Abstract
Rationale
Aberrant approach-avoidance conflict processing may contribute to compulsive seeking that characterizes addiction. Exploration of the relationship between drugs of abuse and approach-avoidance behavior remains limited, especially with ethanol.
Objectives
To investigate the effects of voluntary ethanol consumption on approach-avoidance conflict behavior and to examine the potential approach/avoidance bias to predict drinking in male and female rats.
Methods
Long-Evans rats consumed ethanol for 5 weeks under the intermittent access two-bottle choice (IA2BC) paradigm. Approach-avoidance tendencies were assessed before and after IA2BC drinking using a previously established cued approach-avoidance conflict maze task and the elevated plus maze (EPM).
Results
Female rats displayed higher consumption of and preference for ethanol than males. In the conflict task, males showed greater approach bias towards cues predicting conflict than females. In females only, a median split and regression analysis of cued-conflict preference scores revealed that the more conflict-avoidant group displayed higher intake and preference for ethanol in the first few weeks of drinking. In both sexes, ethanol drinking did not affect cued-conflict preference, but ethanol exposure led to increased time spent in the central hub in the males only. Finally, anxiety levels in EPM predicted subsequent onset of ethanol drinking in males only.
Conclusions
Our results highlight sex and individual differences in both drinking and approach-avoidance bias in the face of cued conflict and further suggest that cued-conflict preference should be examined as a potential predictor of ethanol drinking. Ethanol exposure may also affect the timing of decision-making in the face of conflict.
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References
Amodeo LR, Wills DN, Sanchez-Alavez M, Nguyen W, Conti B, Ehlers CL (2018) Intermittent voluntary ethanol consumption combined with ethanol vapor exposure during adolescence increases drinking and alters other behaviors in adulthood in female and male rats. Alcohol 73:57–66. https://doi.org/10.1016/j.alcohol.2018.04.003
Aupperle RL, Melrose AJ, Francisco A, Paulus MP, Stein MB (2015) Neural substrates of approach-avoidance conflict decision-making. Hum Brain Mapp 36:449–462. https://doi.org/10.1002/hbm.22639
Bannerman DM, Sprengel R, Sanderson DJ, Mchugh SB, Rawlins JNP, Monyer H, Seeburg PH (2014) Hippocampal synaptic plasticity, spatial memory and anxiety. Nat Rev Neurosci 15:181–192. https://doi.org/10.1038/nrn3677
Barkley-Levenson AM, Cunningham CL, Smitasin PJ, Crabbe JC (2015) Rewarding and aversive effects of ethanol in high drinking in the dark selectively bred mice. Addict Biol 20:80–90. https://doi.org/10.1111/adb.12079
Bloch S, Rinker JA, Marcus MM, Mulholland PJ (2020) Absence of effects of intermittent access to alcohol on negative affective and anxiety-like behaviors in male and female C57BL/6J mice. Alcohol 88:91–99. https://doi.org/10.1016/j.alcohol.2020.07.011
Butler TR, Carter E, Weiner JL (2014) Adolescent social isolation does not lead to persistent increases in anxiety-like behavior or ethanol intake in female Long-Evans rats. Alcohol Clin Exp Res 38:2199–2207. https://doi.org/10.1111/acer.12476
Carnicella S, Ron D, Barak S (2014) Intermittent ethanol access schedule in rats as a preclinical model of alcohol abuse. Alcohol 48:243–252. https://doi.org/10.1016/j.alcohol.2014.01.006
Chappell AM, Carter E, McCool BA, Weiner JL (2013) Adolescent rearing conditions influence the relationship between initial anxiety-like behavior and ethanol drinking in male Long Evans rats. Alcohol Clin Exp Res 37:394–403. https://doi.org/10.1111/j.1530-0277.2012.01926.x
