Popovici M, Chavkin C (2003) Kappa opioid receptor antagonist and prodynorphin gene distruption block stress-induced behavioral responses. J Neurosci 23:5674–5683
McLaughlin JP, Land BB, Li S, Pintar JE, Chavkin C (2006) Prior activation of kappa opioid receptors by U50,488H mimics repeated forced swim stress to potentiate cocaine place preference conditioning. Neuropsychopharmacology 31:787–794
Middaugh LD, Kelley BM, Groseclose CH, Cuison ER Jr (2000) Delta-opioid and 5-HT3 receptor antagonist effects on ethanol reward and discrimination in C57BL/6 mice. Pharmacol Biochem Behav 65:145–154
Mitchell JM, Liang MT, Fields HL (2005) A single injection of the kappa opioid antagonist norbinaltorphamine increases ethanol consumption in rats. Psychopharmacology (Berl) 182:384–392
National Research Council (1996) Guide for the care and use of laboratory animals. National Research Council, Washington, DC
Netsby P, Schoffelmeer ANM, Homberg JR, Wardeh G, de Vries TJ, Mulder AJ, Vanderschuren LJMJ (1999) Bremazocine reduces unrestricted free-choice ethanol self-administration in rats without affecting sucrose preference. Psychopharmacology (Berl) 142:309–317
Nielsen CK, Simms JA, Pierson HB, Surendra RI, Saini SK, Ananthan S, Bartlett SE (2008) A novel delta opioid receptor antagonist, SoRI-9409, produces a selective and long-lasting decrease in ethanol consumption in heavy-drinking rats. Biol Psychiatry 64:974–981
O’Brien CP, Volpicelli LA, Volpicelli JR (1996) Naltrexone in the treatment of alcoholism: A clinical review. Alcohol 13:35–39
Oslin DW, Berrettini W, Kranzler HR, Pettinati H, Gelernter J, Volpicelli JR, O'Brien CP (2003) A functional polymorphism of the mu-opioid receptor geneis associated with naltrexone response in alcohol-dependent patients. Neuropsychopharmacology 28:1546–1552
Pastor R, Sanchis-Segura C, Aragon CMG (2005) Effects of selective antagonism of mu(1)-, mu(1/2)-, mu(3)-, and delta-opioid receptors on the locomotor-stimulating actions of ethanol. Drug Alcohol Depend 78:289–295
Paterson SJ, Corbett AD, Gillan MG, Kosterlitz HW, McKnight AT, Robson LE (1984) Radioligands for probing opioid receptors. J Recept Res 4:143–154
Pettinati HM, O'Brien CP, Rabinowitz AR, Wortman SM, Oslin DW, Kampman KM, Dackis CA (2006) The status of naltrexone in the treatment of alcohol dependence: specific effects on heavy drinking. J Clin Psychopharmacol 26:610–625
Ramchandani VA, Umhau J, Pavon FJ, Ruiz-Velasco V, Margas W, Sun H, Damadzic R, Eskay R, Schoor M, Thorsell A, Schwandt ML, Sommer WH, George DT, Parsons LH, Herscovitch P, Hommer D, Heilig M (2011) A genetic determinant of the striatal dopamine response to alcohol in men. Mol Psychiatry 16:809–817
Ray LA, Barr CS, Blendy JA, Oslin D, Goldman D, Anton RF (2012) The role of the Asn40Asp polymorphism of the mu opioid receptor gene (OPRM1) on alcoholism etiology and treatment: A critical review. Alcohol Clin Exp Res 36:385–394
Ray LA, Bujarski S, MacKillop J, Courtney KE, Monti PM, Miotto K (2013) Subjective response to alcohol among alcohol-dependent individuals: Effects of the mu-opioid receptor (OPRM1) gene and alcoholism severity. Alcohol Clin Exp Res 37(s1):E116–E124
Raymond NC, Grant JE, Kim SW, Coleman E (2002) Treatment of compulsive sexual behaviour with naltrexone and serotonin reuptake inhibitors: two case studies. Int Clin Psychopharmacol 17:201–205
