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Psychopharmacology

, Volume 236, Issue 7, pp 2059–2067 | Cite as

Effects of conditioned social fear on ethanol drinking and vice-versa in male mice

  • Johannes Kornhuber
  • Sabine E. Huber
  • Iulia ZoicasEmail author
Original Investigation
  • 175 Downloads

Abstract

Rationale

Social anxiety disorder (SAD) is highly comorbid with alcohol use disorders, but the complex relationship between social fear and alcohol drinking is poorly understood due to the lack of specific animal models.

Objectives

We investigated whether social fear alters ethanol drinking under both stress-free and stress-inducing conditions and whether ethanol alleviates symptoms of social fear.

Methods

We used the social fear conditioning (SFC) paradigm, an animal model with face and predictive validity to SAD, to induce specific social fear in male CD1 mice, i.e., without comorbid depression or anxiety-like behavior. Plasma corticosterone (CORT) levels were measured in conditioned (SFC+) and unconditioned (SFC) mice after exposure to non-social or social stimuli. Ethanol drinking was assessed in the two-bottle free-choice paradigm (1) for 16 days under stress-free conditions and (2) for 6 h after exposure to social stimuli. The effects of ethanol drinking and social fear on anxiety-like behavior and taste preference were tested in the elevated plus-maze and sucrose and quinine preference tests.

Results

We show that exposure to social but not non-social stimuli leads to higher plasma CORT levels in SFC+ compared with SFC mice. We also show that social fear decreases voluntary ethanol consumption under stress-free conditions, but increases ethanol consumption after exposure to social stimuli. Ethanol drinking, on the other hand, reduces social fear without altering anxiety-like behavior, locomotor activity, and taste preference.

Conclusions

These results have important clinical connotations as they suggest that voluntary ethanol drinking might specifically reverse symptoms of social fear in a SAD-relevant animal model.

Keywords

Social fear conditioning Extinction Social investigation Corticosterone CORT ELISA Ethanol drinking Anxiety Taste preference Locomotion 

Notes

Acknowledgements

We thank Prof. Dr. Gunther Moll and Dr. Yulia Golub for the permission to use the TSE system.

Funding information

This work was supported by funding from the Forschungsstiftung Medizin at the University Hospital Erlangen (to JK) and the German Federal Ministry of Education and Research (BMBF, grant number 01EE1401C, to JK).

Compliance with ethical standards

Conflict of interest

The authors declare that there is no conflict of interest.

