Chronic social isolation and chronic variable stress during early development induce later elevated ethanol intake in adult C57BL/6J mice
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Experience with stress situations during early development can have long-lasting effects on stress- and anxiety-related behaviors. Importantly, this can also favor drug self-administration. These studies examined the effects of chronic social isolation and/or variable stress experiences during early development on subsequent voluntary ethanol intake in adult male and female C57BL/6J mice. The experiments were conducted to evaluate the effect of chronic isolation between weaning and adulthood (Experiment 1), chronic isolation during adulthood (Experiment 2), and chronic variable stress (CVS) alone or in combination with chronic social isolation between weaning and adulthood (Experiment 3) on subsequent voluntary ethanol intake. Mice were born in our facility and were separated into two housing conditions: isolate housed (one mouse/cage) or group housed (four mice/cage) according to sex. Separate groups were isolated for 40 days starting either at time of weaning postnatal day 21 (PD 21) (early isolation, Experiments 1 and 3) or at adulthood (PD 60: late isolation, Experiment 2). The effects of housing condition on subsequent ethanol intake were assessed starting at around PD 65 in Experiments 1 and 3 or PD 105 days in Experiment 2. In Experiment 3, starting at PD 32, isolate-housed and group-housed mice were either subjected to CVS or left undisturbed. CVS groups experienced random presentations of mild stressors for 14 days, including exposure to an unfamiliar open field, restraint, physical shaking, and forced swim, among others. All mice were tested for ethanol intake for 14 days using a two-bottle choice (ethanol 15% vol/vol vs. water) for a 2-h limited access procedure. Early social isolation resulted in greater ethanol intake compared with the corresponding group-housed mice (Experiment 1). In contrast, social isolation during adulthood (late isolation) did not increase subsequent ethanol intake compared with the corresponding group-housed mice (Experiment 2). For mice that did not experience CVS, early social isolation resulted in greater ethanol intake compared with group-housed mice (Experiment 3). CVS subsequently resulted in a significant increase in ethanol intake in group-housed mice, but CVS failed to further increase ethanol intake in mice that experienced chronic social isolation early in life (Experiment 3). Overall, female mice consumed more ethanol than males, whether isolated (early or late) or group housed. These results indicate that early but not late social isolation can subsequently influence ethanol consumption in C57BL/6J mice. Thus, the developmental timing of chronic social isolation appears to be an important factor in defining later effects on ethanol self-administration behavior. In addition, experience with CVS early in life results in elevated ethanol intake later in adulthood. Taken together, these results emphasize the important role of early stress experiences that modulate later voluntary ethanol intake during adulthood.
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Adolescent but not adult social isolation increases alcohol consumption in mice.
“In regard to alcohol use, adolescent but not adult, social isolation has been shown to increase alcohol consumption in mice (Lopez et al. 2011), and rats are well documented to increase their alcohol consumption after adolescent social isolation (Schenk et al. 1990; Hall et al. 1998; Chappell et al. 2013; reviewed further in Butler et al. 2016).”
From Decoding the bidirectional links between alcohol misuse and aggression: toward a unified translational framework (2026) · cites this paper as Lopez et al. 2011
Chronic stress during adolescence increases alcohol preference and overall alcohol consumption in adulthood in mice.
“In mice, chronic stress during adolescence has also been shown to increase alcohol preference and overall alcohol consumption in adulthood (Chester, Barrenha, Hughes, & Keuneke, 2008; Lopez, Doremus-Fitzwater, & Becker, 2011).”