Conte R, Ladd FVL, Ladd AABL, Moreira AL, Le Sueur-Maluf L, Viana M de B, Céspedes IC (2019) Behavioral and stereological analysis of the prefrontal cortex of rats submitted to chronic alcohol intake. Behav Brain Res 362:21–27. https://doi.org/10.1016/j.bbr.2019.01.003
Cunningham CL, Clemans JM, Fidler TL (2002) Injection timing determines whether intragastric ethanol produces conditioned place preference or aversion in mice. Pharmacol Biochem Behav 72:659–668. https://doi.org/10.1016/S0091-3057(02)00734-7
Cunningham CL, Henderson CM (2000) Ethanol-induced conditioned place aversion in mice. Behav Pharmacol 11:591–602. https://doi.org/10.1097/00008877-200011000-00006
Cunningham CL, Okorn DM, Howard CE (1997) Interstimulus interval determines whether ethanol produces conditioned place preference or aversion in mice. Anim Learn Behav 25:31–42. https://doi.org/10.3758/BF03199022
Dawson DA, Goldstein RB, Saha TD, Grant BF (2015) Changes in alcohol consumption: United States, 2001-2002 to 2012-2013. Drug Alcohol Depend 148:56–61. https://doi.org/10.1016/j.drugalcdep.2014.12.016
Day HLL, Reed MM, Stevenson CW (2016) Sex differences in discriminating between cues predicting threat and safety. Neurobiol Learn Mem 133:196–203. https://doi.org/10.1016/j.nlm.2016.07.014
Ettenberg A (2004) Opponent process properties of self-administered cocaine. Neurosci Biobehav Rev 27:721–728. https://doi.org/10.1016/j.neubiorev.2003.11.009
Ettenberg A, Geist TD (1991) Animal model for investigating the anxiogenic effects of self-administered cocaine. Psychopharmacology (Berl) 103:455–461. https://doi.org/10.1007/BF02244244
Ettenberg A, Geist TD (1993) Qualitative and quantitative differences in the operant runway behavior of rats working for cocaine and heroin reinforcement. Pharmacol Biochem Behav 44:191–198. https://doi.org/10.1016/0091-3057(93)90298-8
Ewin SE, Morgan JW, Niere F, McMullen NP, Barth SH, Almonte AG, Raab-Graham KF, Weiner JL (2019) Chronic intermittent ethanol exposure selectively increases synaptic excitability in the ventral domain of the rat hippocampus. Neuroscience 398:144–157
Finn DA, Crabbe JC (1997) Exploring alcohol withdrawal syndrome. Alcohol Heal Res World 21:149–156
Fricke K, Vogel S (2020) How interindividual differences shape approach-avoidance behavior: relating self-report and diagnostic measures of interindividual differences to behavioral measurements of approach and avoidance. Neurosci Biobehav Rev 111:30–56. https://doi.org/10.1016/j.neubiorev.2020.01.008
Galaj E, Kipp BT, Floresco SB, Savage LM (2019) Persistent alterations of accumbal cholinergic interneurons and cognitive dysfunction after adolescent intermittent ethanol exposure. Neurosci 404:153–164. https://doi.org/10.1016/j.neuroscience.2019.01.062
George O, Sanders C, Freiling J, Grigoryan E, Vu S, Allen CD, Crawford E, Mandyam CD, Koob GF (2012) Recruitment of medial prefrontal cortex neurons during alcohol withdrawal predicts cognitive impairment and excessive alcohol drinking. Proc Natl Acad Sci 109:18156–18161. https://doi.org/10.1073/pnas.1116523109
Grant BF, Chou SP, Saha TD, Pickering RP, Kerridge BT, Ruan WJ, Huang B, Jung J, Zhang H, Fan A, Hasin DS (2017) Prevalence of 12-month alcohol use, high-risk drinking, and DSM-IV alcohol use disorder in the United States, 2001-2002 to 2012-2013: results from the National Epidemiologic Survey on Alcohol and Related Conditions. JAMA Psychiatry 74:911–923. https://doi.org/10.1001/jamapsychiatry.2017.2161
