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Heilig, Markus
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Publications (10 of 48) Show all publications
Aoun, E. G., Jimenez, V. A., Vendruscolo, L. F., Walter, N. A., Barbier, E., Ferrulli, A., . . . Leggio, L. (2018). A relationship between the aldosterone-mineralocorticoid receptor pathway and alcohol drinking: preliminary translational findings across rats, monkeys and humans. Molecular Psychiatry, 23(6), 1466-1473
Open this publication in new window or tab >>A relationship between the aldosterone-mineralocorticoid receptor pathway and alcohol drinking: preliminary translational findings across rats, monkeys and humans
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2018 (English)In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 23, no 6, p. 1466-1473Article in journal (Refereed) Published
Abstract [en]

Aldosterone regulates electrolyte and fluid homeostasis through binding to the mineralocorticoid receptors (MRs). Previous work provides evidence for a role of aldosterone in alcohol use disorders (AUDs). We tested the hypothesis that high functional activity of the mineralocorticoid endocrine pathway contributes to vulnerability for AUDs. In Study 1, we investigated the relationship between plasma aldosterone levels, ethanol self-administration and the expression of CYP11B2 and MR (NR3C2) genes in the prefrontal cortex area (PFC) and central nucleus of the amygdala (CeA) in monkeys. Aldosterone significantly increased after 6- and 12-month ethanol self-administration. NR3C2 expression in the CeA was negatively correlated to average ethanol intake during the 12 months. In Study 2, we measured Nr3c2 mRNA levels in the PFC and CeA of dependent and nondependent rats and the correlates with ethanol drinking during acute withdrawal. Low Nr3c2 expression levels in the CeA were significantly associated with increased anxiety-like behavior and compulsive-like drinking in dependent rats. In Study 3, the relationship between plasma aldosterone levels, alcohol drinking and craving was investigated in alcohol-dependent patients. Non-abstinent patients had significantly higher aldosterone levels than abstinent patients. Aldosterone levels positively correlated with the number of drinks consumed, craving and anxiety scores. These findings support a relationship between ethanol drinking and the aldosterone/MR pathway in three different species.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Neurosciences
Identifiers
urn:nbn:se:liu:diva-149720 (URN)10.1038/mp.2017.97 (DOI)000437225900008 ()28461696 (PubMedID)
Note

Funding Agencies|European Foundation for Alcohol Research (ERAB) [EA0619]; ERAB exchange award [EXA0802]; National Institutes of Health (NIH) [ZIA-AA000218]; Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism (NIAAA); Intramural Research Program of the National Institute on Drug Abuse (NIDA); National Institute of Mental Health [MH101076]; Swedish Research Council; Pearson Center for Alcoholism and Addiction Research; NIAAA [AA023867, AA010760, AA08459, AA109431]

Available from: 2018-07-24 Created: 2018-07-24 Last updated: 2018-08-14
Badiani, A., Berridge, K. C., Heilig, M., Nutt, D. J. & Robinson, T. E. (2018). Comments: Addiction research and theory: a commentary on the Surgeon Generals Report on alcohol, drugs, and health. Addiction Biology, 23(1), 3-5
Open this publication in new window or tab >>Comments: Addiction research and theory: a commentary on the Surgeon Generals Report on alcohol, drugs, and health
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2018 (English)In: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600, Vol. 23, no 1, p. 3-5Article in journal, Editorial material (Other academic) Published
Abstract [en]

The Office of the Surgeon General recently produced its first Report on the consequences of alcohol and drug abuse on health, making several very laudable policy recommendations. The Report also emphasizes the importance of adequate funding for biomedical research, which is good news for both researchers and patients. However, the Report is marred by a biased viewpoint on the psychology and neurobiology of drug addiction. We highlight here four controversial issues that were depicted as facts in the Report, thereby potentially misleading non-expert readers about the current state-of-the-art understanding of the psychology and neurobiology of drug addiction. It will be important to recognize a fuller range of scientific viewpoints in addiction neuroscience to avoid amplifying this bias in the coming years.

Place, publisher, year, edition, pages
John Wiley & Sons, 2018
National Category
Substance Abuse
Identifiers
urn:nbn:se:liu:diva-145290 (URN)10.1111/adb.12497 (DOI)28224686 (PubMedID)
Available from: 2018-03-06 Created: 2018-03-06 Last updated: 2018-03-06
Van Hedger, K., Keedy, S. K., Mayo, L. M., Heilig, M. & de Wit, H. (2018). Neural responses to cues paired with methamphetamine in healthy volunteers. Neuropsychopharmacology, 43(8), 1732-1737
Open this publication in new window or tab >>Neural responses to cues paired with methamphetamine in healthy volunteers
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2018 (English)In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 43, no 8, p. 1732-1737Article in journal (Refereed) Published
Abstract [en]

