Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

On the early life origins of vulnerability to opioid addiction

Molecular Psychiatry volume 26, pages 4409–4416 (2021)Cite this article

Subjects

Abstract

The origins and neural bases of the current opioid addiction epidemic are unclear. Genetics plays a major role in addiction vulnerability, but cannot account for the recent exponential rise in opioid abuse, so environmental factors must contribute. Individuals with history of early life adversity (ELA) are disproportionately prone to opioid addiction, yet whether ELA interacts with factors such as increased access to opioids to directly influence brain development and function, and cause opioid addiction vulnerability, is unknown. We simulated ELA in female rats and this led to a striking opioid addiction-like phenotype. This was characterized by resistance to extinction, increased relapse-like behavior, and, as in addicted humans, major increases in opioid economic demand. By contrast, seeking of a less salient natural reward was unaffected by ELA, whereas demand for highly palatable treats was augmented. These discoveries provide novel insights into the origins and nature of reward circuit malfunction that may set the stage for addiction.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Early life adversity potentiates heroin-seeking behaviors.
Fig. 2: Early life adversity increases demand for opioids and highly palatable food.

Similar content being viewed by others

Data availability

The data forming the basis of these studies do not include genomic or imaging data sets storable in public repositories. Data will be readily made available when requested from the authors.

References

  1. Volkow ND, Collins FS. The role of science in addressing the opioid crisis. https://doi.org/10.1056/NEJMsr1706626. 2017.

  2. Morrow JD, Flagel SB. Neuroscience of resilience and vulnerability for addiction medicine: From genes to behavior. Prog Brain Res. 2016;223:3–18.

    Article  Google Scholar 

  3. Cates HM, Benca-Bachman CE, de Guglielmo G, Schoenrock SA, Shu C, Kallupi M. National Institute on Drug Abuse genomics consortium white paper: Coordinating efforts between human and animal addiction studies. Genes Brain Behav. 2019;18:e12577.

    Article  Google Scholar 

  4. Van Zee A. The promotion and marketing of oxycontin: commercial triumph, public health tragedy. Am J Public Health. 2009;99:221–7.

    Article  Google Scholar 

  5. Gershon A, Minor K, Hayward C. Gender, victimization, and psychiatric outcomes. Psychol Med. 2008;38:1377–91.

    Article  CAS  Google Scholar 

  6. Shand FL, Degenhardt L, Slade T, Nelson EC. Sex differences amongst dependent heroin users: Histories, clinical characteristics and predictors of other substance dependence. Addict Behav. 2011;36:27–36.

    Article  Google Scholar 

  7. Widom CS, Marmorstein NR, White HR. Childhood victimization and illicit drug use in middle adulthood. Psychol Addict Behav. 2006;20:394–403.

    Article  Google Scholar 

  8. Marsh JC, Park K, Lin YA, Bersamira C. Gender differences in trends for heroin use and nonmedical prescription opioid use, 2007-2014. J Subst Abus Treat. 2018;87:79–85.

    Article  Google Scholar 

  9. Enoch M-A. The role of early life stress as a predictor for alcohol and drug dependence. Psychopharmacology. 2011;214:17–31.

    Article  CAS  Google Scholar 

  10. Danese A, Moffitt TE, Arseneault L, Bleiberg BA, Dinardo PB, Gandelman SB, et al. The origins of cognitive deficits in victimized children: implications for neuroscientists and clinicians. Am J Psychiatry. 2017;174:349–61.

    Article  Google Scholar 

  11. Chen Y, Baram TZ. Toward understanding how early-life stress reprograms cognitive and emotional brain networks. Neuropsychopharmacology. 2016;41:197.

    Article  Google Scholar 

  12. Bolton JL, Molet J, Regev L, Chen Y, Rismanchi N, Haddad E, et al. Anhedonia following early-life adversity involves aberrant interaction of reward and anxiety circuits and is reversed by partial silencing of amygdala corticotropin-releasing hormone gene. Biol Psychiatry. 2018;83:137–47.