Grant BF, Goldstein RB, Saha TD, Patricia Chou S, Jung J, Zhang H, Pickering RP, June Ruan W, Smith SM, Huang B, Hasin DS (2015) Epidemiology of DSM-5 alcohol use disorder results from the national epidemiologic survey on alcohol and related conditions III. JAMA Psychiatry 72:757–766. https://doi.org/10.1001/jamapsychiatry.2015.0584
Gulick D, Gould TJ (2008) Varenicline ameliorates ethanol-induced deficits in learning in C57BL/6 mice. Neurobiol Learn Mem 90:230–236. https://doi.org/10.1016/j.nlm.2008.03.002
Hartwell EE, Ray LA (2013) Sex moderates stress reactivity in heavy drinkers. Addict Behav 38:2643–2646. https://doi.org/10.1016/j.addbeh.2013.06.016
Hellberg SN, Levit JD, Robinson MJF (2018) Under the influence: effects of adolescent ethanol exposure and anxiety on motivation for uncertain gambling-like cues in male and female rats. Behav Brain Res 337:17–33. https://doi.org/10.1016/J.BBR.2017.09.036
Henniger MSH, Spanagel R, Wigger A, Landgraf R, Hölter SM (2002) Alcohol self-administration in two rat lines selectively bred for extremes in anxiety-related behavior. Neuropsychopharmacology 26:729–736. https://doi.org/10.1016/S0893-133X(01)00408-0
Ito R, Lee ACH (2016) The role of the hippocampus in approach-avoidance conflict decision-making: evidence from rodent and human studies. Behav Brain Res 313:345–357. https://doi.org/10.1016/j.bbr.2016.07.039
Jadhav KS, Magistretti PJ, Halfon O, Augsburger M, Boutrel B (2017) A preclinical model for identifying rats at risk of alcohol use disorder. Sci Rep 7:9454. https://doi.org/10.1038/s41598-017-09801-1
Jeanblanc J, Sauton P, Jeanblanc V, Legastelois R, Echeverry-Alzate V, Lebourgeois S, Gonzalez-Marin M del C, Naassila M (2018) Face validity of a pre-clinical model of operant binge drinking: just a question of speed. Addict Biol 24:664–675. https://doi.org/10.1111/adb.12631
Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE (2005) Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the national comorbidity survey replication. Arch Gen Psychiatry 62:593–602. https://doi.org/10.1001/archpsyc.62.6.593
Key J, Hodgson S, Omar RZ, Jensen TK, Thompson SG, Boobis AR, Davies DS, Elliott P (2006) Meta-analysis of studies of alcohol and breast cancer with consideration of the methodological issues. Cancer Causes Control 17:759–770. https://doi.org/10.1007/s10552-006-0011-0
Klatsky AL, Armstrong MA, Friedman GD (1992) Alcohol and mortality. Ann Intern Med 117:646–654. https://doi.org/10.7326/0003-4819-117-8-646
Kliethermes CL (2005) Anxiety-like behaviors following chronic ethanol exposure. Neurosci Biobehav Rev 28:837–850. https://doi.org/10.1016/j.neubiorev.2004.11.001
Kliethermes CL, Cronise K, Crabbe JC (2004) Anxiety-like behavior in mice in two apparatuses during withdrawal from chronic ethanol vapor inhalation. Alcohol Clin Exp Res 28(7):1012–1019
Kranzler HR, Rosenthal RN (2003) Dual diagnosis: alcoholism and comorbid psychiatric disorders. Am J Addict 12:S26–S40. https://doi.org/10.1111/j.1521-0391.2003.tb00494.x
Kushner MG, Abrams K, Borchardt C (2000) The relationship between anxiety disorders and alcohol use disorders: a review of major perspectives and findings. Clin Psychol Rev 20:149–171. https://doi.org/10.1016/S0272-7358(99)00027-6
Logrip ML, Milivojevic V, Bertholomey ML, Torregrossa MM (2018) Sexual dimorphism in the neural impact of stress and alcohol. Alcohol 72:49–59. https://doi.org/10.1016/J.ALCOHOL.2018.02.002
Mann K, Ackermann K, Croissant B, Mundle G, Nakovics H, Diehl A (2005) Neuroimaging of gender differences in alcohol dependence: are women more vulnerable? Alcohol Clin Exp Res 29:896–901. https://doi.org/10.1097/01.ALC.0000164376.69978.6B
