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An investigation of the behavioral actions of ethanol across adolescence in mice

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Abstract

Rationale

The transition from adolescence into adulthood is characterized by rapid maturation of brain systems mediating reward and by increasing experimentation with drugs of abuse including ethanol (EtOH). Previous studies have found marked differences in sensitivity to the behavioral effects of EtOH in adolescent rats as compared to adults, but relatively few studies have been conducted in mice.

Objectives

The present study examined sensitivity to various behavioral effects of EtOH in C57BL/6J mice at various stages of adolescence/adulthood (4, 6, 8 weeks old). Ages were compared for locomotor stimulant (open field), anxiolytic-like (elevated plus-maze), memory-impairing (Pavlovian fear conditioning) and ataxic (accelerating rotarod) effects of EtOH, and the sedative/hypnotic (sleep time) effects of EtOH and pentobarbital. EtOH self-administration was compared using a two-bottle choice paradigm. Measures of EtOH metabolism were also obtained.

Results

Early adolescent mice exhibited increased sensitivity to locomotor stimulant (1.5 g/kg), anxiolytic-like (1.5 g/kg) and ataxic (1.5–2.5 g/kg), but not memory impairing (2.0 g/kg), effects of EtOH relative to adults. Early adolescent, and to some extent peri-adolescent, mice were less sensitive than adults to the sedative/hypnotic effects of EtOH (3.5–4.5 g/kg), but not pentobarbital (40–50 mg/kg). Early adolescent mice showed lower EtOH preference, but not EtOH consumption, than adults. Blood EtOH concentrations were higher at early time points and lower at later time points after (3.0 g/kg) EtOH injection in early and peri-adolescents relative to adults.

Conclusions

Present data demonstrate that sensitivity to the acute intoxicating effects of EtOH changes across mouse adolescent development in a behavior-dependent manner.

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References

  • Arnett JJ (1999) Adolescent storm and stress, reconsidered. Am Psychol 54:317–326

    Article  PubMed  CAS  Google Scholar 

  • Blednov YA, Jung S, Alva H, Wallace D, Rosahl T, Whiting PJ, Harris RA (2003) Deletion of the alpha1 or beta2 subunit of GABAA receptors reduces actions of alcohol and other drugs. J Pharmacol Exp Ther 304:30–36

    Article  PubMed  CAS  Google Scholar 

  • Blizard DA, Vandenbergh DJ, Jefferson AL, Chatlos CD, Vogler GP, McClearn GE (2004) Effects of periadolescent ethanol exposure on alcohol preference in two BALB substrains. Alcohol 34:177–185

    Article  PubMed  CAS  Google Scholar 

  • Boyce-Rustay JM, Holmes A (2005) Functional roles of NMDA receptor NR2A and NR2B subunits in the acute intoxicating effects of ethanol in mice. Synapse 56:222–225

    Article  PubMed  CAS  Google Scholar 

  • Boyce-Rustay JM, Holmes A (2006) Ethanol-related behaviors in NMDA receptor NR2A KO mice. Psychopharmacology (Berl) 187:455–466

    Article  CAS  Google Scholar 

  • Brasser SM, Spear NE (2002) Physiological and behavioral effects of acute ethanol hangover in juvenile, adolescent, and adult rats. Behav Neurosci 116:305–320

    Article  PubMed  Google Scholar 

  • Brunell SC, Spear LP (2005) Effect of stress on the voluntary intake of a sweetened ethanol solution in pair-housed adolescent and adult rats. Alcohol Clin Exp Res 29:1641–1653

    Article  PubMed  Google Scholar 

  • Chambers RA, Taylor JR, Potenza MN (2003) Developmental neurocircuitry of motivation in adolescence: a critical period of addiction vulnerability. Am J Psychiatry 160:1041–1052

    Article  PubMed  Google Scholar 

  • Church AC, Fuller JL, Dann L (1979) Alcohol intake in selected lines of mice: importance of sex and genotype. J Comp Physiol Psychol 93:242–246

