Neurobiological mechanisms of individual vulnerability to alcohol addiction-like behaviors, by Markus Heilig

Summary Neurobiological research on alcohol addiction had grown, but no mechanistically novel medications have been approved in >15 years. Promising candidates have failed in development. What have we been missing?

Three themes have emerged from our attempts to address this question. First, studying neurobiological mechanism in animal models at a group level may be unable to capture mechanisms that render a vulnerable minority of alcohol users prone to disease. Second, patients with alcohol addiction progressively choose alcohol over healthy rewards. The underlying mechanisms may be difficult to identify in animal models that use alcohol as the only reinforcer. Third, in patients, alcohol use continues despite adverse consequences, yet in commonly used animal models, self-administration only results in delivery of the reinforcer.

Through a series of papers, these themes converge to a story, with the amygdala, and its GABA-ergic microcircuitry as key players.

Short Biography 

Markus Heilig received his MD and PhD from Lund University, Sweden, 1986 and 1989, resp. He was a post-doc with George Koob at The Scripps Research Institute, LaJolla, CA 1990 – 1992. Upon returning to Sweden, he completed a psychiatry residency, and served at the Karolinska Institute, Stockholm, Sweden, in various clinical and academic leadership capacities. In 2004, he became the director of intramural clinical and translational research at the National Inst on Alcohol Abuse and Alcoholism. In 2015, Heilig was recruited back to Sweden and Linköping Univ as the founding director of a Center on Social and Affective Neuroscience, a major initiative supported by the Swedish Research Council, Linköping University and the region of Östergötland.

Heilig’s program studies brain brain mechanisms behind addiction and anxiety disorders, using translational approaches. The overall objective is to identify novel therapeutic targets. Research strategies in the program span from analysis of gene expression and its epigenetic programming, through behavioral studies in rodent models, to human experimental medicine that utilizes behavioral, neuroendocrine, psychophysiological and functional brain imaging based methods. This research has over the years generated >300 peer-reviewed papers, including publications in Science, PNAS, Lancet and other high impact journals, yielding close to 30000 citations, and an h-index of 90. Heilig has also authored a textbook on addiction for medical professionals, and popular science books for the lay public.

Heilig is an elected member of the Royal Swedish Academy of Sciences, a Wallenberg Foundation Clinical Fellow, a Fellow of the American College of Neuropsychopharmacology, an editor at Neuropsychopharmacology, and a scientific advisor to the Swedish Medical Products Agency. He has received numerous awards, including the Neuropsychopharmacology Award (European College of Neuropsychopharmacology), the Bowles Award (Bowles Center for Alcohol Studies), the Tabakoff Award (International Society for Biomedical Research on Alcoholism), the Manfred Lautenschläger European Alcohol Research Award (European Society on Biomedical Research on Alcoholism), the Söderberg Award (Swedish Medical Society), the H. David Archibald Award (Center for Addiction and Mental Health, Univ of Toronto), and the Dan Anderson Research Award (Butler Center for Research, Hazelden Foundation).

Recent key reviews:

1. Heilig M, MacKillop J, Martinez D, Rehm J, Leggio L, Vanderschuren L. 2021. Addiction as a brain disease revised: why it still matters, and the need for consilience. Neuropsychopharmacology 10.1038/s41386-020-00950-y
2. Heilig M, Augier E, Pfarr S, Sommer WH. 2019. Developing neuroscience-based treatments for alcohol addiction: A matter of choice? Transl Psychiatry9: 255
3. Heilig M, Barbier E, Johnstone AL, Tapocik J, Meinhardt MW, Pfarr S, Wahlestedt C, Sommer WH. 2017. Reprogramming of mPFC transcriptome and function in alcohol dependence. Genes Brain and Behavior 16: 86-100
4. Heilig M, Epstein DH, Nader MA, Shaham Y. 2016. Time to connect: bringing social context into addiction neuroscience. Nat Rev Neurosci 17: 592-9

Recent key empirical papers:

1. Domi E, Xu L, Toivainen S, Nordeman A, Gobbo F, Venniro M, Shaham Y, Messing RO, Visser E, van den Oever MC, Holm L, Barbier E, Augier E, Heilig M. 2021. A neural substrate of compulsive alcohol use. Sci Adv 7
2. Capusan AJ, Gustafsson PA, Kuja-Halkola R, Igelström K, Mayo L, Heilig M. 2021. Re-examining the link between childhood maltreatment and substance use disorder: a prospective, genetically informative study. Molecular Psychiatry, https://doi.org/10.1038/s41380-021-01071-8
3. Spagnolo PA, Kimes A, Schwandt ML, Shokri-Kojori E, Thada S, Phillips KA, Diazgranados N, Preston KL, Herscovitch P, Tomasi D, Ramchandani VA, Heilig M. 2019. Striatal Dopamine Release in Response to Morphine: A [(11)C]Raclopride Positron Emission Tomography Study in Healthy Men. Biol Psychiatry 86: 356-64
4. Augier E, Barbier E, Dulman RS, Licheri V, Augier G, Domi E, Barchiesi R, Farris S, Natt D, Mayfield RD, Adermark L, Heilig M. 2018. A molecular mechanism for choosing alcohol over an alternative reward. Science 360: 1321-6
5. Mayo LM, Asratian A, Linde J, Holm L, Natt D, Augier G, Stensson N, Vecchiarelli HA, Balsevich G, Aukema RJ, Ghafouri B, Spagnolo PA, Lee FS, Hill MN, Heilig M. 2018. Protective effects of elevated anandamide on stress and fear-related behaviors: translational evidence from humans and mice. Mol Psychiatry, 10.1038/s41380-018-0215-1
6. Barbier E, Johnstone AL, Khomtchouk BB, Tapocik JD, Pitcairn C, Rehman F, Augier E, Borich A, Schank JR, Rienas CA, Van Booven DJ, Sun H, Natt D, Wahlestedt C, Heilig M. 2017. Dependence-induced increase of alcohol self-administration and compulsive drinking mediated by the histone methyltransferase PRDM2. Molecular Psychiatry 22: 1746-58

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