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Noradrenergic tone mediates marble burying behavior after chronic stress and ethanol

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Abstract

Rationale

Stress plays a major role in the development of alcohol use disorder (AUD)—a history of chronic stress contributes to alcohol misuse, and withdrawal from alcohol elevates stress, perpetuating cycles of problematic drinking. Recent studies have shown that, in male mice, repeated chronic intermittent ethanol (CIE) and stress elevates alcohol use above either manipulation alone and impacts cognitive functions such as behavioral flexibility.

Objective

Here, we investigated the impact of CIE and stress on anxiety in both sexes, and whether the norepinephrine (NE) system via locus coeruleus, which is implicated in both stress and alcohol motivation, is involved.

Results

Male and female mice received multiple cycles of CIE and/or repeated forced swim stress (FSS), producing elevated drinking in both sexes. CIE/FSS treatment increased anxiety, which was blocked by treatment with the α1-AR inverse agonist prazosin. In contrast, administration of the corticotropin releasing factor receptor antagonist CP376395 into locus coeruleus did not reduce CIE/FSS-elevated anxiety. We also observed sex differences in behavioral responses to a history of CIE or FSS alone as well as differential behavioral consequences of prazosin treatment.

Conclusions

These data indicate that NE contributes to the development of anxiety following a history of alcohol and/or stress, and that the influence of both treatment history and NE signaling is sex dependent. These results argue for further investigation of the NE system in relation to disrupted behavior following chronic alcohol and stress, and support the assertion that treatments may differ across sex based on differential neural system engagement.

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References

  • Alcohol and Drug Use Collaborators (2018) The global burden of disease attributable to alcohol and drug use in 195 countries and territories, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Psychiatry 5:987–1012

    Article  Google Scholar 

  • Anderson RI, Lopez MF, Becker HC (2016) Forced swim stress increases ethanol consumption in C57BL/6J mice with a history of chronic intermittent ethanol exposure. Psychopharmacology 233:2035–2043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Armstrong JF, Faccenda E, Harding SD, Pawson AJ, Southan C, Sharman JL, Campo B, Cavanagh DR, Alexander SPH, Davenport AP, Spedding M, Davies JA, Nc I (2020) The IUPHAR/BPS Guide to PHARMACOLOGY in 2020: extending immunopharmacology content and introducing the IUPHAR/MMV Guide to MALARIA PHARMACOLOGY. Nucleic Acids Res 48:D1006–D1021

    CAS  PubMed  Google Scholar 

  • Aston-Jones G, Cohen JD (2005) An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. Annu Rev Neurosci 28:403–450

    Article  CAS  PubMed  Google Scholar 

  • Bangasser DA, Zhang X, Garachh V, Hanhauser E, Valentino RJ (2011) Sexual dimorphism in locus coeruleus dendritic morphology: a structural basis for sex differences in emotional arousal. Physiol Behav 103:342–351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Becker HC (2012) Effects of alcohol dependence and withdrawal on stress responsiveness and alcohol consumption. Alcohol Res 34:448–458

    PubMed  PubMed Central  Google Scholar 

  • Becker HC (2017) Influence of stress associated with chronic alcohol exposure on drinking. Neuropharmacology 122:115–126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Becker HC, Lopez MF (2004) Increased ethanol drinking after repeated chronic ethanol exposure and withdrawal experience in C57BL/6 mice. Alcohol Clin Exp Res 28:1829–1838

    Article  CAS  PubMed  Google Scholar 

  • Becker HC, Lopez MF, Doremus-Fitzwater TL (2011) Effects of stress on alcohol drinking: a review of animal studies. Psychopharmacology 218:131–156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Begleiter H (1974) Propranolol and alcohol consumption in the rat. Am J Drug Alcohol Abuse 1:107–110

    Article  CAS  PubMed  Google Scholar 

  • Berridge CW, Waterhouse BD (2003) The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res Brain Res Rev 42:33–84

    Article  PubMed  Google Scholar 

  • Blaine SK, Milivojevic V, Fox H, Sinha R (2016) Alcohol effects on stress pathways: impact on craving and relapse risk. Can J Psychiatr 61:145–153

    Article  Google Scholar 

  • Breese GR, Sinha R, Heilig M (2011) Chronic alcohol neuroadaptation and stress contribute to susceptibility for alcohol craving and relapse. Pharmacol Ther 129:149–171

