Pharmacogenetic Approaches To The Treatment of Alcohol Addiction

REVIEWS
Pharmacogenetic approaches to
the treatment of alcohol addiction
Markus Heilig*, David Goldman, Wade Berrettini and Charles P.OBrien
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.
Disability-adjusted life years

Addictive disorders account for an extensive disease bur- Clearly, extensive unmet medical needs remain in this
Also known as DALY. A den, and disproportionately affect people in the prime of therapeuticarea.
measure of disease burden, their lives. In industrialized countries, alcohol use alone In this Review, we first show that there is considerable
expressed as the number of causes about 10% of total disability-adjusted life years heterogeneity among people with alcohol addiction, and
years lost owing to ill-health,
lost 1, and a recent evaluation in the United Kingdom that this heterogeneity suggests a need for personalized
disability or early death.
concluded that in aggregate, the harm to self and oth- treatment approaches based on, among other factors,
ers inflicted by alcohol exceeds that caused by heroin genetic variation. We then review evidence for func-
or cocaine2. Alcohol consumption in the population is tional genetic variation within biological systems that
markedly skewed, and a large proportion of alcohol- mediate positive and negative reinforcement from alco-
related disability is due to alcohol addiction, hereafter hol including the opioid and corticotropin-releasing
equated with alcoholism. This is a condition that in the factor (CRF; also known as CRH) systems and sum-
United States affects more than 12% of the population marize evidence that this variation is likely to moder-
at some point in their life3. Alcoholism is a chronic, ate treatment effects. An overarching objective of this
*Laboratory of Clinical and relapsing disorder that shares many characteristics with Review is to point the way for translating the consider-
Translational Studies,
other complex chronic conditions, such as diabetes or able advances recently made in the basic neuroscience
National Institute on Alcohol
Abuse and Alcoholism, hypertension: it has a considerable component of genetic of alcohol addiction into therapeutic gains for patients.
National Institutes of Health, susceptibility, is under marked influence of environmen-
Bethesda, Maryland 20892, tal factors, and its onset and course are fundamentally Alcoholics differ from each other
USA. shaped by behavioural choices4,5. This prompts the ques- A clinical diagnosis of alcoholism is currently made
Laboratory of
Neurogenetics, National
tion of whether alcoholism can be tackled with medical on the basis of diagnostic criteria that are standard-
Institute on Alcohol Abuse treatments. Some efficacy of medications for alcohol- ized across addictive disorders by the Diagnostic and
and Alcoholism, National ism6 as well as opiate7 and nicotine8 addiction has been Statistical Manual of Mental Disorders, which is cur-
Institutes of Health, documented and supports the feasibility of addiction rently in its fourth edition (DSM IV)11. In the absence of
Bethesda, Maryland 20892,
pharmacotherapy. However, with the exception of meth- reliable biomarkers, this approach eliminates some of the
USA.
Department of Psychiatry, adone or buprenorphin maintenance therapy for opioid subjective judgement involved in making diagnoses, and
University of Pennsylvania, addictions, the effect sizes of these treatments are small. has clinical utility. However, there is reason to believe
Philadelphia, Pennsylvania Despite evidence-based guidelines that pharmacother- that patients diagnosed using this approach are markedly
19104, USA. apy be considered in all patients with alcoholism, and in heterogeneous. In fact, such heterogeneity was already
Correspondence to M.H.
email: markus.heilig@mail.