References

  1. Abrams K, Kushner M, Medina KL, Voight A (2001) The pharmacologic and expectancy effects of alcohol on social anxiety in individuals with social phobia. Drug Alcohol Depend 64(2):219–231.  https://doi.org/10.1016/S0376-8716(01)00125-9 Google Scholar
  2. Abrams K, Kushner MG, Medina KL, Voight A (2002) Self-administration of alcohol before and after a public speaking challenge by individuals with social phobia. Psychol Addict Behav 16(2):121–128.  https://doi.org/10.1037/0893-164X.16.2.121 Google Scholar
  3. Asher M, Aderka IM (2018) Gender differences in social anxiety disorder. J Clin Psychol 74(10):1730–1741.  https://doi.org/10.1002/jclp.22624 Google Scholar
  4. Avgustinovich DF, Kovalenko IL, Kudryavtseva NN (2005) A model of anxious depression: persistence of behavioral pathology. Neurosci Behav Physiol 35(9):917–924.  https://doi.org/10.1007/s11055-005-0146-6 Google Scholar
  5. Bertoglio LJ, Carobrez AP (2002) Anxiolytic effects of ethanol and phenobarbital are abolished in test-experienced rats submitted to the elevated plus maze. Pharmacol Biochem Behav 73(4):963–969.  https://doi.org/10.1016/S0091-3057(02)00958-9 Google Scholar
  6. Berton O, Durand M, Aguerre S, Mormède P, Chaouloff F (1999) Behavioral, neuroendocrine and serotonergic consequences of single social defeat and repeated fluoxetine pretreatment in the Lewis rat strain. Neuroscience 92(1):327–341.  https://doi.org/10.1016/S0306-4522(98)00742-8 Google Scholar
  7. Caldwell EE, Riccio DC (2010) Alcohol self-administration in rats: modulation by temporal parameters related to repeated mild social defeat stress. Alcohol 44(3):265–274.  https://doi.org/10.1016/j.alcohol.2010.02.012 Google Scholar
  8. Cappell H, Herman CP (1972) Alcohol and tension reduction. A review. Quarterly Journal of Studies on Alcohol 33:33–64Google Scholar
  9. Croft AP, Brooks SP, Cole J, Little HJ (2005) Social defeat increases alcohol preference of C57BL/10 strain mice; effect prevented by a CCKB antagonist. Psychopharmacology 183(2):163–170.  https://doi.org/10.1007/s00213-005-0165-6 Google Scholar
  10. de Wit H, Söderpalm AH, Nikolayev L, Young E (2003) Effects of acute social stress on alcohol consumption in healthy subjects. Alcohol Clin Exp Res 27(8):1270–1277.  https://doi.org/10.1097/01.ALC.0000081617.37539.D6 Google Scholar
  11. Favoretto CA, Macedo GC, Quadros IM (2017) Effects of ethanol on social avoidance induced by chronic social defeat stress in mice. Stress 20(1):68–74.  https://doi.org/10.1080/10253890.2017.1280667 Google Scholar
  12. Fidler TL, LoLordo VM (1996) Failure to find postshock increases in ethanol preference. Alcohol Clin Exp Res 20:110–121.  https://doi.org/10.1111/j.1530-0277.1996.tb01053.x Google Scholar
  13. File SE, Hyde J, Pool M (1976) Effects of ethanol and chlordiazepoxide on social interaction in rats [proceedings]. Br J Pharmacol 58(3):465PGoogle Scholar
  14. Funk D, Harding S, Juzytsch W, Lê AD (2005) Effects of unconditioned and conditioned social defeat on alcohol self-administration and reinstatement of alcohol seeking in rats. Psychopharmacology 183(3):341–349.  https://doi.org/10.1007/s00213-005-0194-1 Google Scholar
  15. Funk D, Vohra S, Le AD (2004) Influence of stressors on the rewarding effects of alcohol in Wistar rats: studies with alcohol deprivation and place conditioning. Psychopharmacology 176:82–87.  https://doi.org/10.1007/s00213-004-1859-x Google Scholar
  16. Gimeno C, Dorado ML, Roncero C, Szerman N, Vega P, Balanzá-Martínez V, Alvarez FJ (2017) Treatment of comorbid alcohol dependence and anxiety disorder: review of the scientific evidence and recommendations for treatment. Front Psychiatry 8:173.  https://doi.org/10.3389/fpsyt.2017.00173 Google Scholar
  17. Grant BF, Hasin DS, Blanco C, Stinson FS, Chou SP, Goldstein RB, Dawson DA, Smith S, Saha TD, Huang B (2005) The epidemiology of social anxiety disorder in the United States: results from the National Epidemiologic Survey on alcohol and related conditions. J Clin Psychiatry 66(11):1351–1361.  https://doi.org/10.4088/JCP.v66n1102 Google Scholar
  18. Himle JA, Abelson JL, Haghightgou H, Hill EM, Nesse RM, Curtis GC (1999) Effect of alcohol on social phobic anxiety. Am J Psychiatr 156(8):1237–1243.  https://doi.org/10.1176/ajp.156.8.1237 Google Scholar