    Article  CAS  PubMed  Google Scholar 

  • Caruso MJ, Seemiller LR, Fetherston TB, Miller CN, Reiss DE, Cavigelli SA, Kamens HM (2018) Adolescent social stress increases anxiety-like behavior and ethanol consumption in adult male and female C57BL/6J mice. Sci Rep 8:10040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen YL, Obach RS, Braselton J, Corman ML, Forman J, Freeman J, Gallaschun RJ, Mansbach R, Schmidt AW, Sprouse JS, Tingley Iii FD, Winston E, Schulz DW (2008) 2-aryloxy-4-alkylaminopyridines: discovery of novel corticotropin-releasing factor 1 antagonists. J Med Chem 51:1385–1392

    Article  CAS  PubMed  Google Scholar 

  • Curtis AL, Bethea T, Valentino RJ (2006) Sexually dimorphic responses of the brain norepinephrine system to stress and corticotropin-releasing factor. Neuropsychopharmacology 31:544–554

    Article  CAS  PubMed  Google Scholar 

  • Daviu N, Bruchas MR, Moghaddam B, Sandi C, Beyeler A (2019) Neurobiological links between stress and anxiety. Neurobiol Stress 11:100191

    Article  PubMed  PubMed Central  Google Scholar 

  • Dhaher R, Finn D, Snelling C, Hitzemann R (2008) Lesions of the extended amygdala in C57BL/6J mice do not block the intermittent ethanol vapor-induced increase in ethanol consumption. Alcohol Clin Exp Res 32:197–208

    Article  CAS  PubMed  Google Scholar 

  • Edwards S, Baynes BB, Carmichael CY, Zamora-Martinez ER, Barrus M, Koob GF, Gilpin NW (2013) Traumatic stress reactivity promotes excessive alcohol drinking and alters the balance of prefrontal cortex-amygdala activity. Transl Psychiatry 3:e296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eriksson K, Pikkarainen PH (1968) Differences between the sexes in voluntary alcohol consumption and liver ADH-activity in inbred strains of mice. Metabolism 17:1037–1042

    Article  CAS  PubMed  Google Scholar 

  • Fox HC, Anderson GM, Tuit K, Hansen J, Kimmerling A, Siedlarz KM, Morgan PT, Sinha R (2012) Prazosin effects on stress- and cue-induced craving and stress response in alcohol-dependent individuals: preliminary findings. Alcohol Clin Exp Res 36:351–360

    Article  CAS  PubMed  Google Scholar 

  • Franklin KBJ, Paxinos G (2008) The mouse brain in stereotaxic coordinates, Third edn. Academic Press, Cambridge

    Google Scholar 

  • Froehlich JC, Hausauer BJ, Federoff DL, Fischer SM, Rasmussen DD (2013) Prazosin reduces alcohol drinking throughout prolonged treatment and blocks the initiation of drinking in rats selectively bred for high alcohol intake. Alcohol Clin Exp Res 37:1552–1560

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Froehlich JC, Hausauer B, Fischer S, Wise B, Rasmussen DD (2015) Prazosin reduces alcohol intake in an animal model of alcohol relapse. Alcohol Clin Exp Res 39:1538–1546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Funk D, Coen K, Tamadon S, Li Z, Loughlin A, Le AD (2016) Effects of prazosin and doxazosin on yohimbine-induced reinstatement of alcohol seeking in rats. Psychopharmacology 233:2197–2207

    Article  CAS  PubMed  Google Scholar 

  • Gilpin NW, Koob GF (2010) Effects of beta-adrenoceptor antagonists on alcohol drinking by alcohol-dependent rats. Psychopharmacology 212:431–439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grant BF, Goldstein RB, Saha TD, Chou SP, Jung J, Zhang H, Pickering RP, Ruan WJ, 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 Psychiat 72:757–766

    Article  CAS  Google Scholar 

  • Griffin WC 3rd, Lopez MF, Yanke AB, Middaugh LD, Becker HC (2009) Repeated cycles of chronic intermittent ethanol exposure in mice increases voluntary ethanol drinking and ethanol concentrations in the nucleus accumbens. Psychopharmacology 201:569–580

    Article  CAS  PubMed  Google Scholar 

  • Hwa LS, Holly EN, DeBold JF, Miczek KA (2016) Social stress-escalated intermittent alcohol drinking: modulation by CRF-R1 in the ventral tegmental area and accumbal dopamine in mice. Psychopharmacology 233:681–690