    Article  CAS  Google Scholar 

  13. Ivy AS, Brunson KL, Sandman C, Baram TZ. Dysfunctional nurturing behavior in rat dams with limited access to nesting material: a clinically relevant model for early-life stress. Neuroscience. 2008;154:1132–42.

    Article  CAS  Google Scholar 

  14. Molet J, Heins K, Zhuo X, Mei YT, Regev L, Baram TZ et al. Fragmentation and high entropy of neonatal experience predict adolescent emotional outcome. Transl Psychiatry. 2016;6:e702.

  15. Molet J, Maras PM, Avishai‐Eliner S, Baram TZ. Naturalistic rodent models of chronic early‐life stress. Dev Psychobiol. 2014;56:1675–88.

    Article  Google Scholar 

  16. Smith RJ, Aston‐Jones G. Orexin / hypocretin 1 receptor antagonist reduces heroin self‐administration and cue‐induced heroin seeking. Eur J Neurosci. 2012;35:798–804.

    Article  Google Scholar 

  17. Bolton JL, Ruiz CM, Rismanchi N, Sanchez GA, Castillo E, Huang J, et al. Early-life adversity facilitates acquisition of cocaine self-administration and induces persistent anhedonia. Neurobiol Stress. 2018;8:57–67.

    Article  Google Scholar 

  18. Porter‐Stransky KA, Bentzley BS, Aston‐Jones G. Individual differences in orexin‐I receptor modulation of motivation for the opioid remifentanil. Addict Biol. 2017;22:303–17.

    Article  Google Scholar 

  19. Bentzley BS, Fender KM, Aston-Jones G. The behavioral economics of drug self-administration: a review and new analytical approach for within-session procedures. Psychopharmacology. 2013;226:113–25.

    Article  CAS  Google Scholar 

  20. Oleson EB, Roberts D. Parsing the addiction phenomenon: Self-administration procedures modeling enhanced motivation for drug and escalation of drug intake. Drug Discov Today. 2009;5:217–26.

    Google Scholar 

  21. Cox BM, Bentzley BS, Regen-Tuero H, See RE, Reichel CM, Aston-Jones G. Oxytocin acts in nucleus accumbens to attenuate methamphetamine seeking and demand. Biol Psychiatry. 2017;81:949–58.

    Article  CAS  Google Scholar 

  22. Bland JM, Altman DG. The logrank test. BMJ 2004;328:1073.

    Article  Google Scholar 

  23. Milton AL, Everitt BJ. The persistence of maladaptive memory: addiction, drug memories and anti-relapse treatments. Neurosci Biobehav Rev. 2012;36:1119–39.

    Article  Google Scholar 

  24. Vanderschuren LJ, Ahmed SH. Animal studies of addictive behavior. Cold Spring Harb Perspect Med. 2013;3:a011932.

    Article  Google Scholar 

  25. Weiss F. Neurobiology of craving, conditioned reward and relapse. Curr Opin Pharm. 2005;5:9–19.

    Article  CAS  Google Scholar 

  26. Brandon TH, Vidrine JI, Litvin EB. Relapse and relapse prevention. Annu Rev Clin Psychol. 2007;3:257–84.

    Article  Google Scholar 

  27. Bickel WK, Johnson MW, Koffarnus MN, MacKillop J, Murphy JG. The behavioral economics of substance use disorders: reinforcement pathologies and their repair. Annu Rev Clin Psychol. 2014;10:641–77.

    Article  Google Scholar 

  28. Hursh SR. Economic concepts for the analysis of behavior. J Exp Anal Behav. 1980;34:219–38.

    Article  CAS  Google Scholar 

  29. Bentzley BS, Jhou TC, Aston-Jones G. Economic demand predicts addiction-like behavior and therapeutic efficacy of oxytocin in the rat. Proc Natl Acad Sci. 2014;111:11822–7.

    Article  CAS  Google Scholar 

  30. Strickland JC, Lile JA, Stoops WW. Evaluating non-medical prescription opioid demand using commodity purchase tasks: test-retest reliability and incremental validity. Psychopharmacology. 2019;236:2641–52.

    Article  CAS  Google Scholar 

  31. Slattery DA, Cryan JF. Modelling depression in animals: at the interface of reward and stress pathways. Psychopharmacology. 2017;234:1451–65.