From Cued for Risk: Evidence for an Incentive Sensitization Framework to Explain the Interplay between Stress and Anxiety, Substance Abuse, and Reward Uncertainty in Disordered Gambling Behavior (2019) · cites this paper as Lopez, Doremus-Fitzwater, & Becker, 2011
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Cites
The adolescent brain and age-related behavioral manifestations
Spear, L. P. (2000) · Neuroscience & Biobehavioral Reviews · doi:10.1016/s0149-7634(00)00014-2 · Cited by 5,433 · see citing works
Adolescent cortical development: A critical period of vulnerability for addiction
Crews, F., He, J., & Hodge, C. (2007) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2006.12.001 · Cited by 1,091 · see citing works
Dube, S. R., Miller, J. W., Brown, D. W., Giles, W. H., Felitti, V. J., Dong, M., & Anda, R. F. (2006) · Journal of Adolescent Health · doi:10.1016/j.jadohealth.2005.06.006 · Cited by 698 · see citing works
Limbic Regulation of Hypothalamo‐Pituitary‐Adrenocortical Function during Acute and Chronic Stress
Jankord, R., & Herman, J. P. (2008) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1410.012 · Cited by 578 · see citing works
Effect of social isolation on stress-related behavioural and neuroendocrine state in the rat
Weiss, I. C., Pryce, C. R., Jongen-Rêlo, A. L., Nanz-Bahr, N. I., & Feldon, J. (2004) · Behavioural Brain Research · doi:10.1016/j.bbr.2003.10.015 · Cited by 512 · cited 1× · see citing works
“This chronic stress situation has, indeed, been shown to have long-lasting effects on various behavioral and neural functions (Lapiz et al., 2003; Weiss et al., 2004).”
Huot, R. L., Thrivikraman, K. V., Meaney, M. J., & Plotsky, P. M. (2001) · Psychopharmacology · doi:10.1007/s002130100701 · Cited by 506 · see citing works
Becker, H. C., & Lopez, M. F. (2004) · Alcoholism Clinical and Experimental Research · doi:10.1097/01.alc.0000149977.95306.3a · Cited by 419 · see citing works
Self-citationAlcohol dependence and anxiety disorders: what is the relationship?
Schuckit, M. A., & HESSELBROCK, V. M. (1994) · American Journal of Psychiatry · doi:10.1176/ajp.151.12.1723 · Cited by 383 · see citing works
Isgor, C., Kabbaj, M., Akil, H., & Watson, S. J. (2004) · Hippocampus · doi:10.1002/hipo.10207 · Cited by 341 · see citing works
Social stress, therapeutics and drug abuse: Preclinical models of escalated and depressed intake
MICZEK, K., YAP, J., & COVINGTONIII, H. (2008) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2008.07.006 · Cited by 338 · see citing works
Lapiz, M. D. S., Fulford, A., Muchimapura, S., Mason, R., Parker, T., & Marsden, C. A. (2003) · Neuroscience and Behavioral Physiology · doi:10.1023/a:1021171129766 · Cited by 305 · see citing works
Bardo, M. T., Klebaur, J. E., Valone, J. M., & Deaton, C. (2001) · Psychopharmacology · doi:10.1007/s002130100720 · Cited by 292 · see citing works
Stress, alcohol and drug interaction: an update of human research
Uhart, M., & Wand, G. S. (2008) · Addiction Biology · doi:10.1111/j.1369-1600.2008.00131.x · Cited by 234 · see citing works
Leussis, M. P., & Andersen, S. L. (2008) · Synapse · doi:10.1002/syn.20462 · Cited by 220 · see citing works
Genetic and Environmental Predictors of Early Alcohol Use
Kaufman, J., Yang, B.-Z., Douglas-Palumberi, H., Crouse-Artus, M., Lipschitz, D., Krystal, J. H., & Gelernter, J. (2007) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.06.039 · Cited by 216 · see citing works
Adolescent brain development and animal models
SPEAR, L. P. (2004) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1308.002 · Cited by 215 · see citing works
Genetic and Environmental Influences on the Development of Alcoholism