particular in those who are not successfully treated with proposed in the 1980s on the basis of clinical characteris-
nih.gov behavioural interventions alone9, only a small minor- tics such as age of onset, but also on family history, which
doi:10.1038/nrn3110 ity of patients receive medication for their alcoholism10. is a marker of genetic susceptibility 12. Numerous other
670 | NOVEMBER 2011 | VOLUME 12 www.nature.com/reviews/neuro
2011 Macmillan Publishers Limited. All rights reserved

F O C U S O N a dRdEic
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Box 1 | Alcohol addiction is an end-stage disease

A clinical diagnosis of alcoholism is probably best
viewed as an end-stage disease, similar to congestive
Patients ultimately diagnosed with the heart failure. In this view, the diagnostic category of
5GXGTKV[QHGPXKTQPOGPVCNVTKIIGTU
.QYIGPGVKETKUM
clinical condition labelled as alcoholism can alcoholism consists of conditions that are phenotypically
*KIJIGPGVKETKUM
arrive at this phenotype through very similar (or constitute phenocopies), but patients arrive at
different trajectories (see the figure, which
the disease state through fundamentally different trajec-
indicates two prototypical examples of such
trajectories). In the graph, which is based on
tories. This is captured by a conceptualization that was
a model adapted from REF. 16, the x axis first put forward for major depression16, but is also likely
represents time and the y axis shows the to apply to addiction (BOX 1). In a kindling-like process,
level of environmental insult such as brain exposure to cycles of intoxication and withdrawal
exposure to stressors or consumption of &KUGCUG\QPG induces progressive neuroadaptations that ultimately
alcohol that is required for triggering result in escalation of alcohol intake17,18. In the absence
relapse to the next episode of compulsive of significant genetic susceptibility, escalation will only
6KOG
[GCTU
alcohol seeking and intake, despite the result following prolonged exposure to alcohol and the
adverse consequences of drinking alcohol. environmental factors with which it interacts, such as
In the example illustrated by the green curve, progression to alcoholism is driven by a
stress. By contrast, when genetic risk factors are pre-
high level of exposure to environmental risk factors in the 0CVWTG4GXKGYU^0GWTQUEKGPEG
absence of significant genetic
susceptibility. In this type of trajectory, a high level of environmental insult is initially
sent, progression can be fast. These individuals can be
required to trigger an episode of compulsive alcohol use. Over time, however, there is a viewed, in terminology borrowed from the depression
kindling-like process, in which a progressively lower level of environmental insult is literature16, as pre-kindled, or already there.
required to trigger the next episode of heavy use, and compulsive alcohol use Emerging evidence indicates that individuals with
ultimately becomes self-perpetuating. In the example illustrated by the blue dashed alcohol addiction who are on trajectories that are driven
curve, genetic susceptibility can instead be thought to have rendered the subject by different biological mechanisms or who are in dif-
pre-kindled, or already there. For these individuals, even small environmental insults ferent stages of addiction can be expected to respond
will trigger episodes of compulsive alcohol use early on in the process. to different treatments. Fundamentally, treatments for
Each of the lines shown in the graph should be considered as representative of a class alcohol addiction must intervene with biological mecha-
of trajectories, because both genetic and environmental risk factors themselves are
nisms that provide motivation for alcohol seeking and
diverse. On average, studies find that genetic factors account for 5060% of disease risk
in alcoholism, but multiple risk alleles in different combinations contribute to the
consumption19. These mechanisms largely fall into two
genetic risk in each individual case5. This results in genetic vulnerability that can be main categories. First, in a similar way to other drugs
mediated through traits as different as impulsivity and heightened alcohol reward on of abuse, alcohol can activate brain reward pathways,
one hand, and stress sensitivity and anxiety on the other. Likewise, environmental leading to positively reinforced alcohol seeking and use.
factors that drive progression to the clinical phenotype of alcoholism can vary, and Secondly, alcohol can acutely suppress negative emo-
include stress and prolonged consumption of alcohol, which initially may only be due to tions that result from stress or withdrawal from alco-
easy availability or low cost. hol itself, such as anxiety and dysphoria, thus setting
As a result of this diversity in genetic and environmental risk factors, patient the scene for negatively reinforced alcohol use18,20. To
populations that are grouped based on clinical diagnosis alone are likely to be markedly highlight the distinction between these two incentives
heterogeneous with regard to underlying biology. This in turn implies that subgroups of
for alcohol use, the terms reward drinking and relief
alcoholics defined by their biology will be amenable to different medical treatments.
Understanding the diverse genetic and environmental factors that contribute to the
drinking have been introduced21. It is reasonable to
pathophysiology of alcoholism in each individual case will be crucial for personalizing expect that these different types of excessive alcohol use
treatment approaches. This theoretical analysis applies in principle to most complex will require different treatments.
disorders, but recent data show that taking it into account will be particularly crucial Alcoholism has a moderate to high heritability,
both for the optimal use of currently available alcoholism treatments, and to enrich and in part shares genetic susceptibility factors with
chances for success in developing new ones. other addictions5. Genetic and environmental factors
in alcoholism can result in very different types of vul-
nerability, ranging from heightened impulsivity and
Phenocopy
attempts at clinical subtyping of people with alcoholism reward from alcohol to enhanced stress responses and
An environmentally
determined observable trait have since followed. The use of genetic markers offers anxious personality traits12. Genetic variants that alter
(phenotype) that mimics one the possibility of more reliably and consistently captur- alcohol reward- or stress-related emotional processing
that is genetic in nature. ing the heterogeneity of people with alcoholism, in ways are therefore probable modifiers of disease trajectories
Frequently, the use of that are closer to its biological underpinnings. and of responses to treatments that target reward and
intermediate phenotypes can
help to distinguish between
Among individuals in the general population who stresssystems.
