Abstract
Rationale
Preclinical studies report attenuated ethanol-induced conditioned taste aversion (CTA) following chronic ethanol exposure, suggesting that tolerance develops to the aversive properties of ethanol. However, these studies are confounded by pre-exposure to the unconditioned stimulus (US; ethanol), which is well known to hinder conditioning.
Objectives
This study was designed to determine whether chronic ethanol exposure produces tolerance to the aversive properties of ethanol in the absence of a US pre-exposure confound.
Methods
CTA was performed in adult male and female Long-Evans rats by pairing 0.1% ingested saccharin with an intraperitoneal injection of ethanol (1.5 or 2.0 g/kg) or saline. Rats were then rendered ethanol dependent using chronic intermittent ethanol (CIE) vapor exposure. Controls were exposed to room air (AIR). The effect of chronic ethanol on CTA expression and reconditioning were examined following vapor exposure.
Results
Prior to vapor exposure, both sexes developed CTA to a comparable degree with 2.0 g/kg producing greater CTA than 1.5 g/kg ethanol. Following vapor exposure, AIR controls exhibited an increase in CTA magnitude compared to pre-vapor levels. This effect was largely absent in CIE-exposed rats. Re-conditioning after vapor exposure facilitated increased CTA magnitude to a similar degree in AIR- and CIE-exposed males. In contrast, CTA magnitude was unchanged by re-conditioning in females.
Conclusions
These data suggest that chronic ethanol does not facilitate tolerance to the aversive properties of ethanol but rather attenuates incubation of ethanol-induced CTA. Loss of CTA incubation suggests that CIE exposure disrupts circuits encoding aversion.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders, 5th ed. American Psychiatric Association.
Antonucci LA, Nettis MA, Juckel G, Roser P, Pergola G, Thoma P (2020) Selective recall deficits for heterogeneous associations in detoxified individuals with alcohol use disorder. Behav Brain Res 390:112688. https://doi.org/10.1016/j.bbr.2020.112688
Barker LM, Johns T (1978) Effect of ethanol preexposure on ethanol-induced conditioned taste aversion. J Stud Alcohol 39(1):39–46. https://doi.org/10.15288/jsa.1978.39.39
Beracochea D, Jaffard R (1985) Memory deficits subsequent to chronic consumption of alcohol in mice: an analysis based on spontaneous alternation behavior. Behav Brain Res 15(1):15–25. https://doi.org/10.1016/0166-4328(85)90014-2
Bernardin F, Maheut-Bosser A, Paille F (2014) Cognitive impairments in alcohol-dependent subjects. Front Psych 5:78. https://doi.org/10.3389/fpsyt.2014.00078
Biederman GB, Milgram NW, Heighington GA, Stockman SM, O’Neill W (1974) Memory of conditioned food aversion follows a U-shape function in rats. Q J Exp Psychol 26(4):610–615. https://doi.org/10.1080/14640747408400453
Bindra D, Cameron L (1953) Changes in experimentally produced anxiety with the passage of time: incubation effect. J Exp Psychol 45(3):197–203. https://doi.org/10.1037/h0055125
Björkstrand PA (1990) Effects of conditioned stimulus pre-exposure on human electrodermal conditioning to fear-relevant and fear-irrelevant stimuli. Biol Psychol 30(1):35–50. https://doi.org/10.1016/0301-0511(90)90089-f
Broadbent J, Muccino KJ, Cunningham CL (2002) Ethanol-induced conditioned taste aversion in 15 inbred mouse strains. Behav Neurosci 116(1):138–148
Cailhol S, Mormède P (2002) Conditioned taste aversion and alcohol drinking: strain and gender differences. J Stud Alcohol 63(1):91–99
Chance P (2003) Learning & behavior. Wadsworth/Thomas Learning
Chang T, Meyer U, Feldon J, Yee BK (2007) Disruption of the US pre-exposure effect and latent inhibition in two-way active avoidance by systemic amphetamine in C57BL/6 mice. Psychopharmacology 191(2):211–221. https://doi.org/10.1007/s00213-006-0649-z
Corbin WR, Scott C, Leeman RF, Fucito LM, Toll BA, O’Malley SS (2013) Early subjective response and acquired tolerance as predictors of alcohol use and related problems in a clinical sample. Alcohol Clin Exp Res 37(3):490–497. https://doi.org/10.1111/j.1530-0277.2012.01956.x