    Article  PubMed  CAS  Google Scholar 

  • Crabbe JC, Metten P, Cameron AJ, Wahlsten D (2005) An analysis of the genetics of alcohol intoxication in inbred mice. Neurosci Biobehav Rev 28:785–802

    Article  PubMed  CAS  Google Scholar 

  • Crabbe JC, Phillips TJ, Harris RA, Arends MA, Koob GF (2006) Alcohol-related genes: contributions from studies with genetically engineered mice. Addict Biol 11:195–269

    Article  PubMed  CAS  Google Scholar 

  • Cryan JF, Holmes A (2005) The ascent of mouse: advances in modelling human depression and anxiety. Nat Rev Drug Discov 4:775–790

    Article  PubMed  CAS  Google Scholar 

  • Daws LC, Montanez S, Munn JL, Owen AM, Baganz NL, Boyce-Rustay J, Millstein RA, Wiedholz L, Murphy DL, Holmes A (2006) Ethanol inhibits clearance of brain serotonin by a serotonin transporter-independent mechanism. J Neurosci 26(24):6431–6438

    Article  PubMed  CAS  Google Scholar 

  • De Bellis MD, Clark DB, Beers SR, Soloff PH, Boring AM, Hall J, Kersh A, Keshavan MS (2000) Hippocampal volume in adolescent-onset alcohol use disorders. Am J Psychiatry 157:737–744

    Article  PubMed  Google Scholar 

  • De Bellis MD, Narasimhan A, Thatcher DL, Keshavan MS, Soloff P, Clark DB (2005) Prefrontal cortex, thalamus, and cerebellar volumes in adolescents and young adults with adolescent-onset alcohol use disorders and comorbid mental disorders. Alcohol Clin Exp Res 29:1590–1600

    Article  PubMed  Google Scholar 

  • DeWit DJ, Adlaf EM, Offord DR, Ogborne AC (2000) Age at first alcohol use: a risk factor for the development of alcohol disorders. Am J Psychiatry 157:745–750

    Article  PubMed  CAS  Google Scholar 

  • Dohler KD, Wuttke W (1975) Changes with age in levels of serum gonadotropins, prolactin and gonadal steroids in prepubertal male and female rats. Endocrinology 97:898–907

    Article  PubMed  CAS  Google Scholar 

  • Doremus TL, Brunell SC, Varlinskaya EI, Spear LP (2003) Anxiogenic effects during withdrawal from acute ethanol in adolescent and adult rats. Pharmacol Biochem Behav 75:411–418

    Article  PubMed  CAS  Google Scholar 

  • Doremus TL, Brunell SC, Rajendran P, Spear LP (2005) Factors influencing elevated ethanol consumption in adolescent relative to adult rats. Alcohol Clin Exp Res 29:1796–1808

    Article  PubMed  Google Scholar 

  • Ernst AJ, Dempster JP, Yee R, Dennis C, Nakano L (1976) Alcohol toxicity, blood alcohol concentration and body water in young and adult rats. J Stud Alcohol 37:347–356

    PubMed  CAS  Google Scholar 

  • Estroff TW, Schwartz RH, Hoffmann NG (1989) Adolescent cocaine abuse. Addictive potential, behavioral and psychiatric effects. Clin Pediatr (Phila) 28:550–555

    Article  CAS  Google Scholar 

  • Grant BF, Dawson DA (1997) Age at onset of alcohol use and its association with DSM-IV alcohol abuse and dependence: results from the National Longitudinal Alcohol Epidemiologic Survey. J Subst Abuse 9:103–110

    Article  PubMed  CAS  Google Scholar 

  • Hefner KH, Holmes A (2006) Ontogeny of fear-, anxiety- and depression-related behavior across adolescence in C57BL/6J mice. Behav Brain Res (in press)

  • Ho A, Chin AJ, Dole VP (1989) Early experience and the consumption of alcohol by adult C57BL/6J mice. Alcohol 6:511–515

    Article  PubMed  CAS  Google Scholar 

  • Hollstedt C, Olsson O, Rydberg U (1977) The effect of alcohol on the developing organism. Genetical, teratological and physiological aspects. Med Biol 55:1–14