  19. Huber SE, Zoicas I, Reichel M, Mühle C, Büttner C, Ekici AB, Eulenburg V, Lenz B, Kornhuber J, Müller CP (2018) Prenatal androgen receptor activation determines adult alcohol and water drinking in a sex-specific way. Addict Biol 23(3):904–920.  https://doi.org/10.1111/adb.12540 Google Scholar
  20. Khantzian EJ (1985) The self-medication hypothesis of addictive disorders: focus on heroin and cocaine dependence. Am J Psychiatr 142(11):1259–1264.  https://doi.org/10.1007/978-1-4613-1837-8_7 Google Scholar
  21. Kudryavtseva N, Gerrits MA, Avgustinovich DF, Tenditnik MV, Van Ree JM (2006) Anxiety and ethanol consumption in victorious and defeated mice; effect of kappa-opioid receptor activation. Eur Neuropsychopharmacol 16(7):504–511.  https://doi.org/10.1016/j.euroneuro.2006.01.002 Google Scholar
  22. Kutlu MG, Gould TJ (2016) Effects of drugs of abuse on hippocampal plasticity and hippocampus-dependent learning and memory: contributions to development and maintenance of addiction. Learn Mem 23(10):515–533.  https://doi.org/10.1101/lm.042192.116 Google Scholar
  23. Lai WS, Ramiro LL, Yu HA, Johnston RE (2005) Recognition of familiar individuals in golden hamsters: a new method and functional neuroanatomy. J Neurosci 25(49):11239–11247.  https://doi.org/10.1523/JNEUROSCI.2124-05.2005 Google Scholar
  24. Lukas M, Toth I, Reber SO, Slattery DA, Veenema AH, Neumann ID (2011) The neuropeptide oxytocin facilitates pro-social behavior and prevents social avoidance in rats and mice. Neuropsychopharmacology 36(11):2159–2168.  https://doi.org/10.1038/npp.2011.95 Google Scholar
  25. Moloney RD, Dinan TG, Cryan JF (2015) Strain-dependent variations in visceral sensitivity: relationship to stress, anxiety and spinal glutamate transporter expression. Genes Brain Behav 14(4):319–329.  https://doi.org/10.1111/gbb.12216 Google Scholar
  26. Müller CP, Kalinichenko LS, Tiesel J, Witt M, Stöckl T, Sprenger E, Fuchser J, Beckmann J, Praetner M, Huber SE, Amato D, Mühle C, Büttner C, Ekici AB, Smaga I, Pomierny-Chamiolo L, Pomierny B, Filip M, Eulenburg V, Gulbins E, Lourdusamy A, Reichel M, Kornhuber J (2017) Paradoxical antidepressant effects of alcohol are related to acid sphingomyelinase and its control of sphingolipid homeostasis. Acta Neuropathol 133(3):463–483.  https://doi.org/10.1007/s00401-016-1658-6 Google Scholar
  27. Newman EL, Leonard MZ, Arena AT, de Almeida RMM, Miczek KA (2018) Social defeat stress and escalation of cocaine and alcohol consumption: focus on CRF. Neurobiology of stress 9:151–165.  https://doi.org/10.1016/j.ynstr.2018.09.007 Google Scholar
  28. Norman KJ, Seiden JA, Klickstein JA, Han X, Hwa LS, DeBold JF, Miczek KA (2015) Social stress and escalated drug self-administration in mice I. Alcohol and corticosterone. Psychopharmacology 232(6):991–1001.  https://doi.org/10.1007/s00213-014-3733-9 Google Scholar
  29. Rodriguez-Arias M, Navarrete F, Blanco-Gandia MC, Arenas MC, Bartoll-Andrés A, Aguilar MA, Rubio G, Miñarro J, Manzanares J (2016) Social defeat in adolescent mice increases vulnerability to alcohol consumption. Addict Biol 21(1):87–97.  https://doi.org/10.1111/adb.12184 Google Scholar
  30. Rutkowska J, Place NJ, Vincent S, Adkins-Regan E (2011) Adrenocortical response to mating, social interaction and restraint in the female Japanese quail. Physiol Behav 104(5):1037–1040.  https://doi.org/10.1016/j.physbeh.2011.07.001 Google Scholar
  31. Silverman JL, Yang M, Turner SM, Katz AM, Bell DB, Koenig JI, Crawley JN (2010) Low stress reactivity and neuroendocrine factors in the BTBR T+tf/J mouse model of autism. Neuroscience 171(4):1197–1208.  https://doi.org/10.1016/j.neuroscience.2010.09.059 Google Scholar
  32. Spanagel R, Montkowski A, Allingham K, Stöhr T, Shoaib M, Holsboer F, Landgraf R (1995) Anxiety: a potential predictor of vulnerability to the initiation of ethanol self-administration in rats. Psychopharmacology 122(4):369–373.  https://doi.org/10.1007/BF02246268 Google Scholar
  33. Stevens S, Cludius B, Bantin T, Hermann C, Gerlach AL (2014) Influence of alcohol on social anxiety: an investigation of attentional, physiological and behavioral effects. Biol Psychol 96:126–133.  https://doi.org/10.1016/j.biopsycho.2013.12.004 Google Scholar
  34. Stevens S, Cooper R, Bantin T, Hermann C, Gerlach AL (2017) Feeling safe but appearing anxious: differential effects of alcohol on anxiety and social performance in individuals with social anxiety disorder. Behav Res Ther 94:9–18.  https://doi.org/10.1016/j.brat.2017.04.008 Google Scholar
