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Time to connect: bringing social context into addiction neuroscience

Abstract

Research on the neural substrates of drug reward, withdrawal and relapse has yet to be translated into significant advances in the treatment of addiction. One potential reason is that this research has not captured a common feature of human addiction: progressive social exclusion and marginalization. We propose that research aimed at understanding the neural mechanisms that link these processes to drug seeking and drug taking would help to make addiction neuroscience research more clinically relevant.

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Figure 1: Structural changes in the insula in alcoholics.
Figure 2: Sex differences in the effects of social hierarchy on cocaine self-administration in non-human primates.
Figure 3: Schematic representation of hypothesized core circuitry linking social exclusion to drug seeking.

References

  1. Robison, A. J. & Nestler, E. J. Transcriptional and epigenetic mechanisms of addiction. Nat. Rev. Neurosci. 12, 623–637 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Koob, G. F. & Le Moal, M. Addiction and the brain antireward system. Annu. Rev. Psychol. 59, 29–53 (2008).

    Article  PubMed  Google Scholar 

  3. Wise, R. A. Dopamine, learning and motivation. Nat. Rev. Neurosci. 5, 483–494 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Kalivas, P. W. The glutamate homeostasis hypothesis of addiction. Nat. Rev. Neurosci. 10, 561–572 (2009).

    Article  CAS  PubMed  Google Scholar 

  5. Everitt, B. J. & Robbins, T. W. Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat. Neurosci. 8, 1481–1489 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Bossert, J. M., Marchant, N. J., Calu, D. J. & Shaham, Y. The reinstatement model of drug relapse: recent neurobiological findings, emerging research topics, and translational research. Psychopharmacology 229, 453–457 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Piazza, P. V. & Deroche-Gamonet, V. A multistep general theory of transition to addiction. Psychopharmacology 229, 387–413 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Schuster, C. R. & Thompson, T. Self administration of and behavioral dependence on drugs. Annu. Rev. Pharmacol. 9, 483–502 (1969).

    Article  CAS  PubMed  Google Scholar 

  9. Brady, J. V. Animal models for assessing drugs of abuse. Neurosci. Biobehav. Rev. 15, 35–43 (1991).

    Article  CAS  PubMed  Google Scholar 

  10. Epstein, D. H., Preston, K. L., Stewart, J. & Shaham, Y. Toward a model of drug relapse: an assessment of the validity of the reinstatement procedure. Psychopharmacology 189, 1–16 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Sinha, R., Shaham, Y. & Heilig, M. Translational and reverse translational research on the role of stress in drug craving and relapse. Psychopharmacology 218, 69–82 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Dole, V. P. & Nyswander, M. A. Medical treatment for diacetylmorphine (heroin) addiction. A clinical trial with methadone hydrochloride. JAMA 193, 646–650 (1965).

    Article  CAS  PubMed  Google Scholar 

  13. Jasinski, D. R., Pevnick, J. S. & Griffith, J. D. Human pharmacology and abuse potential of the analgesic buprenorphine: a potential agent for treating narcotic addiction. Arch. Gen. Psychiatry 35, 501–516 (1978).

    Article  CAS  PubMed  Google Scholar 

  14. Higgins, S. T. et al. A behavioral approach to achieving initial cocaine abstinence. Am. J. Psychiatry 148, 1218–1224 (1991).

    Article  CAS  PubMed  Google Scholar 

  15. Satel, S. & Lilienfeld, S. O. Addiction and the brain-disease fallacy. Front. Psychiatry 4, 141 (2013).

    PubMed  Google Scholar 

  16. Kalant, H. What neurobiology cannot tell us about addiction. Addiction 105, 780–789 (2010).

    Article  PubMed  Google Scholar 

  17. Berkman, L. F. & Kawachi, I. Social Epidemiology (Oxford Univ. Press, 2000).

    Google Scholar 

  18. Havassy, B. E., Hall, S. M. & Wasserman, D. A. Social support and relapse: commonalities among alcoholics, opiate users, and cigarette smokers. Addict. Behav. 16, 235–246 (1991).

    Article  CAS  PubMed  Google Scholar 

  19. Mantsch, J. R., Baker, D. A., Funk, D., Le, A. D. & Shaham, Y. Stress-induced reinstatement of drug seeking: 20 years of progress. Neuropsychopharmacology 41, 335–356 (2016).