Cunningham CL, Tull LE, Rindal KE, Meyer PJ (2002) Distal and proximal pre-exposure to ethanol in the place conditioning task: tolerance to aversive effect, sensitization to activating effect, but no change in rewarding effect. Psychopharmacology 160(4):414–424. https://doi.org/10.1007/s00213-001-0990-1
Davis CM, Riley AL (2010) Conditioned taste aversion learning: implications for animal models of drug abuse. Ann N Y Acad Sci 1187:247–275. https://doi.org/10.1111/j.1749-6632.2009.05147.x
Diaz-Granados JL, Graham DL (2007) The effects of continuous and intermittent ethanol exposure in adolesence on the aversive properties of ethanol during adulthood. Alcohol Clin Exp Res 31(12):2020–2027. https://doi.org/10.1111/j.1530-0277.2007.00534.x
Eysenck HJ (1968) A theory of the incubation of anxiety-fear responses. Behav Res Ther 6(3):309–321. https://doi.org/10.1016/0005-7967(68)90064-8
Gauvin DV, Holloway FA (1992) Ethanol tolerance developed during intoxicated operant performance in rats prevents subsequent ethanol-induced conditioned taste aversion. Alcohol 9(2):167–170. https://doi.org/10.1016/0741-8329(92)90029-a
Glover EJ, McDougle MJ, Siegel GS, Jhou TC, Chandler LJ (2016) Role for the rostromedial tegmental nucleus in signaling the aversive properties of alcohol. Alcohol Clin Exp Res 40(8):1651–1661. https://doi.org/10.1111/acer.13140
Glover EJ, Starr EM, Chao Y, Jhou TC, Chandler LJ (2019) Inhibition of the rostromedial tegmental nucleus reverses alcohol withdrawal-induced anxiety-like behavior. Neuropsychopharmacol 44(11):1896–1905. https://doi.org/10.1038/s41386-019-0406-8
Glover EJ, Khan F, Clayton-Stiglbauer K, Chandler LJ (2021) Impact of sex, strain, and age on blood ethanol concentration and behavioral signs of intoxication during ethanol vapor exposure. Neuropharmacology 184:108393. https://doi.org/10.1016/j.neuropharm.2020.108393
Green AS, Grahame NJ (2008) Ethanol drinking in rodents: is free-choice drinking related to the reinforcing effects of ethanol? Alcohol 42(1):1–11. https://doi.org/10.1016/j.alcohol.2007.10.005
Haass-Koffler CL, Perciballi R (2020) Alcohol tolerance in human laboratory studies for development of medications to treat alcohol use disorder. Alcohol Alcohol (Oxford, Oxfordshire) 55(2):129–135. https://doi.org/10.1093/alcalc/agz103
Hall G, Symonds M (2006) Overshadowing and latent inhibition of context aversion conditioning in the rat. Auton Neurosci: Basic Clin 129(1–2):42–49. https://doi.org/10.1016/j.autneu.2006.07.013
Holdstock T (1973) Body weight and water consumption in rats. Physiol Psychol 1(1):21–23. https://doi.org/10.3758/BF03326861
Holdstock L, King AC, de Wit H (2000) Subjective and objective responses to ethanol in moderate/heavy and light social drinkers. Alcohol Clin Exp Res 24(6):789–794
Kang S, Li J, Zuo W, Fu R, Gregor D, Krnjevic K, Bekker A, Ye J-H (2017) Ethanol withdrawal drives anxiety-related behaviors by reducing M-type potassium channel activity in the lateral habenula. Neuropsychopharmacology 42(9):1813–1824. https://doi.org/10.1038/npp.2017.68
King AC, Houle T, de Wit H, Holdstock L, Schuster A (2002) Biphasic alcohol response differs in heavy versus light drinkers. Alcohol Clin Exp Res 26(6):827–835
King AC, de Wit H, McNamara PJ, Cao D (2011) Rewarding, stimulant, and sedative alcohol responses and relationship to future binge drinking. Arch Gen Psychiatry 68(4):389–399. https://doi.org/10.1001/archgenpsychiatry.2011.26
King AC, Hasin D, O’Connor SJ, McNamara PJ, Cao D (2016) A Prospective 5-year re-examination of alcohol response in heavy drinkers progressing in alcohol use disorder. Biol Psychiat 79(6):489–498. https://doi.org/10.1016/j.biopsych.2015.05.007
Li J, Kang S, Fu R, Wu L, Wu W, Liu H, Gregor D, Zuo W, Bekker A, Ye J-H (2017) Inhibition of AMPA receptor and CaMKII activity in the lateral habenula reduces depressive-like behavior and alcohol intake in rats. Neuropharmacology 126:108–120. https://doi.org/10.1016/j.neuropharm.2017.08.035
Li W, Ren Z, Tang Y, Fu Y, Sun S, Ding R, Hou J, Mai Y, Zhan B, Zhu Y, Zuo W, Ye J-H, Fu R (2023) Rostromedial tegmental nucleus nociceptin/orphanin FQ (N/OFQ) signaling regulates anxiety- and depression-like behaviors in alcohol withdrawn rats. Neuropsychopharmacology 48(6):908–919. https://doi.org/10.1038/s41386-022-01482-3