    Article  CAS  Google Scholar 

  32. Der-Avakian A, Markou A. The neurobiology of anhedonia and other reward-related deficits. Trends Neurosci. 2012;35:68–77.

    Article  CAS  Google Scholar 

  33. Russo SJ, Nestler EJ. The brain reward circuitry in mood disorders. Nat Rev Neurosci. 2013;14:609–25.

    Article  CAS  Google Scholar 

  34. Espinosa JS, Stryker MP. Development and plasticity of the primary visual cortex. Neuron. 2012;75:230–49.

    Article  CAS  Google Scholar 

  35. Barkat TR, Polley DB, Hensch TK. A critical period for auditory thalamocortical connectivity. Nat Neurosci. 2011;14:1189–94.

    Article  CAS  Google Scholar 

  36. Davis EP, Stout SA, Molet J, Vegetabile B, Glynn LM, Sandman CA, et al. Exposure to unpredictable maternal sensory signals influences cognitive development across species. Proc Natl Acad Sci USA. 2017;114:10390–5.

    Article  CAS  Google Scholar 

  37. Rincón-Cortés M, Herman JP, Lupien S, Maguire J, Shansky RM. Stress: Influence of sex, reproductive status and gender. Neurobiol Stress. 2019;10:100155.

  38. Luby JL, Barch D, Whalen D, Tillman R, Belden A. Association between early life adversity and risk for poor emotional and physical health in adolescence: a putative mechanistic neurodevelopmental pathway. JAMA Pediatr. 2017;171:1168–75.

    Article  Google Scholar 

  39. Doherty TS, Blaze J, Keller SM, Roth TL. Phenotypic outcomes in adolescence and adulthood in the scarcity-adversity model of low nesting resources outside the home cage. Dev Psychobiol. 2017;59:703–14.

    Article  Google Scholar 

  40. Goodwill HL, Manzano-Nieves G, Gallo M, Lee H-I, Oyerinde E, Serre T et al. Early life stress leads to sex differences in development of depressive-like outcomes in a mouse model. Neuropsychopharmacology. 2019;44:711–720.

  41. Mavrikaki M, Pravetoni M, Page S, Potter D, Chartoff E. Oxycodone self-administration in male and female rats. Psychopharmacology. 2017;234:977–87.

    Article  CAS  Google Scholar 

  42. Cicero TJ, Aylward SC, Meyer ER. Gender differences in the intravenous self-administration of mu opiate agonists. Pharm Biochem Behav. 2003;74:541–9.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the National Institute on Drug Abuse (NIDA) Drug Supply Program (Research Triangle Park, NC, USA), for providing heroin and remifentanil.

Funding

The research was supported in part by NIH grants MH096889; NS28912; DA035251; DA044118; GM008620; MH119049 and the Hewitt Foundation for Biomedical Research

Author information

Authors and Affiliations

  1. Department of Neurobiology & Behavior, University of California—Irvine, Irvine, CA, USA

    Sophia C. Levis, Christina R. Perrone & Stephen V. Mahler

  2. Department of Anatomy & Neurobiology, University of California—Irvine, Irvine, CA, USA

    Sophia C. Levis, Jenny Molet, Jessica L. Bolton & Tallie Z. Baram

  3. Department of Psychiatry, Stanford University, Stanford, CA, USA

    Brandon S. Bentzley

  4. Department of Pediatrics, University of California—Irvine, Irvine, CA, USA

    Tallie Z. Baram

Authors
  1. Sophia C. Levis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brandon S. Bentzley
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jenny Molet
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jessica L. Bolton
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christina R. Perrone
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tallie Z. Baram
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Stephen V. Mahler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Tallie Z. Baram or Stephen V. Mahler.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Levis, S.C., Bentzley, B.S., Molet, J. et al. On the early life origins of vulnerability to opioid addiction. Mol Psychiatry 26, 4409–4416 (2021). https://doi.org/10.1038/s41380-019-0628-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-019-0628-5

This article is cited by

Search

Advanced search

Quick links