    Article  CAS  PubMed  Google Scholar 

  • Incheglu JM, Bicego KC, Gargaglioni LH (2016) Corticotropin-releasing factor in the locus coeruleus as a modulator of ventilation in rats. Respir Physiol Neurobiol 233:73–80

    Article  CAS  PubMed  Google Scholar 

  • Jury NJ, DiBerto JF, Kash TL, Holmes A (2017) Sex differences in the behavioral sequelae of chronic ethanol exposure. Alcohol 58:53–60

    Article  CAS  PubMed  Google Scholar 

  • Koob GF (2014) Neurocircuitry of alcohol addiction: synthesis from animal models. Handb Clin Neurol 125:33–54

    Article  PubMed  Google Scholar 

  • Koob GF, Volkow ND (2016) Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry 3:760–773

    Article  PubMed  PubMed Central  Google Scholar 

  • Lopez MF, Anderson RI, Becker HC (2016) Effect of different stressors on voluntary ethanol intake in ethanol-dependent and nondependent C57BL/6J mice. Alcohol 51:17–23

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McCall JG, Al-Hasani R, Siuda ER, Hong DY, Norris AJ, Ford CP, Bruchas MR (2015) CRH engagement of the locus coeruleus noradrenergic system mediates stress-induced anxiety. Neuron 87:605–620

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moore RY, Bloom FE (1979) Central catecholamine neuron systems: anatomy and physiology of the norepinephrine and epinephrine systems. Annu Rev Neurosci 2:113–168

    Article  CAS  PubMed  Google Scholar 

  • Mulvey B, Bhatti DL, Gyawali S, Lake AM, Kriaucionis S, Ford CP, Bruchas MR, Heintz N, Dougherty JD (2018) Molecular and functional sex differences of noradrenergic neurons in the mouse locus coeruleus. Cell Rep 23:2225–2235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peltier MR, Verplaetse TL, Mineur YS, Petrakis IL, Cosgrove KP, Picciotto MR, McKee SA (2019) Sex differences in stress-related alcohol use. Neurobiol Stress 10:100149

    Article  PubMed  PubMed Central  Google Scholar 

  • Pinos H, Collado P, Rodriguez-Zafra M, Rodriguez C, Segovia S, Guillamon A (2001) The development of sex differences in the locus coeruleus of the rat. Brain Res Bull 56:73–78

    Article  CAS  PubMed  Google Scholar 

  • Pleil KE, Lowery-Gionta EG, Crowley NA, Li C, Marcinkiewcz CA, Rose JH, McCall NM, Maldonado-Devincci AM, Morrow AL, Jones SR, Kash TL (2015) Effects of chronic ethanol exposure on neuronal function in the prefrontal cortex and extended amygdala. Neuropharmacology 99:735–749

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Prencipe L, Iaccheri E, Manzati C (1987) Enzymic ethanol assay: a new colorimetric method based on measurement of hydrogen peroxide. Clin Chem 33:486–489

    Article  CAS  PubMed  Google Scholar 

  • Rasmussen DD, Beckwith LE, Kincaid CL, Froehlich JC (2014) Combining the alpha1 -adrenergic receptor antagonist, prazosin, with the beta-adrenergic receptor antagonist, propranolol, reduces alcohol drinking more effectively than either drug alone. Alcohol Clin Exp Res 38:1532–1539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rasmussen DD, Kincaid CL, Froehlich JC (2017) Prazosin prevents increased anxiety behavior that occurs in response to stress during alcohol deprivations. Alcohol Alcohol 52:5–11

    Article  CAS  PubMed  Google Scholar 

  • Retson TA, Sterling RC, Van Bockstaele EJ (2016) Alcohol-induced dysregulation of stress-related circuitry: the search for novel targets and implications for interventions across the sexes. Prog Neuro-Psychopharmacol Biol Psychiatry 65:252–259

    Article  CAS  Google Scholar 

  • Reyes BA, Valentino RJ, Van Bockstaele EJ (2008) Stress-induced intracellular trafficking of corticotropin-releasing factor receptors in rat locus coeruleus neurons. Endocrinology 149:122–130

    Article  CAS  PubMed  Google Scholar 

  • Rinaman L (2011) Hindbrain noradrenergic A2 neurons: diverse roles in autonomic, endocrine, cognitive, and behavioral functions. Am J Phys Regul Integr Comp Phys 300:R222–R235