Lopez MF, Griffin WC, Melendez RI, Becker HC (2012) Repeated cycles of chronic intermittent ethanol exposure leads to the development of tolerance to aversive effects of ethanol in C57BL/6J mice. Alcohol Clin Exp Res 36(7):1180–1187. https://doi.org/10.1111/j.1530-0277.2011.01717.x
Marcant P, Schmaltz G, Roy JC, Leconte P (1985) Long-term retention of a poorly learned saccharin aversion: evidence for an incubation effect. Behav Proc 11(1):15–20. https://doi.org/10.1016/0376-6357(85)90098-1
May CE, Haun HL, Griffin WC (2015) Sensitization and tolerance following repeated exposure to caffeine and alcohol in mice. Alcohol Clin Exp Res 39(8):1443–1452. https://doi.org/10.1111/acer.12794
McAllister DE, McAllister WR (1967) Incubation of fear: an examination of the concept. J Exp Res Pers 2(3):180–190
McMichael JS (1966) Incubation of anxiety and instrumental behavior. J Comp Physiol Psychol 61(2):208–211. https://doi.org/10.1037/h0023148
Meyer U, Chang DLT, Feldon J, Yee BK (2004) Expression of the CS- and US-pre-exposure effects in the conditioned taste aversion paradigm and their abolition following systemic amphetamine treatment in C57BL6/J mice. Neuropsychopharmacology 29(12):2140–2148. https://doi.org/10.1038/sj.npp.1300522
Morales M, Schatz KC, Anderson RI, Spear LP, Varlinskaya EI (2014) Conditioned taste aversion to ethanol in a social context: impact of age and sex. Behav Brain Res 261:323–327. https://doi.org/10.1016/j.bbr.2013.12.048
Morean ME, Corbin WR (2008) Subjective alcohol effects and drinking behavior: the relative influence of early response and acquired tolerance. Addict Behav 33(10):1306–1313. https://doi.org/10.1016/j.addbeh.2008.06.007
Morean ME, Corbin WR (2010) Subjective response to alcohol: a critical review of the literature. Alcohol Clin Exp Res 34(3):385–395. https://doi.org/10.1111/j.1530-0277.2009.01103.x
Pickens CL, Theberge FR (2014) Blockade of CB1 receptors prevents retention of extinction but does not increase low preincubated conditioned fear in the fear incubation procedure. Behav Pharmacol 25(1):23–31. https://doi.org/10.1097/FBP.0000000000000020
Pickens CL, Adams-Deutsch T, Nair SG, Navarre BM, Heilig M, Shaham Y (2009a) Effect of pharmacological manipulations of neuropeptide Y and corticotropin-releasing factor neurotransmission on incubation of conditioned fear. Neuroscience 164(4):1398–1406. https://doi.org/10.1016/j.neuroscience.2009.09.079
Pickens CL, Golden SA, Adams-Deutsch T, Nair SG, Shaham Y (2009b) Long-lasting incubation of conditioned fear in rats. Biol Psychiat 65(10):881–886. https://doi.org/10.1016/j.biopsych.2008.12.010
Pickens CL, Navarre BM, Nair SG (2010) Incubation of conditioned fear in the conditioned suppression model in rats: role of food-restriction conditions, length of conditioned stimulus, and generality to conditioned freezing. Neuroscience 169(4):1501–1510. https://doi.org/10.1016/j.neuroscience.2010.06.036
Przybysz KR, Ramirez LA, Pitock JR, Starr EM, Yang H, & Glover EJ (2024) A translational rodent model of individual differences in sensitivity to the aversive properties of ethanol. Alcohol: Clin Exp Res 1–14. https://doi.org/10.1111/acer.15267
Rabin BM, Hunt WA, Lee J (1988) Attenuation and cross-attenuation in taste aversion learning in the rat: studies with ionizing radiation, lithium chloride and ethanol. Pharmacol Biochem Behav 31(4):909–918. https://doi.org/10.1016/0091-3057(88)90404-2
Ray LA, MacKillop J, Monti PM (2010) Subjective responses to alcohol consumption as endophenotypes: advancing behavioral genetics in etiological and treatment models of alcoholism. Subst Use Misuse 45(11):1742–1765. https://doi.org/10.3109/10826084.2010.482427
Revillo DA, Arias C, Spear NE (2013) The unconditioned stimulus preexposure effect in preweanling rats in taste aversion learning: role of the training context and injection cues. Dev Psychobiol 55(2):193–204. https://doi.org/10.1002/dev.21011
Richter CP, Brailey ME (1929) Water-intake and its relation to the surface area of the body. Proc Natl Acad Sci USA 15(7):570–578. https://doi.org/10.1073/pnas.15.7.570