    Article  CAS  PubMed  Google Scholar 

  20. Marlatt, G. A., Baer, J. S., Donovan, D. M. & Kivlahan, D. R. Addictive behaviors: etiology and treatment. Annu. Rev. Psychol. 39, 223–252 (1988).

    Article  CAS  PubMed  Google Scholar 

  21. Brownell, K. D., Marlatt, G. A., Lichtenstein, E. & Wilson, G. T. Understanding and preventing relapse. Am. Psychol. 41, 765–782 (1986).

    Article  CAS  PubMed  Google Scholar 

  22. Eisenberger, N. I. The pain of social disconnection: examining the shared neural underpinnings of physical and social pain. Nat. Rev. Neurosci. 13, 421–434 (2012).

    Article  CAS  PubMed  Google Scholar 

  23. Wager, T. D. et al. An fMRI-based neurologic signature of physical pain. N. Engl. J. Med. 368, 1388–1397 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Garavan, H. Insula and drug cravings. Brain Struct. Funct. 214, 593–601 (2010).

    Article  PubMed  Google Scholar 

  25. Naqvi, N. H., Rudrauf, D., Damasio, H. & Bechara, A. Damage to the insula disrupts addiction to cigarette smoking. Science 315, 531–534 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Dinur-Klein, L. et al. Smoking cessation induced by deep repetitive transcranial magnetic stimulation of the prefrontal and insular cortices: a prospective, randomized controlled trial. Biol. Psychiatry 76, 742–749 (2014).

    Article  PubMed  Google Scholar 

  27. Sullivan, E. V. et al. A selective insular perfusion deficit contributes to compromised salience network connectivity in recovering alcoholic men. Biol. Psychiatry 74, 547–555 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Senatorov, V. V. et al. Reduced anterior insula, enlarged amygdala in alcoholism and associated depleted von Economo neurons. Brain 138, 69–79 (2015).

    Article  PubMed  Google Scholar 

  29. Butti, C., Santos, M., Uppal, N. & Hof, P. R. Von Economo neurons: clinical and evolutionary perspectives. Cortex 49, 312–326 (2013).

    Article  PubMed  Google Scholar 

  30. Naqvi, N. H., Gaznick, N., Tranel, D. & Bechara, A. The insula: a critical neural substrate for craving and drug seeking under conflict and risk. Ann. NY Acad. Sci. 1316, 53–70 (2014).

    Article  PubMed  Google Scholar 

  31. Singer, T., Critchley, H. D. & Preuschoff, K. A common role of insula in feelings, empathy and uncertainty. Trends Cogn. Sci. 13, 334–340 (2009).

    Article  PubMed  Google Scholar 

  32. Gowin, J. L. et al. Attenuated insular processing during risk predicts relapse in early abstinent methamphetamine-dependent individuals. Neuropsychopharmacology 39, 1379–1387 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Uddin, L. Q. Salience processing and insular cortical function and dysfunction. Nat. Rev. Neurosci. 16, 55–61 (2015).

    Article  CAS  PubMed  Google Scholar 

  34. Morgan, D. et al. Social dominance in monkeys: dopamine D2 receptors and cocaine self-administration. Nat. Neurosci. 5, 169–174 (2002).

    Article  CAS  PubMed  Google Scholar 

  35. Martinez, D. et al. Dopamine type 2/3 receptor availability in the striatum and social status in human volunteers. Biol. Psychiatry 67, 275–278 (2010).

    Article  CAS  PubMed  Google Scholar 

  36. Volkow, N. D., Fowler, J. S., Wang, G. J., Swanson, J. M. & Telang, F. Dopamine in drug abuse and addiction: results of imaging studies and treatment implications. Arch. Neurol. 64, 1575–1579 (2007).

    Article  PubMed  Google Scholar 

  37. Chikama, M., McFarland, N. R., Amaral, D. G. & Haber, S. N. Insular cortical projections to functional regions of the striatum correlate with cortical cytoarchitectonic organization in the primate. J. Neurosci. 17, 9686–9705 (1997).

    Article  CAS  PubMed  Google Scholar 

  38. Leong, J. K., Pestilli, F., Wu, C. C., Samanez-Larkin, G. R. & Knutson, B. White-matter tract connecting anterior insula to nucleus accumbens correlates with reduced preference for positively skewed gambles. Neuron 89, 63–69 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Cho, Y. T., Ernst, M. & Fudge, J. L. Cortico–amygdala–striatal circuits are organized as hierarchical subsystems through the primate amygdala. J. Neurosci. 33, 14017–14030 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Nieuwenhuys, R. The insular cortex: a review. Prog. Brain Res. 195, 123–163 (2012).