    PubMed  CAS  Google Scholar 

  • Hollstedt C, Olsson O, Rydberg U (1980) Effects of ethanol on the developing rat. II. Coordination as measured by the tilting-plane test. Med Biol 58:164–168

    PubMed  CAS  Google Scholar 

  • Holmes A (2001) Targeted gene mutation approaches to the study of anxiety-like behavior in mice. Neurosci Biobehav Rev 25:261–273

    Article  PubMed  CAS  Google Scholar 

  • Kakihana R, McClearn GE (1963) Development of alcohol preference in Balb/C mice. Nature 199:511–512

    Article  PubMed  CAS  Google Scholar 

  • Keir WJ, Deitrich RA (1990) Development of central nervous system sensitivity to ethanol and pentobarbital in short- and long-sleep mice. J Pharmacol Exp Ther 254:831–835

    PubMed  CAS  Google Scholar 

  • Kelly SJ, Bonthius DJ, West JR (1987) Developmental changes in alcohol pharmacokinetics in rats. Alcohol Clin Exp Res 11:281–286

    Article  PubMed  CAS  Google Scholar 

  • Laviola G, Macri S, Morley-Fletcher S, Adriani W (2003) Risk-taking behavior in adolescent mice: psychobiological determinants and early epigenetic influence. Neurosci Biobehav Rev 27:19–31

    Article  PubMed  Google Scholar 

  • Lenroot RK, Giedd JN (2006) Brain development in children and adolescents: insights from anatomical magnetic resonance imaging. Neurosci Biobehav Rev 30(6):718–729

    Article  PubMed  Google Scholar 

  • Little PJ, Kuhn CM, Wilson WA, Swartzwelder HS (1996) Differential effects of ethanol in adolescent and adult rats. Alcohol Clin Exp Res 20:1346–1351

    Article  PubMed  CAS  Google Scholar 

  • Lovinger DM, Crabbe JC (2005) Laboratory models of alcoholism: treatment target identification and insight into mechanisms. Nat Neurosci 8:1471–1480

    Article  PubMed  CAS  Google Scholar 

  • Maas JW Jr, Vogt SK, Chan GC, Pineda VV, Storm DR, Muglia LJ (2005) Calcium-stimulated adenylyl cyclases are critical modulators of neuronal ethanol sensitivity. J Neurosci 25:4118–4126

    Article  PubMed  CAS  Google Scholar 

  • Monti PM, Miranda R Jr, Nixon K, Sher KJ, Swartzwelder HS, Tapert SF, White A, Crews FT (2005) Adolescence: booze, brains, and behavior. Alcohol Clin Exp Res 29:207–220

    Article  PubMed  Google Scholar 

  • Moy SS, Duncan GE, Knapp DJ, Breese GR (1998) Sensitivity to ethanol across development in rats: comparison to [3H]zolpidem binding. Alcohol Clin Exp Res 22:1485–1492

    PubMed  CAS  Google Scholar 

  • Naassila M, Ledent C, Daoust M (2002) Low ethanol sensitivity and increased ethanol consumption in mice lacking adenosine A2A receptors. J Neurosci 22:10487–10493

    PubMed  CAS  Google Scholar 

  • Newlin DB, Thomson JB (1990) Alcohol challenge with sons of alcoholics: a critical review and analysis. Psychol Bull 108:383–402

    Article  PubMed  CAS  Google Scholar 

  • O’Malley PM, Johnston LD, Bachman JG (1998) Alcohol use among adolescents. Alcohol Health Res World 22:85–93

    PubMed  CAS  Google Scholar 

  • Palmer AA, Sharpe AL, Burkhart-Kasch S, McKinnon CS, Coste SC, Stenzel-Poore MP, Phillips TJ (2004) Corticotropin-releasing factor overexpression decreases ethanol drinking and increases sensitivity to the sedative effects of ethanol. Psychopharmacology (Berl) 176:386–397