phenocopies. fulfil diagnostic criteria for alcoholism, the majority
about three-quarters never receive treatment 3. Targeting opioid-mediated alcohol reward
Kindling Available data indicate that those people who go on to Alcohol reward is in part mediated by endogenous
Originally, the act of setting
enter treatment and those who do not are fundamentally opioids. Although the exact role of mesolimbic dopa-
something on fire. In neurology,
a process by which repeated different with regard to personality traits, alcohol use mine in addiction remains controversial, activation
electrical or chemical patterns and long-term outcomes1315. Furthermore, clas- of this pathway is thought to confer incentive salience
stimulation, initially of sic longitudinal studies show that long-term outcomes to addictive drugs, to reward their pursuit or con-
insufficient intensity to initiate and alcohol-related harm vary markedly between indi- sumption, or to be otherwise related to their addictive
a seizure, ultimately leads to a
lowering of the seizure
viduals in ways that do not seem to have a simple cor- properties20,2224. Accordingly, studies in experimental
threshold and spontaneous relation with participation in treatment or the level of animals25,26 and humans27,28 have demonstrated that
seizures. alcohol use13,14. alcohol activates the mesolimbic dopamine circuitry.
NATURE REVIEWS | NEUROSCIENCE VOLUME 12 | NOVEMBER 2011 | 671

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#NEQJQN of alcoholism is associated with clinical improvement in

response to naltrexone treatment 32. Support for a role
/14 of family history in the clinical response to naltrexone
s has also been found in laboratory studies; family history
'2 influenced both the effect of naltrexone on subjective
/GUQNKODKE feelings of a high from a standard alcohol dose33 and
&QRCOKPG RCVJYC[ s the level of alcohol self-administration34. Although a role
)#$# )#$# of family history could reflect genetic or environment
KPVGTPGWTQP
factors (or both), emerging evidence strongly suggests
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a major role of pharmacogenetics in the clinical response
Figure 1 | An alcoholendogenous opioiddopamine cascade is the target of to naltrexone, as discussedbelow.
naltrexone. Schematic of the alcoholopioiddopamine0CVWTG4GXKGYU^0GWTQUEKGPEG
cascade that is thought to be
the target of naltrexone, based on integration of circuitries originally proposed in REFS Functional variation at the OPRM1 locus as a phar-
29,156. Dopaminergic ventral tegmental area (VTA) neurons that project to the nucleus macogenetic determinant. The possibility of pharma-
accumbens (NAc) are under tonic inhibition by GABAergic interneurons within the VTA.
cogenetic heterogeneity in the response to naltrexone is
GABA release from these neurons is in turn under negative regulation by the mu-opioid
particularly important to consider, because more than a
receptor (MOR). When alcohol is ingested, endogenous opioids such as endorphins
(-EPs) are released, resulting in inhibition of GABA release in the VTA and removal of the decade ago a common functional variant was discovered
inhibitory tone from the dopamine cells. This cascade ultimately results in increased in the OPRM1 gene, which encodes the MOR, the target
dopamine release in the terminal areas in the NAc. for naltrexone35,36. This non-synonymous 118AG single
nucleotide polymorphism (SNP), rs1799971, encodes an
asparagine (N) aspartate (D) substitution in position
Dopamine neurotransmission in the corticomesolimbic 40 of the receptor protein (N40D). The exchange occurs
Withdrawal
Sudden and complete cessation
system is modulated by the muopioid receptor (MOR; in the aminoterminal extracellular loop of the recep-
of drug taking. The term is also also known as MOR1). Inhibitory tone from GABAergic tor, and results in the loss of a putative glycosylation
used to denote the syndrome interneurons onto dopamine cell bodies in the ven- site (BOX 2). The frequency of the less common (minor)
that results when drug is tral tegmental area (VTA) is removed through MOR 118G allele at this locus varies between populations of
withdrawn after dependence,
activation on GABA neurons by endogenous opioids, different ancestry (see below). The precise functional
including tolerance to drug
effects, has developed. which ultimately results in increased dopamine release consequences of the N40D substitution for MOR func-
in terminal areas in the ventral striatum29,30. The exact tion remain unclear, and its role as a genetic risk factor in
Cohens D mechanism by which alcohol interacts with this circuitry addictive disorders is controversial3641. However, based
A measure of standardized remains unknown. However, studies in experimental on a secondary analysis of three clinical trials, it was sug-
effect size, most commonly
used in treatment studies, and