    Article  PubMed  Google Scholar 

  41. Heilig, M. & Koob, G. F. A key role for corticotropin-releasing factor in alcohol dependence. Trends Neurosci. 30, 399–406 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Orban, C. et al. Resting state synchrony in anxiety-related circuits of abstinent alcohol-dependent patients. Am. J. Drug Alcohol Abuse 39, 433–440 (2013).

    Article  PubMed  Google Scholar 

  43. Machin, A. J. & Dunbar, R. I. M. The brain opioid theory of social attachment: a review of the evidence. Behaviour 148, 985–1025 (2011).

    Article  Google Scholar 

  44. Panksepp, J., Herman, B. H., Vilberg, T., Bishop, P. & DeEskinazi, F. G. Endogenous opioids and social behavior. Neurosci. Biobehav. Rev. 4, 473–487 (1980).

    Article  CAS  PubMed  Google Scholar 

  45. Moles, A., Kieffer, B. L. & D'Amato, F. R. Deficit in attachment behavior in mice lacking the μ-opioid receptor gene. Science 304, 1983–1986 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Fabre-Nys, C., Meller, R. E. & Keverne, E. B. Opiate antagonists stimulate affiliative behaviour in monkeys. Pharmacol. Biochem. Behav. 16, 653–659 (1982).

    Article  CAS  PubMed  Google Scholar 

  47. Panksepp, J., Herman, B., Conner, R., Bishop, P. & Scott, J. P. The biology of social attachments: opiates alleviate separation distress. Biol. Psychiatry 13, 607–618 (1978).

    CAS  PubMed  Google Scholar 

  48. Barr, C. S. et al. Variation at the mu-opioid receptor gene (OPRM1) influences attachment behavior in infant primates. Proc. Natl Acad. Sci. USA 105, 5277–5281 (2008).

    Article  PubMed  Google Scholar 

  49. Copeland, W. E. et al. Child μ-opioid receptor gene variant influences parent-child relations. Neuropsychopharmacology 36, 1165–1170 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Baumgartner, U. et al. High opiate receptor binding potential in the human lateral pain system. Neuroimage 30, 692–699 (2006).

    Article  PubMed  Google Scholar 

  51. Way, B. M., Taylor, S. E. & Eisenberger, N. I. Variation in the μ-opioid receptor gene (OPRM1) is associated with dispositional and neural sensitivity to social rejection. Proc. Natl Acad. Sci. USA 106, 15079–15084 (2009).

    Article  PubMed  Google Scholar 

  52. Hsu, D. T. et al. Response of the μ-opioid system to social rejection and acceptance. Mol. Psychiatry 18, 1211–1217 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Lutz, P. E. & Kieffer, B. L. The multiple facets of opioid receptor function: implications for addiction. Curr. Opin. Neurobiol. 23, 473–479 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Mick, I. et al. Blunted endogenous opioid release following an oral amphetamine challenge in pathological gamblers. Neuropsychopharmacology 41, 1742–1750 (2016).

    Article  CAS  PubMed  Google Scholar 

  55. Khantzian, E. J. The self-medication hypothesis of substance use disorders: a reconsideration and recent applications. Harv. Rev. Psychiatry 4, 231–244 (1997).

    Article  CAS  PubMed  Google Scholar 

  56. Mitchell, J. M. et al. Alcohol consumption induces endogenous opioid release in the human orbitofrontal cortex and nucleus accumbens. Sci. Transl Med. 4, 116ra6 (2012).

    Article  CAS  PubMed  Google Scholar 

  57. Lucantonio, F., Stalnaker, T. A., Shaham, Y., Niv, Y. & Schoenbaum, G. The impact of orbitofrontal dysfunction on cocaine addiction. Nat. Neurosci. 22, 358–366 (2012).

    Article  CAS  Google Scholar 

  58. de Wit, H. Impulsivity as a determinant and consequence of drug use: a review of underlying processes. Addict. Biol. 14, 22–31 (2009).

    Article  PubMed  Google Scholar 

  59. Bickel, W. K. & Marsch, L. A. Toward a behavioral economic understanding of drug dependence: delay discounting processes. Addiction 96, 73–86 (2001).