Manzo L, Gómez MJ, Callejas-Aguilera JE, Donaire R, Sabariego M, Fernández-Teruel A, Cañete A, Blázquez G, Papini MR, Torres C (2014) Relationship between ethanol preference and sensation/novelty seeking. Physiol Behav 133:53–60. https://doi.org/10.1016/J.PHYSBEH.2014.05.003
McCool BA, Chappell AM (2009) Early social isolation in male Long-Evans rats alters both appetitive and consummatory behaviors expressed during operant ethanol self-administration. Alcohol Clin Exp Res 33:273–282. https://doi.org/10.1111/j.1530-0277.2008.00830.x
Morales M, McGinnis MM, McCool BA (2015) Chronic ethanol exposure increases voluntary home cage intake in adult male, but not female, long–Evans rats. Pharmacol Biochem Behav 139:67–76
Morales M, McGinnis MM, Robinson SL, Chappell AM, McCool BA (2018) Chronic intermittent ethanol exposure modulation of Glutamatergic neurotransmission in rat lateral/Basolateral amygdala is duration-, input-, and sex-dependent. Neuroscience 371:277–287
Nguyen D, Schumacher A, Erb S, Ito R (2015) Aberrant approach-avoidance conflict resolution following repeated cocaine pre-exposure. Psychopharmacology (Berl) 232:3573–3583. https://doi.org/10.1007/s00213-015-4006-y
Orsini CA, Willis ML, Gilbert RJ, Bizon JL, Setlow B (2016) Sex differences in a rat model of risky decision making. Behav Neurosci 130:50–61. https://doi.org/10.1037/bne0000111
Peters S, Slattery DA, Flor PJ, Neumann ID, Reber SO (2013) Differential effects of baclofen and oxytocin on the increased ethanol consumption following chronic psychosocial stress in mice. Addict Biol 18:66–77. https://doi.org/10.1111/adb.12001
Pigott TA (1999) Gender differences in the epidemiology and treatment of anxiety disorders. J Clin Psychiat 60:4–15
Priddy BM, Carmack SA, Thomas LC, Vendruscolo JCM, Koob GF, Vendruscolo LF (2017) Sex, strain, and estrous cycle influences on alcohol drinking in rats. Pharmacol Biochem Behav 152:61–67. https://doi.org/10.1016/j.pbb.2016.08.001
Quintanilla ME, Callejas O, Tampier L (2001) Differences in sensitivity to the aversive effects of ethanol in low-alcohol drinking (UChA) and high-alcohol drinking (UChB) rats. Alcohol 23:177–182. https://doi.org/10.1016/S0741-8329(01)00128-8
Risinger FO, Cunningham CL (1992) Ethanol produces rapid biphasic hedonic effects. Ann N Y Acad Sci 654(1 The Neurobiol):506–508
Roeckner AR, Bowling A, Butler TR (2017) Chronic social instability increases anxiety-like behavior and ethanol preference in male Long Evans rats. Physiol Behav 173:179–187. https://doi.org/10.1016/J.PHYSBEH.2017.02.010
Rubonis AV, Colby SM, Monti PM, Rohsenow DJ, Gulliver SB, Sirota AD (1994) Alcohol cue reactivity and mood induction in male and female alcoholics. J Stud Alcohol 55:487–494. https://doi.org/10.15288/jsa.1994.55.487
Schindler AG, Tsutsui KT, Clark JJ (2014) Chronic alcohol intake during adolescence, but not adulthood, promotes persistent deficits in risk-based decision making. Alcohol Clin Exp Res 38:1622–1629. https://doi.org/10.1111/acer.12404
Schneider P, Ho YJ, Spanagel R, Pawlak CR (2011) A novel elevated plus-maze procedure to avoid the one-trial tolerance problem. Front Behav Neurosci 5:43. https://doi.org/10.3389/fnbeh.2011.00043
Schumacher A, Vlassov E, Ito R (2016) The ventral hippocampus, but not the dorsal hippocampus is critical for learned approach-avoidance decision making. Hippocampus 26:530–542. https://doi.org/10.1002/hipo.22542
Simms JA, Steensland P, Medina B, Abernathy KE, Chandler LJ, Wise R, Bartlett SE (2008) Intermittent access to 20% ethanol induces high ethanol consumption in Long-Evans and Wistar rats. Alcohol Clin Exp Res 32:1816–1823. https://doi.org/10.1111/j.1530-0277.2008.00753.x
