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Pharmacogenetic approaches to the treatment of alcohol addiction

Key Points

  • Addictive disorders are common, account for a tremendous disease burden and are in need of improved medical treatments. Alcohol use accounts for more disease burden than any other addictive drug with the exception of nicotine.

  • The discovery of naltrexone as a medication for alcoholism was conceptually groundbreaking, because it demonstrated the feasibility of pharmacotherapy for an addictive disorder using a mechanism other than replacement therapy. Overall, however, the effect size of naltrexone turned out to be small, and despite its evidence base, this medication has not gained widespread clinical use.

  • Clinical experience and meta-analyses have long indicated that clinical response to naltrexone is remarkably variable. Over a decade ago, functional genetic variation was discovered at the locus encoding the target for naltrexone, the mu-opioid receptor (MOR), and this was shortly followed by the suggestion that efficacy of naltrexone may be restricted to carriers of the minor allele at this locus.

  • Recently, a series of translational studies in humans, non-human primates and humanized mice has provided consistent support for the notion that alcohol reward is in part mediated by an alcohol–endogenous opioid–dopamine cascade, that this cascade is more vigorously activated by alcohol in carriers of the minor allele at the OPRM1 gene locus that encodes the MOR, and that these subjects are thereby rendered particularly or maybe selectively sensitive to naltrexone.

  • Alcohol reinforcement is mediated by multiple systems, among which opioids and dopamine are but two, and are mostly involved in pleasurable, positively reinforcing alcohol effects experienced mostly in earlier stages of the addictive process. As patients continue heavy alcohol use, a pathological activation of brain stress systems occurs, and sets the scene for negatively reinforced alcohol use — that is, alcohol use aimed at eliminating anxiety and dysphoria that emerges during abstinence.

  • Corticotropin-releasing factor (CRF), the hypothalamic release factor for pituitary adrenocorticotropic hormone (ACTH), is also widely expressed in extrahypothalamic networks that mediate behavioural and emotional stress responses. Recent work has shown that the CRF system becomes activated following a prolonged history of brain alcohol exposure, and its activity is key to negatively reinforced alcohol seeking and use.

  • Genetic variation that influences the functional activity of the CRF system has been found in rats, non-human primates and humans, and has been shown to be associated with various alcohol use phenotypes in all three species. This suggests that pharmacogenetic effects may need to be considered when CRF receptor 1 (CRF1) antagonists are developed for the treatment of alcoholism.

  • GABAergic and serotonergic transmission are also involved in the pathophysiology of alcoholism, and pharmacogenetic effects of variants within both these systems have also been suggested. A potential implication of these findings is that pharmacogenetic effects may turn out to be the rule rather than the exception, and that much more attention will have to be paid to personalizing pharmacotherapy of addictive disorders.

Abstract

Addictive disorders are partly heritable, chronic, relapsing conditions that account for a tremendous disease burden. Currently available addiction pharmacotherapies are only moderately successful, continue to be viewed with considerable scepticism outside the scientific community and have not become widely adopted as treatments. More effective medical treatments are needed to transform addiction treatment and address currently unmet medical needs. Emerging evidence from alcoholism research suggests that no single advance can be expected to fundamentally change treatment outcomes. Rather, studies of opioid, corticotropin-releasing factor, GABA and serotonin systems suggest that incremental advances in treatment outcomes will result from an improved understanding of the genetic heterogeneity among patients with alcohol addiction, and the development of personalized treatments.

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Figure 1: An alcohol–endogenous opioid–dopamine cascade is the target of naltrexone.
Figure 2: Efficacy of naltrexone is moderated by OPRM1 variation in rhesus macaques and humans.
Figure 3: Dopamine release in the ventral striatum in response to alcohol is restricted to OPRM1 118G carriers.
Figure 4: Innate or acquired hyperactivity of extrahypothalamic CRF systems is associated with high alcohol preference.
Figure 5: CRF1 antagonism suppresses stress-induced relapse-like behaviour in msP rats.