animals show that MOR blockade in the VTA largely gested that this polymorphism might moderate the thera-
defined as the difference prevents accumbal dopamine release induced by alcohol peutic efficacy of naltrexone, and that beneficial effects
between group means divided intake, indirectly showing that alcohol leads to release of of naltrexone might be largely restricted to OPRM1 118G
by the pooled variance. By endogenous opioids within this structure and thereby carriers42. This finding was subsequently replicated in
convention, 0.2, 0.4 and 0.8
drives dopamine release31 (FIG. 1). Another, independent a secondary analysis of the large, US National Institute
or greater are considered to be
small, medium and large effect line of research led to development and approval of the on Alcohol Abuse and Alcoholism (NIAAA)-sponsored
sizes, respectively. opioid receptor antagonist naltrexone as a medication COMBINE trial, in which naltrexone almost doubled
for alcoholism6 (BOX 2). A synthesis of these two research the proportion of patients with a good clinical outcome
Pharmacogenetics lines leads to the hypothesis that the mechanism through in the group of 118G carriers (from ~50% to ~90%),
The study of inherited variation
in the pharmacokinetic or
which naltrexone exerts its therapeutic action is by but had no effect on outcome in 118A homozygous
pharmacodynamic effects of disrupting the cascade that leads to striatal dopamine patients43. Although one clinical study failed to replicate
drugs. In addictive disorders, release following alcoholintake. this finding 44, a role of OPRM1 variation as a moderator
the term is used both for the However, although a meta-analysis6 supports the effi- of alcohol reward and naltrexone effects was also sup-
genetic modulation of
cacy of naltrexone treatment in alcoholism, the average ported by results of elegant human laboratory studies45,46.
psychotropic effects produced
by the addictive substance and effect size is small, with a Cohens D of approximately The evaluation of pharmacogenetic factors poses
the modulation of therapeutic 0.2. One possible conclusion is that endogenous opioids considerable challenges. Unless subjects in clinical trials
effects produced by only play a minor part in alcohol reward and excessive are apriori recruited and randomization is stratified by
medications used for alcohol use, limiting the utility of treatments that target genotype, undetected sources of bias may obscure true
treatment.
this mechanism. In fact, despite solid evidence for its findings. Drug effects that are restricted to carriers of
Non-synonymous efficacy, naltrexone has not come into widespread clini- a minor allele are difficult to detect, because the sam-
A non-synonymous cal use, and scepticism about its efficacy is one of the ple size may simply be too small. Rodent models can-
polymorphism is a coding DNA reasons given by clinicians10. not easily be used to address the role of specific human
variation that results in altered
However, an alternative interpretation of the limited genetic variants in drug responses, because variants that
amino acid sequence.
overall effect size of naltrexone is that it reflects hetero- are functionally equivalent to those found in humans are
Single nucleotide geneity of response among patients. In fact, both clini- rarely if ever found in rodents owing to the large phylo-
polymorphism cal experience and meta-analyses have long indicated genetic distance between these species. Studies in non-
(SNP). A one-letter exchange of a heterogeneity of naltrexone responses in people with human primates can be helpful in this regard, because
the genetic code, the most
common class of genetic
alcoholism, and have implied a possible role of genetic functional equivalents of behaviourally important
polymorphism between factors in this heterogeneity. For instance, a meta-analy- human variants have frequently arisen in non-human
individuals. sis of available clinical trials suggests that a family history primates47. This is of evolutionary interest in its own

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Box 2 | The development of naltrexone as a medication for alcohol addiction

that activation of the mesolimbic circuitry in response
to alcohol primarily occurs in OPRM1 77G carriers. This
Naltrexone was the first centrally acting medication approved for the treatment of prompted the hypothesis that OPRM1 77G carriers would
alcohol addiction. Its development provides several useful lessons with regard to the also be preferentially sensitive to suppression of alcohol
type of mechanism that can be targeted for treatment of addictive disorders, the preference by naltrexone. When this was tested, naltrex-
importance of clinical observation and translational research for advancing
one indeed only suppressed alcohol preference in carriers
development of medications, and the role of pharmacogenetics in optimally targeting
patient populations.