Rubio G, Ponce G, Rodriguez-Jimenez R, Jimenez-Arriero MA, Hoenicka J, Palomo T (2005) Clinical predictors of response to naltrexone in alcoholic patients: who benefits most from treatment with naltrexone? Alcohol Alcohol 40:227–233
Samson HH (1986) Initiation of ethanol reinforcement using a sucrose-substitution procedure in food- and water-sated rats. Alcohol Clin Exp Res 10:436–442
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
Samson HH, Sharpe AL, Denning C (1999) Initiation of ethanol self-administration in the rat using sucrose substitution in a sipper-tube procedure. Psychopharmacology (Berl) 147:274–279
Samson HH, Czachowski CL, Slawecki CJ (2000) A new assessment of the ability of oral ethanol to function as a reinforcing stimulus. Alcohol Clin Exp Res 24:766–773
Spanagel R (1996) The influence of opioid antagonist on the discriminative stimulus effects of ethanol. Pharmacol Biochem Behav 4:645–649
Stromberg MF, Casale M, Volpicelli L, Volpicelli JR, O'Brien CP (1998) A comparison of the effects of the opioid antagonists naltrexone, naltrindole, and beta-funaltrexamine on ethanol consumption in the rat. Alcohol 15:281–289
Symons FJ, Thompson A, Rodriguez MC (2004) Self-injurious behavior and the efficacy of naltrexone treatment: a quantitative synthesis. Ment Retard Dev Disabil Res Rev 10:193–200
Verplaetse TL, Rasmussen DD, Froehlich JC, Czachowski CL (2012) Effects of prazosin, an alpha1-adrenergic receptor antagonist, on the seeking and intake of alcohol and sucrose in alcohol-preferring (P) rats. Alcohol Clin Exp Res 36:881–886
Volpicelli JR, Alterman AI, Hayashida M, O'Brien CP (1992) Naltrexone in the treatment of alcohol dependence. Arch Gen Psychiatry 49:876–880
Walker BM, Koob GF (2008) Pharmacological evidence for a motivational role of κ-opioid systems in ethanol dependence. Neuropsychopharmacology 33:643–652
Walker BM, Zorrilla EP, Koob GF (2010) Systemic kappa-opioid receptor antagonism by nor-binaltorphamine reduces dependence-induced excessive alcohol self-administration in rats. Addict Biol 16:116–119
Walsh SL, Geter-Douglas B, Strain EC, Bigelow GE (2001) Enadoline and butorphanol: Evaluation of kappa-agonists on cocaine pharmadynapics and cocaine self-administration in humans. J Pharmacol Exp Ther 299:147–158
Wee S, Koob GF (2010) The role of the dynorphin-κ opioid system in the reinforcing effects of drugs of abuse. Psychopharmacology (Berl) 210:121–135
Weiss F, Lorang MT, Bloom FE, Koob GF (1993) Ethanol self-administration stimulates dopamine release in the rat nucleus accumbens: Genetic and motivational determinants. J Pharmacol Exp Ther 267:250–258
Williams KL, Woods JH (1998) Oral ethanol-reinforced responding in rhesus monkeys: Effects of opioid antagonists selective for the mu-, kappa-, or delta-receptor. Alcohol Clin Exp Res 22:1634–1639
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This work was supported in part by NIAAA T32 AA007462 and P60 AA007611.
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Henderson-Redmond, A., Czachowski, C. Effects of systemic opioid receptor ligands on ethanol- and sucrose seeking and drinking in alcohol-preferring (P) and Long Evans rats. Psychopharmacology 231, 4309–4321 (2014). https://doi.org/10.1007/s00213-014-3571-9
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DOI: https://doi.org/10.1007/s00213-014-3571-9