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Acknowledgements

The authors want to acknowledge many co-workers in their respective laboratories who over the years have contributed to work reviewed here; C.P.O. particularly wishes to acknowledge contributions by D. Oslin. The laboratories of M.H. and D.G. are supported by the intramural programme of the US National Institute on Alcohol Abuse and Alcoholism. W.H.B. is supported by US National Institutes of Health (NIH) grants P20-DA-025995, R01-DA-025201 and P60-DA 05186. C.P.O. is supported by NIH grants P60-DA-005186-23, 5-P50-DA-012756-11, R01-DA-024553 and R01-AA017164-2.

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M.H., D.G. and W.H.B. have no competing interests to declare. C.P.O. has been a paid consultant for Alkermes, a company that markets an injectable depot formulation of naltrexone.

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Glossary

Disability-adjusted life years

Also known as DALY. A measure of disease burden, expressed as the number of years lost owing to ill-health, disability or early death.

Phenocopy

An environmentally determined observable trait (phenotype) that mimics one that is genetic in nature. Frequently, the use of intermediate phenotypes can help to distinguish between phenocopies.

Kindling

Originally, the act of setting something on fire. In neurology, a process by which repeated electrical or chemical stimulation, initially of insufficient intensity to initiate a seizure, ultimately leads to a lowering of the seizure threshold and spontaneous seizures.

Withdrawal

Sudden and complete cessation of drug taking. The term is also used to denote the syndrome that results when drug is withdrawn after dependence, including tolerance to drug effects, has developed.

Cohen's D

A measure of standardized effect size, most commonly used in treatment studies, and defined as the difference between group means divided by the pooled variance. By convention, 0.2, 0.4 and 0.8 or greater are considered to be small, medium and large effect sizes, respectively.

Pharmacogenetics

The study of inherited variation in the pharmacokinetic or pharmacodynamic effects of drugs. In addictive disorders, the term is used both for the genetic modulation of psychotropic effects produced by the addictive substance and the modulation of therapeutic effects produced by medications used for treatment.

Non-synonymous

A non-synonymous polymorphism is a coding DNA variation that results in altered amino acid sequence.

Single nucleotide polymorphism

(SNP). A one-letter exchange of the genetic code, the most common class of genetic polymorphism between individuals.

Allele

A specific sequence variant encountered at a given position within the genome.

Polymorphism

A common genetic variation (typically considered to be with a frequency >1.0%) within a species.

Linkage disequilibrium

The degree with which a certain combination of alleles at different chromosomal locations is encountered together in a population, in excess of what would be expected by chance alone.

Haplotype block

A block or stretch of DNA that encompasses polymorphisms that are in linkage disequilibrium.

Haplotype

A combination of alleles at different loci on the same chromosome.

Isoform

In relation to proteins, isoforms are different forms of a protein that arise from the same gene.

Reverse translational strategy

Applying findings from humans to model organisms. For example, human genetic variants are inserted into a model organism, allowing their functional role to be studied under better controlled conditions.

Haplotype tagging

The concept that most of the alleles and haplotypes (allele combinations) in a particular chromosomal region can be captured by genotyping a small number of markers.

Chromosomal inversion

A chromosome rearrangement in which a segment of a chromosome is reversed from end to end. An inversion occurs when a single chromosome undergoes breakage and rearrangement within itself.

Intronic

Located in a stretch of DNA between exons; although regulatory elements can reside within introns, genetic variation within introns is often without functional consequences.

Intermediate phenotypes

A genetically influenced trait that is less complex and more proximal to the genetic information than the actual behavioural trait of interest, and is informative of the more distal complex trait while being possible to measure with less variance.

Exon

A stretch of DNA that will be represented in the mature, spliced messenger RNA (mRNA).

Synonymous

A coding sequence variant that, owing to the redundancy of the genetic code, does not result in an amino acid substitution.

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Heilig, M., Goldman, D., Berrettini, W. et al. Pharmacogenetic approaches to the treatment of alcohol addiction. Nat Rev Neurosci 12, 670–684 (2011). https://doi.org/10.1038/nrn3110

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