    Article  CAS  Google Scholar 

  • Philpot RM, Badanich KA, Kirstein CL (2003) Place conditioning: age-related changes in the rewarding and aversive effects of alcohol. Alcohol Clin Exp Res 27:593–599

    PubMed  CAS  Google Scholar 

  • Schuckit MA (1985) Behavioral effects of alcohol in sons of alcoholics. Recent Dev Alcohol 3:11–19

    PubMed  CAS  Google Scholar 

  • Siegmund S, Vengeliene V, Singer MV, Spanagel R (2005) Influence of age at drinking onset on long-term ethanol self-administration with deprivation and stress phases. Alcohol Clin Exp Res 29:1139–1145

    Article  PubMed  Google Scholar 

  • Silveri MM, Spear LP (1998) Decreased sensitivity to the hypnotic effects of ethanol early in ontogeny. Alcohol Clin Exp Res 22:670–676

    Article  PubMed  CAS  Google Scholar 

  • Silveri MM, Spear LP (2000) Ontogeny of ethanol elimination and ethanol-induced hypothermia. Alcohol 20:45–53

    Article  PubMed  CAS  Google Scholar 

  • Slawecki CJ, Betancourt M (2002) Effects of adolescent ethanol exposure on ethanol consumption in adult rats. Alcohol 26:23–30

    Article  PubMed  Google Scholar 

  • Spear LP (2000) The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev 24:417–463

    Article  PubMed  CAS  Google Scholar 

  • Spear LP, Brake SC (1983) Periadolescence: age-dependent behavior and psychopharmacological responsivity in rats. Dev Psychobiol 16:83–109

    Article  PubMed  CAS  Google Scholar 

  • Spear LP, Varlinskaya EI (2005) Adolescence. Alcohol sensitivity, tolerance, and intake. Recent Dev Alcohol 17:143–159

    Article  PubMed  Google Scholar 

  • Thiele TE, Willis B, Stadler J, Reynolds JG, Bernstein IL, McKnight GS (2000) High ethanol consumption and low sensitivity to ethanol-induced sedation in protein kinase A-mutant mice. J Neurosci 20:RC75

    PubMed  CAS  Google Scholar 

  • Varlinskaya EI, Spear LP (2002) Acute effects of ethanol on social behavior of adolescent and adult rats: role of familiarity of the test situation. Alcohol Clin Exp Res 26:1502–1511

    PubMed  Google Scholar 

  • Wanwimolruk S, Levy G (1987) Effect of age on the pharmacodynamics of phenobarbital and ethanol in rats. J Pharm Sci 76:503–507

    Article  PubMed  CAS  Google Scholar 

  • Wehner JM, Keller JJ, Keller AB, Picciotto MR, Paylor R, Booker TK, Beaudet A, Heinemann SF, Balogh SA (2004) Role of neuronal nicotinic receptors in the effects of nicotine and ethanol on contextual fear conditioning. Neuroscience 129:11–24

    Article  PubMed  CAS  Google Scholar 

  • White AM, Swartzwelder HS (2005) Age-related effects of alcohol on memory and memory-related brain function in adolescents and adults. Recent Dev Alcohol 17:161–176

    Article  PubMed  Google Scholar 

  • White AM, Truesdale MC, Bae JG, Ahmad S, Wilson WA, Best PJ, Swartzwelder HS (2002) Differential effects of ethanol on motor coordination in adolescent and adult rats. Pharmacol Biochem Behav 73:673–677

    Article  PubMed  CAS  Google Scholar 

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Acknowledgment

The authors would like to thank Rose-Marie Karlsson for technical assistance. Research supported by the National Institute on Alcohol Abuse and Alcoholism Intramural Research Program.

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Correspondence to Andrew Holmes.

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Hefner, K., Holmes, A. An investigation of the behavioral actions of ethanol across adolescence in mice. Psychopharmacology 191, 311–322 (2007). https://doi.org/10.1007/s00213-006-0646-2

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  • DOI: https://doi.org/10.1007/s00213-006-0646-2

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