Skip to main content
Download PDF

Neural responses to threat and reward interact to predict stress-related problem drinking: A novel protective role of the amygdala

Biology of Mood & Anxiety Disorders volume 2, Article number: 19 (2012) Cite this article

Abstract

Background

Research into neural mechanisms of drug abuse risk has focused on the role of dysfunction in neural circuits for reward. In contrast, few studies have examined the role of dysfunction in neural circuits of threat in mediating drug abuse risk. Although typically regarded as a risk factor for mood and anxiety disorders, threat-related amygdala reactivity may serve as a protective factor against substance use disorders, particularly in individuals with exaggerated responsiveness to reward.

Findings

We used well-established neuroimaging paradigms to probe threat-related amygdala and reward-related ventral striatum reactivity in a sample of 200 young adult students from the ongoing Duke Neurogenetics Study. Recent life stress and problem drinking were assessed using self-report. We found a significant three-way interaction between threat-related amygdala reactivity, reward-related ventral striatum reactivity, and recent stress, wherein individuals with higher reward-related ventral striatum reactivity exhibit higher levels of problem drinking in the context of stress, but only if they also have lower threat-related amygdala reactivity. This three-way interaction predicted both contemporaneous problem drinking and problem drinking reported three-months later in a subset of participants.

Conclusions

These findings suggest complex interactions between stress and neural responsiveness to both threat and reward mediate problem drinking. Furthermore, they highlight a novel protective role for threat-related amygdala reactivity against drug use in individuals with high neural reactivity to reward.

Findings

Increased amygdala reactivity to threat has been consistently associated with heightened risk for mood and anxiety disorders [1]. In contrast to this heightened risk, a few studies have suggested that threat-related amygdala reactivity may buffer risk for drug abuse. Specifically, one study reported that individuals at high familial risk for alcoholism exhibit relatively reduced threat-related amygdala reactivity [2]. The authors speculate that this pattern may indicate reduced sensitivity to the harmful consequences of excessive alcohol use in those at risk.

Consistent with these findings, a recent study has linked a genetic variant conferring increased risk for drug abuse [3] with relatively decreased threat-related amygdala reactivity [4]. Interestingly, the same genetic risk variant was associated with heightened reward-related reactivity of the ventral striatum (VS), a neural phenotype associated with both risk for and pathophysiology of drug abuse [5, 6]. These data suggest a potentially synergistic effect of threat-related amygdala reactivity and reward-related VS reactivity in precipitating drug abuse risk. In addition to variability in these neural phenotypes, drug abuse risk is moderated by environmental factors, such as recent life stress [7]. Both VS and amygdala function are also affected by stress [8], suggesting that complex interactions between these neural circuits may contribute to variability in stress-related risk for drug abuse.

Here, we explore the interactions of recent life stress, threat-related amygdala and reward-related VS reactivity in predicting variability in self-reported problem drinking in a sample of 200 young adults. We focused on drinking because alcohol is the most commonly used and abused drug in adolescents and young adults [9], and its use is often triggered by stress [7]. Using two well-characterized BOLD fMRI paradigms ([10] Figure 1A-B), we quantified threat-related amygdala and reward-related VS reactivity. Recent life stress and problem drinking were assessed using the Life Events Scale for Students (LESS, [11]) and the Alcohol Use Disorder Identification Test (AUDIT, [12]), respectively. Based on prior research, we predicted that higher threat-related amygdala reactivity would protect against increased problem drinking in the context of stress, particularly in those whose risk is exaggerated by higher reward-related VS reactivity.

Figure 1
figure1

Amygdala and VS reactivity interact with recent stress to predict problem drinking. (A) Statistical parametric map illustrating mean bilateral threat-related amygdala reactivity (left: x=−22, y=−6, z=−18, t=19.76, p<0.000001, kE=173; right: x=28, y=−4, z=−20, t=20.16, p<0.000001, kE=199). (B) Statistical parametric map illustrating mean bilateral reward-related VS reactivity (left: x=−12, y=10, z=−10, t=6.19, p=3.07 x 10-7, kE=357; right: x=12, y=10, z=−8, t=7.31, p=1.03 x 10-9, kE=383). Activation clusters in (A) and (B) are overlaid onto canonical structural brain images in the axial plane. (C) Among participants with low VS reactivity, (1 SD below the mean), recent stress (LESS Highest Impact) was not associated with increased problem drinking (total scores on the AUDIT; square root transformed) regardless of amygdala reactivity. (D) For participants with high (1 SD above the mean) VS reactivity, recent stress predicted significant increases in problem drinking only for those who also had relatively low (1 SD below the mean) amygdala reactivity (blue line). Plotted values are adjusted for sex, age and race/ethnicity.