  35. Thomas SE, Randall CL, Carrigan MH (2003) Drinking to cope in socially anxious individuals: a controlled study. Alcoholism:Clinical and Experimental Research 27(12):1937–1943.  https://doi.org/10.1097/01.ALC.0000100942.30743.8C Google Scholar
  36. Toth I, Neumann ID (2013) Animal models of social avoidance and social fear. Cell Tissue Res 354(1):107–118.  https://doi.org/10.1007/s00441-013-1636-4 Google Scholar
  37. Toth I, Neumann ID, Slattery DA (2012) Social fear conditioning: a novel and specific animal model to study social anxiety disorder. Neuropsychopharmacology 37(6):1433–1443.  https://doi.org/10.1038/npp.2011.329 Google Scholar
  38. Turner S, Mota N, Bolton J, Sareen J (2018) Self-medication with alcohol or drugs for mood and anxiety disorders: a narrative review of the epidemiological literature. Depress Anxiety 35(9):851–860.  https://doi.org/10.1002/da.22771 Google Scholar
  39. van Erp AM, Miczek KA (2001) Persistent suppression of ethanol self-administration by brief social stress in rats and increased startle response as index of withdrawal. Physiol Behav 73(3):301–311.  https://doi.org/10.1016/S0031-9384(01)00458-9 Google Scholar
  40. van Erp AM, Tachi N, Miczek KA (2001) Short or continuous social stress: suppression of continuously available ethanol intake in subordinate rats. Behav Pharmacol 12(5):335–342.  https://doi.org/10.1097/00008877-200109000-00004 Google Scholar
  41. Varlinskaya EI, Doremus-Fitzwater TL, Spear LP (2010) Repeated restraint stress alters sensitivity to the social consequences of ethanol in adolescent and adult rats. Pharmacol Biochem Behav 96(2):228–235.  https://doi.org/10.1016/j.pbb.2010.05.011 Google Scholar
  42. Varlinskaya EI, Spear LP (2012) Increases in anxiety-like behavior induced by acute stress are reversed by ethanol in adolescent but not adult rats. Pharmacol Biochem Behav 100(3):440–450.  https://doi.org/10.1016/j.pbb.2011.10.010 Google Scholar
  43. Varlinskaya EI, Spear LP, Spear NE (2001) Acute effects of ethanol on behavior of adolescent rats: role of social context. Alcohol Clin Exp Res 25(3):377–385.  https://doi.org/10.1111/j.1530-0277.2001.tb02224.x Google Scholar
  44. Vengeliene V, Siegmund S, Singer MV, Sinclair JD, Li TK, Spanagel R (2003) A comparative study on alcohol-preferring rat lines: effects of deprivation and stress phases on voluntary alcohol intake. Alcohol Clin Exp Res 27:1048–1054.  https://doi.org/10.1097/01.ALC.0000075829.81211.0C Google Scholar
  45. Venzala E, García-García AL, Elizalde N, Tordera RM (2013) Social vs. environmental stress models of depression from a behavioural and neurochemical approach. Eur Neuropsychopharmacol 23(7):697–708.  https://doi.org/10.1016/j.euroneuro.2012.05.010 Google Scholar
  46. Willey AR, Spear LP (2014) Effects of ethanol on social approach and 50 kHz ultrasonic vocalization production in adolescent male Sprague-Dawley rats. Dev Psychobiol 56(4):857–863.  https://doi.org/10.1002/dev.21143 Google Scholar
  47. Yoneyama N, Crabbe JC, Ford MM, Murillo A, Finn DA (2008) Voluntary ethanol consumption in 22 inbred mouse strains. Alcohol 42(3):149–160.  https://doi.org/10.1016/j.alcohol.2007.12.006 Google Scholar
  48. Zoicas I, Menon R, Neumann ID (2016) Neuropeptide S reduces fear and avoidance of con-specifics induced by social fear conditioning and social defeat, respectively. Neuropharmacology 108:284–291.  https://doi.org/10.1016/j.neuropharm.2016.03.054 Google Scholar
  49. Zoicas I, Neumann ID (2016) Maternal separation facilitates extinction of social fear in adult male mice. Behav Brain Res 297:323–328.  https://doi.org/10.1016/j.bbr.2015.10.034 Google Scholar
  50. Zoicas I, Slattery DA, Neumann ID (2014) Brain oxytocin in social fear conditioning and its extinction: involvement of the lateral septum. Neuropsychopharmacology 39(13):3027–3035.  https://doi.org/10.1038/npp.2014.156 Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Johannes Kornhuber
    • 1
  • Sabine E. Huber
    • 1
  • Iulia Zoicas
    • 1
    Email author
  1. 1.Department of Psychiatry and Psychotherapy, University HospitalFriedrich-Alexander-University Erlangen-NurembergErlangenGermany

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