Drug cues, or conditioned responses to stimuli paired with drugs, are widely believed to promote drug use. The acquisition of these conditioned responses has been well characterized in laboratory animals: neutral stimuli paired with drugs elicit conditioned responses resembling the motivational and incentive properties of the drug itself. However, few studies have examined acquisition of conditioning, or the nature of the conditioned response, in humans. In this study, we used fMRI to examine neural responses to stimuli that had been paired with methamphetamine or placebo in healthy young adults. Participants first underwent four conditioning sessions in which visual-auditory stimuli were paired with either methamphetamine (20 mg, oral) or placebo. Then on a drug-free test day, the stimuli were presented during an fMRI scan to assess neural responses to the stimuli. We hypothesized that the stimuli would elicit drug-like brain activity, especially in regions related to reward. Instead, we found that the methamphetamine-paired stimuli, compared to placebo-paired stimuli, produced greater activation in regions related to visual and auditory processing, consistent with the drugs unconditioned effects on sensory processing. This is the first study to demonstrate conditioned neural responses to drug-paired stimuli after just two pairings of methamphetamine in healthy adults. The study also illustrates that conditioned responses may develop to unexpected components of the drugs effects.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:liu:diva-149467 (URN)10.1038/s41386-017-0005-5 (DOI)000435633100015 ()29463908 (PubMedID)
Note

Funding Agencies|NIMH [T32MH020065]; [DA037011]; [S10OD018448]

Available from: 2018-07-05 Created: 2018-07-05 Last updated: 2018-08-10
Bäckryd, E., Heilig, M. & Hoffmann, M. (2017). Dynamiken i förskrivningen av opioider i Sverige 2000–2015 - Markanta omfördelningar inom opioidgruppen, men ingen »epidemi«. Läkartidningen, 114
Open this publication in new window or tab >>Dynamiken i förskrivningen av opioider i Sverige 2000–2015 - Markanta omfördelningar inom opioidgruppen, men ingen »epidemi«
2017 (English)In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 114Article in journal (Refereed) Published
Abstract [en]

Opioid prescription changes in Sweden 2000-2015 In contrast to the well-established »opioid epidemic« in the US, very little is known about how the prescription of opioids in Sweden has developed during the last decade. Aggregated data from the open Statistical database of the Swedish Board of Health and Welfare were analyzed descriptively. The yearly prevalence of opioid prescription did not change 2006-2015, but there were dramatic shifts in the choice of opioids. During this period, dextropropoxyphene was pulled off the market. Tramadol was used by fewer individuals (-54 % over the decade), but dosages expressed as Defined Daily Dose/patient/year (DDD/pat/y) increased (+41 %). In contrast, oxycodone and morphine were used by more individuals (+465 % and +137 %, respectively), but DDD/pat/y decreased during the period (-56% and -54%). Studies on non-aggregated data from available registries are needed to further elucidate the circumstances and possible consequences of these shifts in opioid prescription patterns.

Place, publisher, year, edition, pages
Läkartidningen Förlag, 2017
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:liu:diva-146143 (URN)28485763 (PubMedID)
Available from: 2018-03-29 Created: 2018-03-29 Last updated: 2018-04-13
Lindell, S. G., Schwandt, M. L., Suomi, S. J., Rice, K. C., Heilig, M. & Barr, C. S. (2017). Intermittent Access to Ethanol Induces Escalated Alcohol Consumption in Primates. Journal of addictive behaviors, therapy and rehabilitation, 6(1)
Open this publication in new window or tab >>Intermittent Access to Ethanol Induces Escalated Alcohol Consumption in Primates
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2017 (English)In: Journal of addictive behaviors, therapy and rehabilitation, ISSN 2324-9005, Vol. 6, no 1Article in journal (Refereed) Published
Abstract [en]

Escalation of voluntary alcohol drinking is characteristic of alcohol addiction and can be induced in rodents using intermittent access to alcohol. This model has been used to evaluate candidate therapeutics, but key systems involved in the transition into alcohol addiction, such as CRF, differ in their organization between rodents and primates. We examined the ability of an intermittent access schedule to induce escalation of voluntary alcohol drinking in non-human primates and used this model to assess the role of corticotropin releasing hormone (CRF) signaling in this process.