    Article  CAS  PubMed  Google Scholar 

  60. MacKillop, J. et al. Delayed reward discounting and addictive behavior: a meta-analysis. Psychopharmacology 216, 305–321 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Uekermann, J. & Daum, I. Social cognition in alcoholism: a link to prefrontal cortex dysfunction? Addiction 103, 726–735 (2008).

    Article  PubMed  Google Scholar 

  62. Preller, K. H. et al. Impaired emotional empathy and related social network deficits in cocaine users. Addict. Biol. 19, 452–466 (2014).

    Article  PubMed  Google Scholar 

  63. North, C. S., Eyrich, K. M., Pollio, D. E. & Spitznagel, E. L. Are rates of psychiatric disorders in the homeless population changing? Am. J. Publ. Health 94, 103–108 (2004).

    Article  Google Scholar 

  64. Mullainathan, S. & Shafir, E. Scarcity: Why Having Too Little Means So Much (Times Books, 2013).

    Google Scholar 

  65. Wise, R. A. & Bozarth, M. A. A psychomotor stimulant theory of addiction. Psychol. Rev. 94, 469–492 (1987).

    Article  CAS  PubMed  Google Scholar 

  66. Anthony, J. C., Warner, L. A. & Kessler, R. C. Comparative epidemiology of dependence on tobacco, alcohol, controlled substances, and inhalants: basic findings from the National Comorbidity Survey. Exp. Clin. Psychopharmacol. 2, 244–268 (1994).

    Article  Google Scholar 

  67. Kendler, K. S. et al. Recent advances in the genetic epidemiology and molecular genetics of substance use disorders. Nat. Neurosci. 15, 181–189 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Lopez-Quintero, C. et al. Probability and predictors of transition from first use to dependence on nicotine, alcohol, cannabis, and cocaine: results of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Drug Alcohol Depend. 115, 120–130 (2011).

    Article  PubMed  Google Scholar 

  69. Wolffgramm, J. & Heyne, A. From controlled drug intake to loss of control: the irreversible development of drug addiction in the rat. Behav. Brain Res. 70, 77–94 (1995).

    Article  CAS  PubMed  Google Scholar 

  70. Ahmed, S. H. Validation crisis in animal models of drug addiction: beyond non-disordered drug use toward drug addiction. Neurosci. Biobehav. Rev. 35, 172–184 (2010).

    Article  CAS  PubMed  Google Scholar 

  71. Nader, M. A. & Woolverton, W. L. Effects of increasing the magnitude of an alternative reinforcer on drug choice in a discrete-trials choice procedure. Psychopharmacology 105, 169–174 (1991).

    Article  CAS  PubMed  Google Scholar 

  72. Bozarth, M. A. & Wise, R. A. Toxicity associated with long-term intravenous heroin and cocaine self-administration in the rat. JAMA 254, 81–83 (1985).

    Article  CAS  PubMed  Google Scholar 

  73. Johanson, C. E., Balster, R. L. & Bonese, K. Self-administration of psychomotor stimulant drugs: the effects of unlimited access. Pharmacol. Biochem. Behav. 4, 45–51 (1976).

    Article  CAS  PubMed  Google Scholar 

  74. Cantin, L. et al. Cocaine is low on the value ladder of rats: possible evidence for resilience to addiction. PLoS ONE 5, e11592 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Caprioli, D. et al. Effect of the novel positive allosteric modulator of metabotropic glutamate receptor 2 AZD8529 on incubation of methamphetamine craving after prolonged voluntary abstinence in a rat model. Biol. Psychiatry 78, 463–473 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Deroche-Gamonet, V., Belin, D. & Piazza, P. V. Evidence for addiction-like behavior in the rat. Science 305, 1014–1017 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Krasnova, I. N. et al. Incubation of methamphetamine and palatable food craving after punishment-induced abstinence. Neuropsychopharmacology 39, 2008–2016 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Nader, M. A. & Banks, M. L. Environmental modulation of drug taking: nonhuman primate models of cocaine abuse and PET neuroimaging. Neuropharmacology 76, 510–517 (2014).

