Familial Transmission of Substance Use Disorders

Merikangas, Kathleen R.; Stolar, Marilyn; Stevens, Denise; Goulet, Joseph L.; Preisig, Martin; Fenton, Brenda T.; Zhang, Heping; O’Malley, Stephanie S.; Rounsaville, Bruce J.

doi:10.1001/archpsyc.55.11.973

Cited by 707 publications

(464 citation statements)

References 53 publications

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Section: Vulnerability To Addiction and Allostasis: Genetic Contributmentioning

confidence: 99%

“…In other words, such vulnerability -whatever the cause, genetic and/ or environmental life events -may reflect a potential or already constituted state of reward system allostasis. Such vulnerability may be a drug-specific phenomenon in that a large component of the heritability is specific for a particular drug (Bierut et al 1998;Merikangas et al 1998).Substantial evidence exists for an important genetic contribution to the vulnerability to develop alcoholism and tobacco addiction. Twin studies with adoption have provided strong evidence for an important genetic influence on the risk of becoming an alcoholic in both men and women (Heath et al 1997a).…”

mentioning

confidence: 99%

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Drug Addiction, Dysregulation of Reward, and Allostasis

Koob

Moal

2001

Neuropsychopharmacology

2,561

1,962

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This paper reviews recent developments in the neurocircuitry and neurobiology of addiction from a perspective of allostasis. A model is proposed for brain changes that occur during the development of addiction that explain the persistent vulnerability to relapse long after drug-taking has ceased. Addiction is presented as a cycle of spiralling dysregulation of brain reward systems that progressively increases, resulting in the compulsive use and loss of control over drug-taking. The development of addiction recruits different sources of reinforcement, different neuroadaptive mechanisms, and different neurochemical changes to dysregulate the brain reward system. Counteradaptive processes such as opponent-process that are part of normal homeostatic limitation of reward function fail to return within the normal homeostatic range and are hypothesized to form an allostatic state. Allostasis from the addiction perspective is defined as the process of maintaining apparent reward function stability by changes in brain reward mechanisms. The allostatic state represents a chronic deviation of reward set point and is fueled not only by dysregulation of reward circuits per se, but also by the activation of brain and hormonal stress responses. The manifestation of this allostatic state as compulsive drugtaking and loss of control over drug-taking is hypothesized to be expressed through activation of brain circuits involved in compulsive behavior such as the cortico-striatal-thalamic loop. The view that addiction is the pathology that results from an allostatic mechanism using the circuits established for natural rewards provides a realistic approach to BACKGROUNDDrug addiction is a chronically relapsing disorder that is defined by two major characteristics: a compulsion to take the drug with a narrowing of the behavioral repertoire toward excessive drug intake, and a loss of control in limiting intake (American Psychiatric Association 1994; World Health Organization 1992). An important challenge for neurobiological research is to understand the neuroadaptive differences between controlled drug use and loss of control, and by extension, the molecular, cellular and system processes that lead to addiction (Koob and Le Moal 1997).Animal models are critical for understanding the neuropharmacological mechanisms involved in the development of addiction. While there are no complete animal models of addiction, animal models do exist for many elements of the syndrome. These elements can be derived from symptoms or diagnostic criteria for addiction or conceptual frameworks such as different sources of reinforcement (American Psychiatric Association 1994; World Health Organization 1992). Linking neu- 24 , NO . 2 ropharmacological events to animal models can occur at multiple levels of analysis -molecular, cellular and system -and it will only be the integration of these changes across dimensions of analysis that will allow a full understanding of the neurobiology of drug addiction.Advances in neuroscience research are rapidly unr...