Full size image

As expected [7], there was a significant positive correlation between recent stress and problem drinking (r=0.22, p=0.004). Critically, however, this relationship was moderated by amygdala and VS reactivity (Figure 1A-B). Specifically, a three-way interaction predicting problem drinking emerged between recent stress, left amygdala reactivity, and left VS reactivity (ΔR2=0.035, b=−0.26, p=0.012). Among participants with low VS reactivity (1 SD below mean; Figure 1C), stress did not predict any increases in drinking, regardless of amygdala reactivity. Among participants with high VS reactivity (1 SD above mean), who are likely to be at increased risk for drug abuse [5], stress predicted increased problem drinking only for those who also had low amygdala reactivity (1 SD below mean; Figure 1D). This three-way interaction remained significant after controlling for gender, age, and race/ethnicity (ΔR2=0.031, b=−0.25, p=0.012). There was no such interaction for right VS or amygdala reactivity (p values > 0.10), and no significant main effects of either amygdala or VS reactivity on problem drinking (p values > 0.14).

Demonstrating the specificity of these findings to recent, as opposed to early, life stress, the three-way interaction remained significant when total scores from the Childhood Trauma Questionnaire [13] were added as an additional covariate (left VS: R2=0.033, b=−0.25, p=0.011). Furthermore, childhood trauma did not interact with amygdala or VS reactivity to predict problem drinking (p values > 0.63). Finally, the same three-way interaction emerged in a subsample of participants (N=85) who completed a three-month follow-up assessment of stress and problem drinking (without covariates: ΔR2=0.085, b=−0.365, p=0.008; with covariates: ΔR2=0.063, b=−0.324, p=0.019). The temporal stability of this interaction suggests that stress-related problem drinking reflects rather than affects the relative neural responsiveness to threat and reward.

An important caveat to consider when interpreting these findings is the possibility that participants drinking more alcohol may experience more stressful life events partially as a result of their increased drinking, rather than the other way around. Since our measures of stress and problem drinking are based on retrospective self-report spanning the past 12 months, the directionality of the association between stress and drinking cannot be determined on the basis of these analyses. Thus we cannot rule out the alternative interpretation that individuals with high VS reactivity and low amygdala reactivity are more likely to experience highly impactful stressful life events in the context of problem drinking. This interpretation would be consistent with a heightened drive to pursue immediate rewards, coupled with a reduced ability to recognize and avoid threat in those individuals.

Limitations notwithstanding, we provide novel evidence that recent life stress is associated with increased problem drinking only in individuals with higher reward-related VS reactivity and lower threat-related amygdala reactivity. Consistent with the relative temporal stability of amygdala [14] and VS [15] reactivity, the interactions between these neural phenotypes and recent life stress predicted future problem drinking in a subset of participants. This finding suggests that the pattern we observe spans longer periods of time and may be useful in identifying individuals at particularly high risk for developing alcohol and possibly other substance use disorders in the wake of stress. Future research identifying factors that predict the observed variability in neural responsiveness to threat and reward (e.g., functional genetic polymorphisms) can inform the development of biomarkers for drug abuse risk and interventions targeting these specific intermediate phenotypes.

Abbreviations

AUDIT:

Alcohol Use Disorder Identification Test

BOLD fMRI:

Blood oxygen level dependent functional magnetic resonance imaging

LESS:

Life Events Scale for Students

VS:

Ventral striatum.

References

  1. 1.

    Stein MB, Simmons AN, Feinstein JS, Paulus MP: Increased amygdala and insula activation during emotion processing in anxiety-prone subjects. A J Psychiatry. 2007, 164: 318-327. 10.1176/appi.ajp.164.2.318.

    Article  Google Scholar 

  2. 2.

    Glahn DC, Lovallo WR, Fox PT: Reduced amygdala activation in young adults at high risk of alcoholism: studies from the Oklahoma family health patterns project. Biol Psychiatry. 2007, 61: 1306-1309. 10.1016/j.biopsych.2006.09.041.

    PubMed Central  Article  PubMed  Google Scholar 

  3. 3.

    Sipe JC, Chiang K, Gerber AL, Beutler E, Cravatt BF: A missense mutation in human fatty acid amide hydrolase associated with problem drug use. Proc Natl Acad Sci USA. 2002, 99: 8394-8399. 10.1073/pnas.082235799.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  4. 4.

    Hariri AR, Gorka A, Hyde LW, Kimak M, Halder I, Ducci F, Ferrell RE, Goldman D, Manuck SB: Divergent effects of genetic variation in endocannabinoid signaling on human threat- and reward-related brain function. Biol Psychiatry. 2009, 66: 9-16. 10.1016/j.biopsych.2008.10.047.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  5. 5.

    Evans AH, Pavese N, Lawrence AD, Tai YF, Appel S, Doder M, Brooks DJ, Lees AJ, Piccini P: Compulsive drug use linked to sensitized ventral striatal dopamine transmission. Ann Neurol. 2006, 59: 852-858. 10.1002/ana.20822.