of the 77G variant50, a finding that has been independently
The endogenous opioid systems and their receptors were discovered in the 1970s, corroborated51. Both the rhesus and the human data may
and functional analysis of their role was facilitated by the development of two have limitations when considered separately, but their
small-molecule competitive antagonists derived from the analgesic opioid convergence supports a role of OPRM1 variation as a
oxymorphone: naloxone, which is only bioavailable upon parenteral administration, moderator of naltrexone effects, in a manner that is very
and naltrexone, which is bioavailable upon oral administration146,147. Naltrexone given to similar for the rhesus and human variants (FIG. 2a,b).
rhesus monkeys suppressed alcohol drinking at doses that did not significantly affect the Interestingly, in monkeys that were homozygous for
drinking of water148. Similar findings were subsequently obtained in numerous animal the major (OPRM1 77C) allele, naltrexone tended to
studies149. increase alcohol preference, an effect opposite to that
Influenced by these data, in 1983, researchers at the Philadelphia VA Medical Center
observed in the 77G carriers. This pattern parallels that
obtained approval from the US Food and Drug Administration (FDA) to use naltrexone
as an Investigational New Drug in actively drinking individuals with alcohol addiction.
of a human laboratory study in which naltrexone sup-
During dose-ranging, unblinded trials, several patients reported a lack of enjoyment pressed alcohol self-administration in individuals with a
from drinking alcohol while taking naltrexone. In a subsequent placebo-controlled positive family history of alcoholism, but increased it in
trial150, male veterans in an outpatient treatment programme received counselling and people without such a family history 34. These observa-
group therapy (using the 12step methods of Alcoholics Anonymous) and were tions highlight that treatments may need to be personal-
randomized to receive either 50mg naltrexone daily or placebo. The dose was selected ized not only to achieve therapeutic benefits but perhaps
because it had been used in treatment of heroin addiction, and had been observed to also to avoid worsening outcomes in other patients.
block the high from heroin. Despite the intensive behavioural treatment they received,
54% of patients receiving placebo relapsed to heavy drinking within 3months, a result OPRM1 118G: correlation or causation? Establishing
that is fairly typical151. By contrast, relapse occurred in only 23% of patients receiving
whether the OPRM1 A118G SNP is causal for the
naltrexone. In addition to the lower relapse rate, patients receiving naltrexone reported
less alcohol craving and less reward from alcohol if they did drink. The results from this
functional phenotypes described above is challenging.
study were not widely accepted until they were replicated at Yale University by Because a high degree of linkage disequilibrium is present
OMalley and colleagues, who conducted a study in male and female outpatients and between numerous SNPs across the OPRM1 locus, their
obtained very similar results152. genotypes are highly correlated, and their respective con-
Through a series of lucky coincidences, the data from these two academic studies tribution to phenotypic outcomes cannot be easily disen-
were eventually presented to the FDA, and as a result alcoholism was added to opioid tangled in association studies. For instance, one human
addiction as an indication for the use of naltrexone. Subsequent clinical trials in the study found that polymorphisms other than A118G
United States and other countries found mostly positive results of naltrexone treatment within the same haplotype block were associated with
for reductions in heavy drinking, but not necessarily for total abstinence6. Clinical diagnoses of alcohol and drug dependence52. By contrast,
observations indicated that some individuals with alcohol addiction showed no
a haplotype-based reanalysis of the COMBINE study
response, whereas others improved dramatically. An effort to identify the
characteristics of a naltrexone responder revealed the following factors: a strong family
found naltrexone responses to be specifically attributable
history of alcoholism and self-report of strong alcohol craving153. Meanwhile, it had to OPRM1 118G53. Furthermore, evidence was recently
been reported that subjects who are at genetic risk for alcoholism (that is, non-alcoholics reported for a functional role of another OPRM1 SNP,
with a positive family history of alcoholism) showed a significantly greater plasma rs563649, for pain sensitivity and MOR expression54. This
endorphin response to alcohol in the laboratory154. The working hypothesis that emerged SNP is located in the 5 untranslated region of the OPRM1
from these findings was that alcohol can activate endogenous opioid transmission gene, and is strongly associated with the expression of a
producing reward via some of the same pathways as heroin and that the strength of novel MOR isoform, MOR1K. Although consequences of
this activation might in part be genetically determined. Recent neuropharmacological this variant for alcohol or naltrexone effects have, to our
and genetic studies have provided support for both parts of this hypothesis. knowledge, not yet been examined, modulation of other
opioid-mediated phenotypes by rs563649 suggests that
such effects are possible. Because the rs563649 SNP is in
right, but it also offers a resource for addressing ques- strong linkage disequilibrium with other SNPs within the
tions of addiction vulnerability and pharmacogenetics OPRM1 locus, an association between any of those SNPs
in humans (BOX 3). and clinical naltrexone response could be indirect and be
Accordingly, an OPRM1 SNP that is functionally caused by differential expression of the MOR1K isoform.