Risinger FO, Cunningham CL (1995) Genetic differences in ethanol-induced conditioned taste aversion after ethanol preexposure. Alcohol (Fayetteville, N.Y.) 12(6):535–539. https://doi.org/10.1016/0741-8329(95)00040-2
Roberto M, Madamba SG, Stouffer DG, Parsons LH, Siggins GR (2004) Increased GABA release in the central amygdala of ethanol-dependent rats. J Neurosc 24(45):10159–10166. https://doi.org/10.1523/JNEUROSCI.3004-04.2004
Roberto M, Gilpin NW, Siggins GR (2012) The central amygdala and alcohol: role of γ-aminobutyric acid, glutamate, and neuropeptides. Cold Spring Harb Perspect Med 2(12):a012195. https://doi.org/10.1101/cshperspect.a012195
Roche DJO, Palmeri MD, King AC (2014) Acute alcohol response phenotype in heavy social drinkers is robust and reproducible. Alcohol Clin Exp Res 38(3):844–852. https://doi.org/10.1111/acer.12280
Sachdeva A, Chandra M, Choudhary M, Dayal P, Anand KS (2016) Alcohol-related dementia and neurocognitive impairment: a review study. Int J High Risk Behav Addict 5(3):e27976. https://doi.org/10.5812/ijhrba.27976
Sandin B, Chorot P (1989) The incubation theory of fear/anxiety: experimental investigation in a human laboratory model of Pavlovian conditioning. Behav Res Ther 27(1):9–18. https://doi.org/10.1016/0005-7967(89)90114-9
Santollo J, Edwards AA (2021) How predictive is body weight on fluid intake in rats? It depends on sex. Physiol Behav 229:113262. https://doi.org/10.1016/j.physbeh.2020.113262
Schramm-Sapyta NL, Francis R, MacDonald A, Keistler C, O’Neill L, Kuhn CM (2014) Effect of sex on ethanol consumption and conditioned taste aversion in adolescent and adult rats. Psychopharmacology 231(8):1831–1839. https://doi.org/10.1007/s00213-013-3319-y
Schuckit MA, Risch SC, Gold EO (1988) Alcohol consumption, ACTH level, and family history of alcoholism. Am J Psychiatry 145(11):1391–1395. https://doi.org/10.1176/ajp.145.11.1391
Sherrill LK, Berthold C, Koss WA, Juraska JM, & Gulley JM (2011) Sex differences in the effects of ethanol pre-exposure during adolescence on ethanol-induced conditioned taste aversion in adult rats. Behav Brain Res 225(1). https://doi.org/10.1016/j.bbr.2011.07.003
Stewart RB, McBride WJ, Lumeng L, Li TK, Murphy JM (1991) Chronic alcohol consumption in alcohol-preferring P rats attenuates subsequent conditioned taste aversion produced by ethanol injections. Psychopharmacology 105(4):530–534. https://doi.org/10.1007/BF02244375
Substance Abuse and Mental Health Services Administration. (2022). Key substance use and mental health indicators in the United States: Results from the 2021 National Survey on Drug Use and Health (HHS Publication No. PEP22-07-01-005, NSDUH Series H-57). Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration. https://www.samhsa.gov/data/report/2021-nsduh-annual-national-report
Verendeev A, Riley AL (2013) The role of the aversive effects of drugs in self-administration: assessing the balance of reward and aversion in drug-taking behavior. Behav Pharmacol 24(5–6):363–374. https://doi.org/10.1097/FBP.0b013e32836413d5
Vetter-O’Hagen C, Varlinskaya E, Spear L (2009) Sex differences in ethanol intake and sensitivity to aversive effects during adolescence and adulthood. Alcohol Alcohol (Oxford, Oxfordshire) 44(6):547–554. https://doi.org/10.1093/alcalc/agp048
Walker DW, Hunter BE (1978) Short-term memory impairment following chronic alcohol consumption in rats. Neuropsychologia 16(5):545–553. https://doi.org/10.1016/0028-3932(78)90082-9
Acknowledgements
The authors would like to thank the following lab members for technical assistance: Christen Amegashie, Alex Brown, Nidhi Chetan, Kacey Clayton-Stiglbauer, Karl Bosque-Cordero, Andres Gascon, Shikun Hou, Nikki Kinarasri, Autumn Ollice, Arleen Perez Ayala, Jacqueline Sanchez, Shree Srinivasan, and Shannon Wheeler.
Funding
This work was supported by NIH grants R01 AA029130 (EJG), P50 AA022538 (EJG), R00 AA024208 (EJG), T32 AA026577 (LAR; KRP).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Ramirez, L.A., Przybysz, K.R., Pitock, J.R. et al. Attenuated incubation of ethanol-induced conditioned taste aversion in a model of dependence. Psychopharmacology (2024). https://doi.org/10.1007/s00213-024-06553-5
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s00213-024-06553-5