Spanagel R, Montkowski A, Allingham K, Shoaib M, Holsboer F, Landgraf R (1995) Anxiety: a potential predictor of vulnerability to the initiation of ethanol self-administration in rats. Psychopharmacology (Berl) 122:369–373. https://doi.org/10.1007/BF02246268
Spoelder M, Flores Dourojeanni JP, de Git KCG, Baars AM, Lesscher HMB, Vanderschuren LJMJ (2017) Individual differences in voluntary alcohol intake in rats: relationship with impulsivity, decision making and Pavlovian conditioned approach. Psychopharmacology (Berl) 234:2177–2196. https://doi.org/10.1007/s00213-017-4617-6
Stein JS, Renda CR, Barker SM, Liston KJ, Shahan TA, Madden GJ (2015) Impulsive choice predicts anxiety-like behavior, but not alcohol or sucrose consumption, in male Long-Evans rats. Alcohol Clin Exp Res 39:932–940. https://doi.org/10.1111/acer.12713
Stragier E, Martin V, Davenas E, Poilbout C, Mongeau R, Corradetti R, Lanfumey L (2015) Brain plasticity and cognitive functions after ethanol consumption in C57BL/6J mice. Transl Psychiatry 5:e696. https://doi.org/10.1038/tp.2015.183
Urbano-Márquez A, Estruch R, Fernandez-Sola J, Nicolas, JM, Pare JC, Rubin E (1995) The greater risk of alcoholic cardiomyopathy and myopathy in women compared with men. JAMA J Am Med Assoc 274:149–154. https://doi.org/10.1001/jama.1995.03530020067034
Valdez GR, Roberts AJ, Chan K, Davis H, Brennan M, Zorrilla EP, Koob GF (2002) Increased ethanol self-administration and anxiety-like behavior during acute ethanol withdrawal and protracted abstinence: regulation by Corticotropin-releasing factor. Alcohol Clin Exp Res 26(10):1494–1501
van den Bos R, Jolles J, van der Knaap L, Baars A, de Visser L (2012) Male and female Wistar rats differ in decision-making performance in a rodent version of the Iowa gambling task. Behav Brain Res 234(2):375–379
Verendeev A, Riley AL (2012) Conditioned taste aversion and drugs of abuse: history and interpretation. Neurosci Biobehav Rev 36:2193–2205. https://doi.org/10.1016/J.NEUBIOREV.2012.08.004
Verendeev A, Riley AL (2013) The role of the aversive effects of drugs in self-administration. Behav Pharmacol 24:363–374. https://doi.org/10.1097/FBP.0b013e32836413d5
West RK, Maynard ME, Leasure JL (2018) Binge ethanol effects on prefrontal cortex neurons, spatial working memory and task-induced neuronal activation in male and female rats. Physiol Behav 188:79–85. https://doi.org/10.1016/j.physbeh.2018.01.027
Wise RA (1973) Voluntary ethanol intake in rats following exposure to ethanol on various schedules. Psychopharmacologia 29:203–210. https://doi.org/10.1007/BF00414034
Xie Q, Buck LA, Bryant KG, Barker JM (2019) Sex differences in ethanol reward seeking under conflict in mice. Alcohol Clin Exp Res 43:1556–1566. https://doi.org/10.1111/acer.14070
Acknowledgements
The authors acknowledge Ada Nexha, Marc Danzell Lopez, and Alyssa Ho for their assistance in data collection and Jeff Kates for his help in reviewing the manuscript.
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This work was funded by the Canada Institutes of Health Research (156070).
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McNamara, T.A., Ito, R. Relationship between voluntary ethanol drinking and approach-avoidance biases in the face of motivational conflict: novel sex-dependent associations in rats. Psychopharmacology 238, 1817–1832 (2021). https://doi.org/10.1007/s00213-021-05810-1
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DOI: https://doi.org/10.1007/s00213-021-05810-1