Enoch, M. (2006) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1376.019 · Cited by 214 · see citing works
Ontogeny of fear-, anxiety- and depression-related behavior across adolescence in C57BL/6J mice
HEFNER, K., & HOLMES, A. (2007) · Behavioural Brain Research · doi:10.1016/j.bbr.2006.10.001 · Cited by 183 · see citing works
Ostrander, M. M., Ulrich‐Lai, Y. M., Choi, D. C., Richtand, N. M., & Herman, J. P. (2006) · Endocrinology · doi:10.1210/en.2005-1041 · Cited by 168 · see citing works
McCool, B. A., & Chappell, A. M. (2008) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2008.00830.x · Cited by 160 · see citing works
Howes, S. R., Dalley, J. W., Morrison, C. H., Robbins, T. W., & Everitt, B. J. (2000) · Psychopharmacology · doi:10.1007/s002130000451 · Cited by 156 · see citing works
Social behavior, dominance, and social deprivation of rats determine drug choice
Wolffgramm, J., & Heyne, A. (1991) · Pharmacology Biochemistry and Behavior · doi:10.1016/0091-3057(91)90297-f · Cited by 155 · see citing works
Ethanol Consumption by C57BL/6 Mice
Middaugh, L. D., Kelley, B. M., Bandy, A. E., & McGroarty, K. K. (1999) · Alcohol · doi:10.1016/s0741-8329(98)00055-x · Cited by 152 · see citing works
Early environmental stress and biological vulnerability to drug abuse
Gordon, H. W. (2002) · Psychoneuroendocrinology · doi:10.1016/s0306-4530(01)00039-7 · Cited by 148 · see citing works
Chronic stress‐induced neurotransmitter plasticity in the PVN
Flak, J. N., Ostrander, M. M., Tasker, J. G., & Herman, J. P. (2009) · The Journal of Comparative Neurology · doi:10.1002/cne.22142 · Cited by 143 · see citing works
Free choice ethanol intake of laboratory rats under different social conditions
Wolffgramm, J. (1990) · Psychopharmacology · doi:10.1007/bf02244132 · Cited by 139 · see citing works
Griffin, W. C., Lopez, M. F., Yanke, A. B., Middaugh, L. D., & Becker, H. C. (2008) · Psychopharmacology · doi:10.1007/s00213-008-1324-3 · Cited by 136 · see citing works
Self-citationAge-dependent effects of isolation housing on the self-administration of ethanol in laboratory rats
Schenk, S., Gorman, K., & Amit, Z. (1990) · Alcohol · doi:10.1016/0741-8329(90)90090-y · Cited by 110 · see citing works
Maternal separation stress in male mice: long-term increases in alcohol intake
Cruz, F. C., Quadros, I. M., da S. Planeta, C., & Miczek, K. A. (2008) · Psychopharmacology · doi:10.1007/s00213-008-1307-4 · Cited by 109 · see citing works
Sex difference in psychological behavior changes induced by long-term social isolation in mice
Guo, M., Wu, C. F., Liu, W., Yang, J., & Chen, D. (2003) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2003.09.027 · Cited by 107 · see citing works
McCormick, C. M., Merrick, A., Secen, J., & Helmreich, D. L. (2006) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2006.01515.x · Cited by 106 · see citing works
McCormick, C. M., Robarts, D., Gleason, E., & Kelsey, J. E. (2004) · Hormones and Behavior · doi:10.1016/j.yhbeh.2004.05.004 · Cited by 105 · see citing works
Hall, F. S., Huang, S., Pert, A., Linnoila, M., & Fong, G. W. (1998) · Psychopharmacology · doi:10.1007/s002130050706 · Cited by 104 · see citing works
Hall, F. S., Huang, S., Fong, G., Pert, A., & Linnoila, M. (1998) · Psychopharmacology · doi:10.1007/s002130050705 · Cited by 102 · see citing works
Cullinan, W. E., & Wolfe, T. J. (2000) · Brain Research · doi:10.1016/s0006-8993(00)03000-6 · Cited by 102 · see citing works
Leussis, M. P., Lawson, K., Stone, K., & Andersen, S. L. (2008) · Synapse · doi:10.1002/syn.20483 · Cited by 95 · see citing works