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    Forbes EE, Brown SM, Kimak M, Ferrell RE, Manuck SB, Hariri AR: Genetic variation in components of dopamine neurotransmission impacts ventral striatal reactivity associated with impulsivity. Mol Psychiatry. 2009, 14: 60-70. 10.1038/sj.mp.4002086.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  7. 7.

    Sinha R: How does stress increase risk of drug abuse and relapse?. Psychopharmacology (Berl). 2001, 158: 343-359. 10.1007/s002130100917.

    Article  CAS  Google Scholar 

  8. 8.

    Rademacher DJ, Meier SE, Shi L, Ho WS, Jarrahian A, Hillard CJ: Effects of acute and repeated restraint stress on endocannabinoid content in the amygdala, ventral striatum, and medial prefrontal cortex in mice. Neuropharmacology. 2008, 54: 108-116. 10.1016/j.neuropharm.2007.06.012.

    Article  CAS  PubMed  Google Scholar 

  9. 9.

    Young SE, Corley RP, Stallings MC, Rhee SH, Crowley TJ, Hewitt JK: Substance use, abuse and dependence in adolescence: prevalence, symptom profiles and correlates. Drug Alcohol Depend. 2002, 68: 309-322. 10.1016/S0376-8716(02)00225-9.

    Article  CAS  PubMed  Google Scholar 

  10. 10.

    Supplementary Online Methods: http://www.biolmoodanxietydisord.com/,

  11. 11.

    Nikolova YS, Bogdan R, Brigidi BD, Hariri AR: Ventral Striatum Reactivity to Reward and Recent Life Stress Interact to Predict Positive Affect. Biol Psychiatry. 2012

    Google Scholar 

  12. 12.

    Saunders JB, Aasland OG, Babor TF, de la Fuente JR, Grant M: Development of the Alcohol Use Disorders Identification Test (AUDIT): WHO Collaborative Project on Early Detection of Persons with Harmful Alcohol Consumption–II. Addiction. 1993, 88: 791-804. 10.1111/j.1360-0443.1993.tb02093.x.

    Article  CAS  PubMed  Google Scholar 

  13. 13.

    Bernstein D, Stein JA, Newcomb MD, Walker E, Pogge D, Ahluvalia T, Stokes J, Handelsman L, Medrano M, Desmond D, Zule W: Development and validation of a brief screening version of the Childhood Trauma Questionnaire. Child Abuse Negl. 2002, 27: 169-190.

    Article  Google Scholar 

  14. 14.

    Manuck SB, Brown SM, Forbes EE, Hariri AR: Temporal stability of individual differences in amygdala reactivity. A J Psychiatry. 2007, 164: 1613-1614. 10.1176/appi.ajp.2007.07040609.

    Article  Google Scholar 

  15. 15.

    Plichta MM, Schwarz AJ, Grimm O, Morgen K, Mier D, Sauer C, Gerdes AB, Haddad L, Tost H, Esslinger C, et al: Test-retest reliability of evoked BOLD signals from a cognitive-emotive fMRI test battery. NeuroImage. 2012, 60: 1746-1758. 10.1016/j.neuroimage.2012.01.129.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

YSN is supported by a Howard Hughes Medical Institute International Student Research fellowship. The Duke Neurogenetics study is supported by Duke University. We would like to thank Annchen Knodt, Adam Gorka, Bart D. Brigidi, and Vanessa V. Sochat for their assistance in data collection and pre-processing.

Author information

Affiliations

  1. Laboratory of NeuroGenetics, Department of Psychology & Neuroscience and Institute for Genome Sciences & Policy, Duke University, NC, 27708, Durham, USA

    Yuliya S Nikolova & Ahmad R Hariri

Authors
  1. Yuliya S Nikolova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ahmad R Hariri
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yuliya S Nikolova.

Additional information

Competing interests

YSN and ARH declare no competing interests.

Authors’ contributions

YSN and ARH designed this study. YSN conducted the statistical analyses and drafted the manuscript. ARH edited the manuscript. Both authors read and approved the final manuscript.

Authors’ original submitted files for images

Below are the links to the authors’ original submitted files for images.

Authors’ original file for figure 1

Rights and permissions

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and Permissions

About this article

Cite this article

Nikolova, Y.S., Hariri, A.R. Neural responses to threat and reward interact to predict stress-related problem drinking: A novel protective role of the amygdala. Biol Mood Anxiety Disord 2, 19 (2012). https://doi.org/10.1186/2045-5380-2-19

Download citation

Keywords

  • Amygdala
  • Ventral striatum
  • Threat
  • Reward
  • Stress
  • Alcohol

Biology of Mood & Anxiety Disorders

ISSN: 2045-5380

Contact us