Place, publisher, year, edition, pages
SciTechnol, 2017
Keywords
Alcohol; CRF; Dependence; Intermittent access; Rhesus macaque
National Category
Substance Abuse
Identifiers
urn:nbn:se:liu:diva-146056 (URN)10.4172/2324-9005.1000163 (DOI)29082267 (PubMedID)
Available from: 2018-03-28 Created: 2018-03-28 Last updated: 2018-04-26
Karlsson, C., Schank, J. R., Rehman, F., Stojakovic, A., Björk, K., Barbier, E., . . . Heilig, M. (2017). Proinflammatory signaling regulates voluntary alcohol intake and stress-induced consumption after exposure to social defeat stress in mice. Addiction Biology, 22(5), 1279-1288
Open this publication in new window or tab >>Proinflammatory signaling regulates voluntary alcohol intake and stress-induced consumption after exposure to social defeat stress in mice
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2017 (English)In: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600, Vol. 22, no 5, p. 1279-1288Article in journal (Refereed) Published
Abstract [en]

Proinflammatory activity has been postulated to play a role in addictive processes and stress responses, but the underlying mechanisms remain largely unknown. Here, we examined the role of interleukin 1 (IL-1) and tumor necrosis factor-a (TNF-a) in regulation of voluntary alcohol consumption, alcohol reward and stress-induced drinking. Mice with a deletion of the IL-1 receptor I gene (IL-1RI KO) exhibited modestly decreased alcohol consumption. However, IL-1RI deletion affected neither the rewarding properties of alcohol, measured by conditioned place preference (CPP), nor stress-induced drinking induced by social defeat stress. TNF-a signaling can compensate for phenotypic consequences of IL1-RI deletion. We therefore hypothesized that double deletion of both IL-1RI and TNF-1 receptors (TNF-1R) may reveal the role of these pathways in regulation of alcohol intake. Double KOs consumed significantly less alcohol than control mice over a range of alcohol concentrations. The combined deletion of TNF-1R and IL-1RI did not influence alcohol reward, but did prevent increased alcohol consumption resulting from exposure to repeated bouts of social defeat stress. Taken together, these data indicate that IL-1RI and TNF-1R contribute to regulation of stress-induced, negatively reinforced drinking perhaps through overlapping signaling events downstream of these receptors, while leaving rewarding properties of alcohol largely unaffected.

Place, publisher, year, edition, pages
John Wiley & Sons, 2017
Keywords
CPP; IL-1RI; TNF-1R; alcohol; cytokines; social defeat stress
National Category
Substance Abuse
Identifiers
urn:nbn:se:liu:diva-146330 (URN)10.1111/adb.12416 (DOI)000408409700012 ()27273552 (PubMedID)
Available from: 2018-04-07 Created: 2018-04-07 Last updated: 2018-04-07
Bejerot, S., Landén, M., Heilig, M., Anckarsäter, H. & Waern, M. (2017). Socialstyrelsens målnivåer signalerar brist på tillit in Lakartidningen, vol 114, issue , pp [Letter to the editor]. Läkartidningen, 114
Open this publication in new window or tab >>Socialstyrelsens målnivåer signalerar brist på tillit in Lakartidningen, vol 114, issue , pp
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2017 (Swedish)In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 114Article in journal, Letter (Other academic) Published
Place, publisher, year, edition, pages
Stockholm, Sweden: Läkartidningen Förlag AB, 2017
National Category
Psychiatry
Identifiers
urn:nbn:se:liu:diva-146348 (URN)29292910 (PubMedID)
Available from: 2018-04-07 Created: 2018-04-07 Last updated: 2018-04-20Bibliographically approved
Augier, E., Dulman, R. S., Damadzic, R., Pilling, A., Hamilton, P. & Heilig, M. (2017). The GABA(B) Positive Allosteric Modulator ADX71441 Attenuates Alcohol Self-Administration and Relapse to Alcohol Seeking in Rats. Neuropsychopharmacology, 42(9), 1789-1799
Open this publication in new window or tab >>The GABA(B) Positive Allosteric Modulator ADX71441 Attenuates Alcohol Self-Administration and Relapse to Alcohol Seeking in Rats
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2017 (English)In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 42, no 9, p. 1789-1799Article in journal (Refereed) Published
Abstract [en]

GABAergic signaling is involved in modulating the reinforcing properties of alcohol, and GABA(B) receptors have been proposed as a potential target for clinical treatment of alcoholism. The orthosteric GABA(B) receptor agonist baclofen has been shown to suppress operant self-administration of alcohol in animals and alcohol use in alcohol-dependent patients, but its utility is limited by a narrow therapeutic index. We tested the effects of ADX71441, a novel GABA(B) receptor positive allosteric modulator, on alcohol-related behaviors in rats. We first assessed the effects of ADX71441 ( 1, 3, 10 and 30 mg/kg, I.P.) on both non-dependent and dependent male Wistar rats trained to self-administer 20% alcohol. We then determined the effects of ADX71441 on stress-induced as well as cue-induced relapse-like behavior. Finally, we sought to identify the brain regions through which ADX71441 may act to prevent relapse-like behavior by mapping the neuronal activation induced by stress-induced reinstatement of alcohol-seeking using c-Fos immunohistochemistry. ADX71441 dose-dependently decreased alcohol self-administration of both dependent and non-dependent animals, but its potency was higher in alcohol-dependent rats. Furthermore, both cue-and stress-induced alcohol seeking were blocked by the GABA(B) receptor positive allosteric modulator. Finally, pretreatment with 3 mg/kg of ADX71441 before stress-induced reinstatement significantly decreased c-Fos expression in a network of brain regions implicated in stress-induced relapse, comprising the nucleus accumbens shell, the dorsal raphe nucleus and the medial prefrontal cortex. Our findings support a causal role of GABAB receptors in alcohol reinforcement and relapse to alcohol seeking. These effects are observed in the absence of significant sedative side effects. Jointly, these observations indicate that GABAB receptor positive allosteric modulators merit being tested clinically for the treatment of alcoholism. Our data also point to a potential biomarker of target engagement for early clinical studies.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2017
National Category
Neurosciences
Identifiers
urn:nbn:se:liu:diva-139537 (URN)10.1038/npp.2017.53 (DOI)000405372200005 ()28294133 (PubMedID)
Note