    Article  CAS  PubMed  Google Scholar 

  79. Bardo, M. T., Neisewander, J. L. & Kelly, T. H. Individual differences and social influences on the neurobehavioral pharmacology of abused drugs. Pharmacol. Rev. 65, 255–290 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Miczek, K. A., Yap, J. J. & Covington, H. E. III. Social stress, therapeutics and drug abuse: preclinical models of escalated and depressed intake. Pharmacol. Ther. 120, 102–128 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Neisewander, J. L., Peartree, N. A. & Pentkowski, N. S. Emotional valence and context of social influences on drug abuse-related behavior in animal models of social stress and prosocial interaction. Psychopharmacology 224, 33–56 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Lu, L., Shepard, J. D., Hall, F. S. & Shaham, Y. Effect of environmental stressors on opiate and psychostimulant reinforcement, reinstatement and discrimination in rats: a review. Neurosci. Biobehav. Rev. 27, 457–491 (2003).

    Article  CAS  PubMed  Google Scholar 

  83. Bruchas, M. R., Land, B. B. & Chavkin, C. The dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors. Brain Res. 1314, 44–55 (2010).

    Article  CAS  PubMed  Google Scholar 

  84. Alexander, B. K., Coambs, R. B. & Hadaway, P. F. The effect of housing and gender on morphine self-administration in rats. Psychopharmacology 58, 175–179 (1978).

    Article  CAS  PubMed  Google Scholar 

  85. Meisch, R. A. & Carroll, M. E. in Methods of Assessing the Reinforcing Properties of Abused Drugs (ed. Bozarth, M. A.) 143–161 (Springer, 1987).

    Book  Google Scholar 

  86. Bozarth, M. A., Murray, A. & Wise, R. A. Influence of housing conditions on the acquisition of intravenous heroin and cocaine self-administration in rats. Pharmacol. Biochem. Behav. 33, 903–907 (1989).

    Article  CAS  PubMed  Google Scholar 

  87. Wolffgramm, J. & Heyne, A. Social behavior, dominance, and social deprivation of rats determine drug choice. Pharmacol. Biochem. Behav. 38, 389–399 (1991).

    Article  CAS  PubMed  Google Scholar 

  88. Solinas, M., Thiriet, N., Chauvet, C. & Jaber, M. Prevention and treatment of drug addiction by environmental enrichment. Prog. Neurobiol. 92, 572–592 (2010).

    Article  CAS  PubMed  Google Scholar 

  89. Blanchard, D. C. & Blanchard, R. J. Behavioral correlates of chronic dominance–subordination relationships of male rats in a seminatural situation. Neurosci. Biobehav Rev. 14, 455–462 (1990).

    Article  CAS  PubMed  Google Scholar 

  90. Blanchard, R. J., Hori, K., Tom, P. & Blanchard, D. C. Social structure and ethanol consumption in the laboratory rat. Pharmacol. Biochem. Behav. 28, 437–442 (1987).

    Article  CAS  PubMed  Google Scholar 

  91. Heyne, A. The development of opiate addiction in the rat. Pharmacol. Biochem. Behav. 53, 11–25 (1996).

    Article  CAS  PubMed  Google Scholar 

  92. Helms, C. M., McClintick, M. N. & Grant, K. A. Social rank, chronic ethanol self-administration, and diurnal pituitary-adrenal activity in cynomolgus monkeys. Psychopharmacology 224, 133–143 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Jupp, B. et al. Social dominance in rats: effects on cocaine self-administration, novelty reactivity and dopamine receptor binding and content in the striatum. Psychopharmacology 233, 579–589 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Volkow, N. D., Fowler, J. S., Wang, G. J. & Swanson, J. M. Dopamine in drug abuse and addiction: results from imaging studies and treatment implications. Mol. Psychiatry 9, 557–569 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. Nader, M. A. et al. Social dominance in female monkeys: dopamine receptor function and cocaine reinforcement. Biol. Psychiatry 72, 414–421 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Cahill, L. Sex influences on brain and emotional memory: the burden of proof has shifted. Prog. Brain Res. 186, 29–40 (2010).

    Article  PubMed  Google Scholar 

  97. Nader, M. A., Czoty, P. W., Gould, R. W. & Riddick, N. V. Review. Positron emission tomography imaging studies of dopamine receptors in primate models of addiction. Phil. Trans. R. Soc. B 363, 3223–3232 (2008).

    Article  PubMed  Google Scholar 

  98. Eisenberger, N. I., Lieberman, M. D. & Williams, K. D. Does rejection hurt? An fMRI study of social exclusion. Science 302, 290–292 (2003).

    Article  CAS  PubMed  Google Scholar 

  99. Czoty, P. W. & Nader, M. A. Effects of oral and intravenous administration of buspirone on food–cocaine choice in socially housed male cynomolgus monkeys. Neuropsychopharmacology 40, 1072–1083 (2015).