Zurita, A., Martijena, I. D., Cuadra, G. R., Brandão, M. L., & Molina, V. A. (2000) · Behavioural Brain Research · doi:10.1016/s0166-4328(00)00302-8 · Cited by 94 · see citing works
Differential Rearing Conditions Alter Operant Responding for Ethanol in Outbred Rats
Deehan, G. A., Cain, M. E., & Kiefer, S. W. (2007) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2007.00466.x · Cited by 87 · see citing works
Stress during adolescence alters behavioral sensitization to amphetamine
Kabbaj, M., Isgor, C., Watson, S. J., & Akil, H. (2002) · Neuroscience · doi:10.1016/s0306-4522(02)00188-4 · Cited by 76 · see citing works
The effects of individual housing on mice and rats: a review
Krohn, T. C., Sørensen, D. B., Ottesen, J. L., & Hansen, A. (2006) · Animal Welfare · doi:10.1017/s0962728600030669 · Cited by 76 · see citing works
Effect of early rearing conditions on alcohol drinking and 5-HT1A receptor function in C57BL/6J mice
Advani, T., Hensler, J. G., & Koek, W. (2006) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145706007401 · Cited by 75 · see citing works
Lepsch, L. B., Gonzalo, L., Magro, F., DeLucia, R., Scavone, C., & Planeta, C. S. (2005) · Addiction Biology · doi:10.1080/13556210500269366 · Cited by 74 · see citing works
Lodge, D. J., & Lawrence, A. J. (2003) · Neuroscience · doi:10.1016/s0306-4522(02)00793-5 · Cited by 73 · see citing works
Operant Ethanol Reward in C57BL/6 Mice
Middaugh, L. D., & Kelley, B. M. (1999) · Alcohol · doi:10.1016/s0741-8329(98)00056-1 · Cited by 71 · see citing works
Sillaber, I., & Henniger, M. S. H. (2004) · Annals of Medicine · doi:10.1080/07853890410018862 · Cited by 65 · see citing works
Enhanced cocaine self-administration in adult rats with adolescent isolation experience
Ding, Y., Kang, L., Li, B., & Ma, L. (2005) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2005.11.007 · Cited by 64 · see citing works
Increased alcohol drinking in isolate-housed alcohol-preferring rats.
Ehlers, C. L., Walker, B. M., Pian, J. P., Roth, J., & Slawecki, C. J. (2007) · Behavioral Neuroscience · doi:10.1037/0735-7044.121.1.111 · Cited by 63 · see citing works
Roman, E., Gustafsson, L., Hyytiä, P., & Nylander, I. (2005) · Alcoholism Clinical and Experimental Research · doi:10.1097/01.alc.0000158933.70242.fc · Cited by 59 · see citing works
Chester, J. A., Barrenha, G. D., Hughes, M. L., & Keuneke, K. J. (2008) · Alcoholism: Clinical and Experimental Research · doi:10.1111/j.1530-0277.2008.00763.x · Cited by 54 · see citing works
Social experience alters the response to social stress in mice
Avitsur, R., Stark, J. L., Dhabhar, F. S., Kramer, K. A., & Sheridan, J. F. (2003) · Brain Behavior and Immunity · doi:10.1016/s0889-1591(03)00034-5 · Cited by 53 · see citing works
Lin, D. C.-H., Bruijnzeel, A. W., Schmidt, P., & Markou, A. (2002) · Neuroscience · doi:10.1016/s0306-4522(02)00366-4 · Cited by 49 · see citing works
Juárez, J., & Vázquez‐Cortés, C. (2003) · Developmental Psychobiology · doi:10.1002/dev.10133 · Cited by 46 · see citing works
Nash, J. F., & Maickel, R. P. (1988) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/0278-5846(88)90010-3 · Cited by 46 · see citing works
Ostrander, M. M., Ulrich‐Lai, Y. M., Choi, D. C., Flak, J. N., Richtand, N. M., & Herman, J. P. (2009) · Stress · doi:10.3109/10253890802641966 · Cited by 45 · see citing works
Influence of rearing conditions on voluntary ethanol intake and response to stress in rats
Rockman, G. E., Hall, A. M., Markert, L. E., & Glavin, G. B. (1988) · Behavioral and Neural Biology · doi:10.1016/s0163-1047(88)90506-7 · Cited by 42 · see citing works
Zhu, S., Pham, T. M., Åberg, E., Brené, S., Winblad, B. G., Mohammed, A. H. S., & Baumans, V. (2005) · Behavioural Brain Research · doi:10.1016/j.bbr.2005.02.038 · Cited by 42 · see citing works