Funding Agencies|Intramural Research Programs of the National Institute on Drug Abuse; National Institute on Alcohol Abuse and Alcoholism; Swedish Research Council

Available from: 2017-08-08 Created: 2017-08-08 Last updated: 2018-05-02
Sells, J. R., Waters, A. J., Schwandt, M. L., Kwako, L. E., Heilig, M., George, D. T. & Ramchandani, V. A. (2016). Characterization of comorbid PTSD in treatment-seeking alcohol dependent inpatients: Severity and personality trait differences. Drug And Alcohol Dependence, 163, 242-246
Open this publication in new window or tab >>Characterization of comorbid PTSD in treatment-seeking alcohol dependent inpatients: Severity and personality trait differences
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2016 (English)In: Drug And Alcohol Dependence, ISSN 0376-8716, E-ISSN 1879-0046, Vol. 163, p. 242-246Article in journal (Refereed) Published
Abstract [en]

Background: Post-traumatic stress disorder (PTSD) is often comorbid with alcohol dependence (AD), but little is known about the characteristics of AD treatment-seeking inpatients with PTSD. We examined differences between treatment-seeking alcohol dependent inpatients with and without comorbid PTSD. We hypothesized that those with AD and PTSD would have higher levels of: (1) alcohol use and AD severity; (2) anxiety and mood disorders; (3) neuroticism. Methods: Individuals (N = 411, mean age = 41.7 +/- 10.0 years) with AD were monitored over 30 days in a suburban inpatient alcohol treatment setting. Patients were evaluated to identify AD and comorbid PTSD, mood and anxiety disorders, alcohol use and dependence severity, personality, and aggression. Results: Those with PTSD (19% of the sample) did not differ in the amount of alcohol consumed, but had greater: (1) severity of AD (p = 0.001, d = 0.44); (2) diagnosis of anxiety (p = 0.000, OR = 3.64) and mood (p = 0.000, OR = 4.83) disorders; and (3) levels of neuroticism (p amp;lt; 0.001, d = 0.67) and aggression (p amp;lt; 0.001, d = 0.81). Conclusions: AD patients with comorbid PTSD present a more severe phenotype across AD severity, frequency of anxiety and mood disorders, and levels of neuroticism and aggression. This group may benefit from concurrent treatment of both AD and PTSD. Future research can investigate neuroticism as a potential treatment target. Published by Elsevier Ireland Ltd.

Place, publisher, year, edition, pages
ELSEVIER IRELAND LTD, 2016
Keywords
Alcohol dependence; Alcoholism; PTSD; Neuroticism; Aggression
National Category
Substance Abuse
Identifiers
urn:nbn:se:liu:diva-130288 (URN)10.1016/j.drugalcdep.2016.03.016 (DOI)000378457000032 ()27114205 (PubMedID)
Available from: 2016-08-01 Created: 2016-07-28 Last updated: 2017-05-23
Heilig, M. & Carlezon, W. A. (2016). Editorial Material: Circumspectives: Cannabis and Psychiatric Illness: Blunt Thoughts in NEUROPSYCHOPHARMACOLOGY, vol 41, issue 2, pp 391-392. Neuropsychopharmacology, 41(2), 391-392
Open this publication in new window or tab >>Editorial Material: Circumspectives: Cannabis and Psychiatric Illness: Blunt Thoughts in NEUROPSYCHOPHARMACOLOGY, vol 41, issue 2, pp 391-392
2016 (English)In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 41, no 2, p. 391-392Article in journal, Editorial material (Other academic) Published
Abstract [en]

n/a

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2016
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-124112 (URN)10.1038/npp.2015.321 (DOI)000366599400001 ()26555278 (PubMedID)
Available from: 2016-01-22 Created: 2016-01-19 Last updated: 2017-05-23
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