    Article  CAS  PubMed  Google Scholar 

  100. Shaham, Y., Shalev, U., Lu, L., De Wit, H. & Stewart, J. The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology 168, 3–20 (2003).

    Article  CAS  PubMed  Google Scholar 

  101. Shaham, Y., Erb, S. & Stewart, J. Stress-induced relapse to heroin and cocaine seeking in rats: a review. Brain Res. Brain Res. Rev. 33, 13–33 (2000).

    Article  CAS  PubMed  Google Scholar 

  102. Jobes, M. L. et al. Clonidine blocks stress-induced craving in cocaine users. Psychopharmacology 218, 83–88 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Kowalczyk, W. J. et al. Clonidine maintenance prolongs opioid abstinence and decouples stress from craving in daily life: a randomized controlled trial with ecological momentary assessment. Am. J. Psychiatry 172, 760–767 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Vendruscolo, L. F. et al. Corticosteroid-dependent plasticity mediates compulsive alcohol drinking in rats. J. Neurosci. 32, 7563–7571 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Vendruscolo, L. F. et al. Glucocorticoid receptor antagonism decreases alcohol seeking in alcohol-dependent individuals. J. Clin. Invest. 125, 3193–3197 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Grimm, J. W., Hope, B. T., Wise, R. A. & Shaham, Y. Neuroadaptation. Incubation of cocaine craving after withdrawal. Nature 412, 141–142 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Bedi, G. et al. Incubation of cue-induced cigarette craving during abstinence in human smokers. Biol. Psychiatry 69, 708–711 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Caprioli, D. et al. Ambience and drug choice: cocaine- and heroin-taking as a function of environmental context in humans and rats. Biol. Psychiatry 65, 893–899 (2009).

    Article  CAS  PubMed  Google Scholar 

  109. Xue, Y. X. et al. A memory retrieval–extinction procedure to prevent drug craving and relapse. Science 336, 241–245 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Cunningham, K. A., Bradberry, C. W., Chang, A. S. & Reith, M. E. The role of serotonin in the actions of psychostimulants: molecular and pharmacological analyses. Behav. Brain Res. 73, 93–102 (1996).

    Article  CAS  PubMed  Google Scholar 

  111. Schmitz, J. M. et al. Fluoxetine treatment of cocaine-dependent patients with major depressive disorder. Drug Alcohol Depend. 63, 207–214 (2001).

    Article  CAS  PubMed  Google Scholar 

  112. Robinson, T. E. & Berridge, K. C. The neural basis of drug craving: an incentive–sensitization theory of addiction. Brain Res. Rev. 18, 247–291 (1993).

    Article  CAS  PubMed  Google Scholar 

  113. Bradberry, C. W. Cocaine sensitization and dopamine mediation of cue effects in rodents, monkeys, and humans: areas of agreement, disagreement, and implications for addiction. Psychopharmacology 191, 705–717 (2007).

    Article  CAS  PubMed  Google Scholar 

  114. Anton, R. F. et al. A randomized, multicenter, double-blind, placebo-controlled study of the efficacy and safety of aripiprazole for the treatment of alcohol dependence. J. Clin. Psychopharmacol. 28, 5–12 (2008).

    Article  CAS  PubMed  Google Scholar 

  115. Tiihonen, J. et al. A comparison of aripiprazole, methylphenidate, and placebo for amphetamine dependence. Am. J. Psychiatry 164, 160–162 (2007).

    Article  PubMed  Google Scholar 

  116. Nutt, D. J., Lingford-Hughes, A., Erritzoe, D. & Stokes, P. R. The dopamine theory of addiction: 40 years of highs and lows. Nat. Rev. Neurosci. 16, 305–312 (2015).