Gariépy, J., Gendreau, P. L., Mailman, R. B., Tancer, M. E., & Lewis, M. H. (1995) · Pharmacology Biochemistry and Behavior · doi:10.1016/0091-3057(95)00028-u · Cited by 38 · see citing works
Effects of early weaning and social isolation on subsequent alcohol intake in rats
Fahlke, C., Hȧrd, E., & Eriksson, C. J. P. (1997) · Alcohol · doi:10.1016/s0741-8329(96)00141-3 · Cited by 30 · see citing works
Increased sensitivity to chronic ethanol in isolated mice
Yanai, J., & Ginsburg, B. E. (1976) · Psychopharmacology · doi:10.1007/bf00421390 · Cited by 29 · see citing works
Molina, V. A., Heyser, C. J., & SPEAR, L. P. (1994) · European Journal of Pharmacology · doi:10.1016/0014-2999(94)90009-4 · Cited by 29 · see citing works
Blood alcohol concentrations after scheduled access in high-alcohol-preferring mice
Grahame, N. J., & Grose, A. M. (2003) · Alcohol · doi:10.1016/j.alcohol.2003.08.002 · Cited by 26 · see citing works
Sex Differences in Voluntary Drinking by Long Evans Rats following Early Stress
Lancaster, F. E. (1998) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.1998.tb03875.x · Cited by 25 · see citing works
Winkler, A., Roske, I., Furkert, J., et al. (1995) · Alcohol and Alcoholism · doi:10.1093/oxfordjournals.alcalc.a045719 · Cited by 25 · see citing works
Alcohol Dependence and Anxiety Disorders
Schuckit, M. A., & HESSELBROCK, V. M. (2004) · FOCUS The Journal of Lifelong Learning in Psychiatry · doi:10.1176/foc.2.3.440 · Cited by 22 · see citing works
Sprague, J. E., & Maickel, R. P. (1994) · Life Sciences · doi:10.1016/0024-3205(94)90043-4 · Cited by 20 · see citing works
The age of drinking onset and housing condition influences rat alcohol drinking behavior.
Yoshimoto, K., Komura, S., & Yasuhara, M. (2003) · PubMed · Cited by 5 · see citing works
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- Lopez MF Becker HC 2003 Gender differences in ethanol intake prior to and following repeated chronic ethanol exposure and withdrawal in C57BL/6J mice Alcohol Clin Exp Res 27 15A 15608599
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- Authors
- Lopez, M. F., Doremus-Fitzwater, T. L., & Becker, H. C.
- Affiliations
- Medical University of South Carolina (US)
- Corresponding author
- Lopez, Marcelo F.
- Venue
- Alcohol
- Publisher
- Elsevier BV
- Published
- 2011-06
- Volume
- 45
- Issue
- 4
- Pages
- 355-364
- ISSN
- 0741-8329 (ISSN-L)
- PMC
- PMC3013234
- OpenAlex
- W1996943462
- Cited by
- 146
- References
- 66
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 9 · 2023: 7 · 2022: 7 · 2021: 6 · 2020: 15 · 2019: 11 · 2018: 13 · 2017: 9 · 2016: 16 · 2015: 5 · 2014: 11 · 2013: 10 · 2012: 5
- FWCI
- 2.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Alcohol (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Medical University of South Carolina
- National Institute on Alcohol Abuse and Alcoholism (AA 10761, AA014095, U01AA014095, P50AA010761, T32AA007474, AA-007474)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Keywords
- chronic social isolation, chronic variable stress, early life stress, ethanol consumption, voluntary ethanol consumption, sex differences, C57BL/6J mice, housing conditions, weaning, stress resilience, self-administration, restraint stress, forced swim stress, sex differences in alcohol consumption, sex differences in stress response
- MeSH terms
- Alcohol Drinking, Ethanol, Animals, Female, Male, Mice, Inbred C57BL, Self Administration, Sex Factors, Social Isolation, Stress, Psychological, Weaning, Mice
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