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Section: Vulnerability To Addiction and Allostasis: Genetic Contributmentioning

confidence: 99%

mentioning

confidence: 99%

Drug Addiction, Dysregulation of Reward, and Allostasis

Koob

Moal

2001

Neuropsychopharmacology

2,561

1,962

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“…In addition to the adaptation that accompanies alcohol abuse, genetic background can unquestionably contribute to the susceptibility of an individual for alcoholism (Cloninger et al 1981;Cloninger 1987;Dick et al 2002;Heath et al 1997;Merikangas 1990;Merikangas et al 1998;Reich et al 1998). To account for this susceptibility, it is presumed that the adaptive consequences of repeated chronic alcohol exposures and stresses are facilitated in individuals with a genetic vulnerability for alcohol abuse.…”

Section: Stress During Withdrawal From Multiple Alcohol Exposures Incmentioning

confidence: 99%

Conceptual framework for the etiology of alcoholism: a ?kindling?/stress hypothesis

2004

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Rationale-The rationale for proposing the "kindling"/stress hypothesis is to provide a conceptual basis for the insidious development and maintenance of alcohol abuse.Objective and results-An objective of the hypothesis is to emphasize how continued alcohol abuse is linked to progressive neural adaptation. Work has shown that repeated withdrawals from chronic low levels of alcohol sensitize ("kindle") anxiety-like behavior ("anxiety") in rats, a finding consistent with multiple withdrawal kindling of seizure activity. Additionally, stress substitutes for initial cycles of the multiple withdrawal protocol to sensitize withdrawal-induced anxiety, which is indicative that stress is capable of facilitating neuroadaptive processes related to withdrawal. The persistence of adaptation caused by stress and multiple withdrawals is revealed by the appearance of withdrawal-induced anxiety following a future re-exposure to a single 5-day period of alcohol. This persisting adaptation also permits stress to induce anxiety during a period of abstinence-a response not observed in animals without previous exposure to alcohol. Furthermore, stress interacts with repeated withdrawals to enhance voluntary alcohol drinking. Results of other preclinical and clinical studies reported in the literature are integrated with these investigations in support of the proposed hypothesis.Conclusions-The "kindling"/stress hypothesis is based on the premise that repeated withdrawals from cycles of chronic alcohol exposure contribute to a progressive development of persisting adaptive change that sensitizes withdrawal-induced anxiety and allows stress to evoke symptoms associated with negative affect during abstinence. Thus, these consequences of repeated withdrawals account for the evolution of major characteristics of alcoholism, which include worsened acute withdrawal symptoms and increased stress-induced negative affect during abstinence, both of which enhance the likelihood of relapse-and with relapse an inability to limit an abusive pattern of alcohol intake. The "kindling"/stress hypothesis provides a clear strategy for future studies to explore the advancing neural adaptation proposed to contribute to the pathogenesis of alcoholism.

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“…Family, twin and adoption studies suggest that genetic factors are implicated in vulnerability of substance abuse (Merikangas et al, 1998;Kendler, 2001;Kendler et al, 2000;Tsuang et al, 2001). The genome-scanning study of poly-substance abuse vulnerability demonstrated that the brain-derived neurotrophic factor (BDNF) gene might be one of the strong candidate genes to drug abuse (Uhl et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Association study between brain‐derived neurotrophic factor gene polymorphisms and methamphetamine abusers in Japan

Itoh

Hashimoto

Shimizu

et al. 2004

American J of Med Genetics Pt B

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Several lines of evidence suggest that genetic factors might contribute to drug abuse vulnerability. Recent genomic scans for association demonstrated that the brain-derived neurotrophic factor (BDNF) gene was associated with drug abuse vulnerability. In this study, we analyzed association of two BDNF gene single nucleotide polymorphisms (SNPs), 132C>T (C270T named formerly) in the noncoding region of exon V and 196G >A (val66met)

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Familial Transmission of Substance Use Disorders

Cited by 707 publications

References 53 publications

Drug Addiction, Dysregulation of Reward, and Allostasis

Drug Addiction, Dysregulation of Reward, and Allostasis

Conceptual framework for the etiology of alcoholism: a ?kindling?/stress hypothesis

Association study between brain‐derived neurotrophic factor gene polymorphisms and methamphetamine abusers in Japan

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