    CAS  Google Scholar 

  • Rodberg EM, den Hartog CR, Anderson RI, Becker HC, Moorman DE, Vazey EM (2017) Stress facilitates the development of cognitive dysfunction after chronic ethanol exposure. Alcohol Clin Exp Res 41:1574–1583

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rose JH, Karkhanis AN, Chen R, Gioia D, Lopez MF, Becker HC, McCool BA, Jones SR (2016) Supersensitive kappa opioid receptors promotes ethanol withdrawal-related behaviors and reduce dopamine signaling in the nucleus accumbens. Int J Neuropsychopharmacol 19(5):pyv127

    Article  PubMed  CAS  Google Scholar 

  • Rossier O, Abuin L, Fanelli F, Leonardi A, Cotecchia S (1999) Inverse agonism and neutral antagonism at alpha(1a)- and alpha(1b)-adrenergic receptor subtypes. Mol Pharmacol 56:858–866

    Article  CAS  PubMed  Google Scholar 

  • Skelly MJ, Weiner JL (2014) Chronic treatment with prazosin or duloxetine lessens concurrent anxiety-like behavior and alcohol intake: evidence of disrupted noradrenergic signaling in anxiety-related alcohol use. Brain Behav 4:468–483

    Article  PubMed  PubMed Central  Google Scholar 

  • Swanson LW, Hartman BK (1975) The central adrenergic system. An immunofluorescence study of the location of cell bodies and their efferent connections in the rat utilizing dopamine-beta-hydroxylase as a marker. J Comp Neurol 163:467–505

    Article  CAS  PubMed  Google Scholar 

  • Tanaka M, Tsuda A, Yokoo H, Yoshida M, Ida Y, Nishimura H (1990) Involvement of the brain noradrenaline system in emotional changes caused by stress in rats. Ann N Y Acad Sci 597:159–174

    Article  CAS  PubMed  Google Scholar 

  • Umathe S, Bhutada P, Dixit P, Shende V (2008) Increased marble-burying behavior in ethanol-withdrawal state: modulation by gonadotropin-releasing hormone agonist. Eur J Pharmacol 587:175–180

    Article  CAS  PubMed  Google Scholar 

  • Valentino RJ, Wehby RG (1988) Corticotropin-releasing factor: evidence for a neurotransmitter role in the locus ceruleus during hemodynamic stress. Neuroendocrinology 48:674–677

    Article  CAS  PubMed  Google Scholar 

  • Valentino RJ, Foote SL, Aston-Jones G (1983) Corticotropin-releasing factor activates noradrenergic neurons of the locus coeruleus. Brain Res 270:363–367

    Article  CAS  PubMed  Google Scholar 

  • Varlinskaya EI, Spear LP (2015) Social consequences of ethanol: impact of age, stress, and prior history of ethanol exposure. Physiol Behav 148:145–150

    Article  CAS  PubMed  Google Scholar 

  • Vazey EM, den Hartog CR, Moorman DE (2018) Central noradrenergic interactions with alcohol and regulation of alcohol-related behaviors. Handb Exp Pharmacol 248:239–260

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgments

This work was generated as part of the INIA Stress Consortium.

Funding

This work was supported National Institute of Health research grants U01AA025481 (DEM, EMV), R21AA024571 (DEM), and a NARSAD Young Investigator Award (DEM).

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Authors and Affiliations

  1. Department of Biology, University of Massachusetts Amherst, 611 North Pleasant St, Amherst, MA, 01003, USA

    Carolina R. den Hartog, Katrina L. Blandino, McKenzie L. Nash, Emily R. Sjogren, Michael A. Grampetro & Elena M. Vazey

  2. Department of Psychological and Brain Sciences, University of Massachusetts Amherst, Amherst, MA, 01003, USA

    David E. Moorman

Authors
  1. Carolina R. den Hartog
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  2. Katrina L. Blandino
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  3. McKenzie L. Nash
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  4. Emily R. Sjogren
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  5. Michael A. Grampetro
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  6. David E. Moorman
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  7. Elena M. Vazey
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Contributions

CdH, DEM, and EMV designed the experiments and wrote the paper. CdH, KLB, MLN, ERS, MAG, and EMV performed experiments and analyzed the data.

Corresponding author

Correspondence to Elena M. Vazey.

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den Hartog, C.R., Blandino, K.L., Nash, M.L. et al. Noradrenergic tone mediates marble burying behavior after chronic stress and ethanol. Psychopharmacology 237, 3021–3031 (2020). https://doi.org/10.1007/s00213-020-05589-7

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