    Article  CAS  PubMed  Google Scholar 

  117. Badiani, A., Belin, D., Epstein, D., Calu, D. & Shaham, Y. Opiate versus psychostimulant addiction: the differences do matter. Nat. Rev. Neurosci. 12, 685–700 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Thomas, M. J., Kalivas, P. W. & Shaham, Y. Neuroplasticity in the mesolimbic dopamine system and cocaine addiction. Br. J. Pharmacol. 154, 327–342 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Wolf, M. E. & Ferrario, C. R. AMPA receptor plasticity in the nucleus accumbens after repeated exposure to cocaine. Neurosci. Biobehav. Rev. 35, 185–211 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. LaRowe, S. D. et al. A double-blind placebo-controlled trial of N-acetylcysteine in the treatment of cocaine dependence. Am. J. Addict. 22, 443–452 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Le, A. D., Harding, S., Juzytsch, W., Fletcher, P. J. & Shaham, Y. The role of corticotropin-releasing factor in the median raphe nucleus in relapse to alcohol. J. Neurosci. 22, 7844–7849 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Kwako, L. E. et al. The corticotropin releasing hormone-1 (CRH1) receptor antagonist pexacerfont in alcohol dependence: a randomized controlled experimental medicine study. Neuropsychopharmacology 40, 1053–1063 (2015).

    Article  CAS  PubMed  Google Scholar 

  123. Schwandt, M. L. et al. The CRF1 antagonist verucerfont in anxious alcohol dependent women: translation of neuroendocrine, but not of anti-craving effects. Neuropsychopharmacology http://dx.doi.org/10.1038/npp.2016.61 (2016).

  124. Coric, V. et al. Multicenter, randomized, double-blind, active comparator and placebo-controlled trial of a corticotropin-releasing factor receptor-1 antagonist in generalized anxiety disorder. Depress. Anxiety 27, 417–425 (2010).

    Article  CAS  PubMed  Google Scholar 

  125. Binneman, B. et al. A 6-week randomized, placebo-controlled trial of CP-316,311 (a selective CRH1 antagonist) in the treatment of major depression. Am. J. Psychiatry 165, 617–620 (2008).

    Article  PubMed  Google Scholar 

  126. Grillon, C. et al. The CRH1 antagonist GSK561679 increases human fear but not anxiety as assessed by startle. Neuropsychopharmacology 40, 1064–1071 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Maurage, P. et al. Disrupted regulation of social exclusion in alcohol-dependence: an fMRI study. Neuropsychopharmacology 37, 2067–2075 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The writing of this article was supported in part by a grant from the Swedish Research Council (M.H.), the Intramural Research Program of the US National Institutes of Health and the US National Institute on Drug Abuse (D.H.E. and Y.S.) and grants DA010584 and DA017763 (M.A.N.). The authors are grateful to S. N. Haber at the University of Rochester, New York, USA, and her co-workers for producing and providing Figure 3. The authors apologize to their many friends and colleagues for not citing many reviews and empirical papers relevant to the topic of their paper, owing to format restrictions.

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Glossary

Compulsive drug use

Continued use of a drug despite (known) adverse consequences.

Contingency management

A treatment based on systematic reinforcement of a desired, clinically beneficial behaviour.

Craving

The subjective experience of a strong desire to consume a particular substance, to experience its effects or to avoid the symptoms of its withdrawal.

Drug addiction

A clinical condition in which an individual knowingly continues to pursue and consume a chemical substance in a manner that is harmful to that individual or to others.

Pain matrix

A term proposed for a set of brain structures, including the anterior insula and the dorsal anterior cingulate cortex, that are consistently shown by functional MRI to be activated during physical pain.

Postdictive validity

The ability to retrospectively demonstrate an established human phenomenon in an animal model.

Predictive validity

In the context of medications development, the extent to which a drug effect in laboratory animals prospectively predicts therapeutic effects of the same drug in humans.

Protracted withdrawal

The affective symptoms of drug withdrawal — including low mood, elevated anxiety and increased sensitivity to stress — that persist beyond the time frame of acute physical withdrawal (which typically does not last beyond 3–7 days).

Reinstatement

In the context of addiction research, the resumption of drug seeking after extinction of the drug-reinforced responding, induced by exposure to priming doses of drug, drug cues or stressors.

Relapse

Resumption of drug taking after achieving abstinence.

Social defeat

A type of social stress used in laboratory-animal studies that is typically induced by placing a rodent in a cage with an unfamiliar rodent that is expected to attack and defeat the intruder, owing to increased strength, aggression or established dominance.

Social integration

A central concept of sociology, developed by the French sociologist Émile Durkheim, that refers to the web of relationships and interactions — family, kinship groups, traditions or economic activity — through which individuals are connected to each other to form a society; social exclusion is defined as a failure of this process.

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Heilig, M., Epstein, D., Nader, M. et al. Time to connect: bringing social context into addiction neuroscience. Nat Rev Neurosci 17, 592–599 (2016). https://doi.org/10.1038/nrn.2016.67

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