equivalent to the human A118G polymorphism, namely Against this background, combining the non-human pri-
C77G (resulting in a proline (P) arginine (R) exchange mate and human alcohol and naltrexone data reviewed
Allele
in position 26 of the receptor protein, or P26R amino above helps to isolate the influence of OPRM1 77G (in
A specific sequence variant
encountered at a given position acid exchange) was identified in the rhesus macaque48. rhesus macaques) and OPRM1 118G (in humans) from
within the genome. Male carriers of the rhesus OPRM1 77G allele showed that of other functional polymorphisms with which the
increased psychomotor stimulation in response to respective variants might be in linkage disequilibrium.
Polymorphism alcohol, increased alcohol preference and increased The findings show that the OPRM1 C77G SNP in rhe-
A common genetic variation
(typically considered to be with
frequency of alcohol consumption to intoxication49. sus macaques and the OPRM1 A118G SNP in humans
a frequency >1.0%) within a Because psychomotor stimulation is a proxy marker of are directly linked to alcohol reward and the response
species. mesolimbic dopamine activity, these findings suggested to naltrexone.

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Box 3 | OPRM1 variation in non-human primates: a model for studying alcohol and naltrexone responses
The target for the FDA-approved alcoholism medication naltrexone is the muopioid receptor (MOR), which is a
seventransmembrane domain Gi/Go-protein coupled receptor. Its activation by endogenous opioid peptides, such as
enkephalins or endorphin, results in inhibition of cyclic AMP formation, suppression of intracellular Ca2+ levels and,
ultimately, reduced cellular excitability. The dimerization and trafficking of this receptor are not fully understood but
seem to be of major importance for the regulation of MOR function, and are in part thought to be related to glycosylation
of the receptor protein155. The MOR is highly conserved between humans and non-human primates, and comprises 400
amino acids in both humans and rhesus macaques. In humans, an OPRM1 gene 118AG mutation encodes an ND amino
acid substitution in position 40 of the receptor protein, resulting in the loss of a putative glycosylation site. A functionally
equivalent 77CG mutation exists in rhesus macaques and encodes an R26P exchange, offering a model system in which
effects on alcohol and naltrexone responses have been possible to study47.
These links are, however, still correlational. Subsequent in position 118 or 112 resulted in decreased sensitivity to
studies have obtained direct evidence for a causal role morphine56,57, a seemingly paradoxical phenotype that is
of the human 118G variant in alcohol reward using a also found in human OPRM1 118G carriers58. As already
translational strategy perhaps more appropriately mentioned, it is currently unclear how the N40D sub-
termed a reverse translational strategy in humans and stitution that is encoded by the human OPRM1 118G
genetically modified mice. First, a positron emission variant modifies MOR function. The mutation seems
tomography (PET) study was carried out to determine to be a loss-of-function mutation in terms of its effects
whether alcohol-induced dopamine release in the stria- on morphine sensitivity 56, but a gain-of-function muta-
tum varies as a function of the OPRM1 A118G genotype tion in terms of its effects on alcohol-induced dopamine
in humans55. Displacement of the dopamineD2 receptor release55. The reason for this discrepancy is a most strik-
ligand [11C]-raclopride was used to determine endog- ing issue that awaits resolution. Nevertheless, in both
enous dopamine release. In this approach, a high level cases, introducing the human MOR variant into mice
of displacement that is, reduction in [11C]-raclopride consistently reproduces the human phenotype that
binding potential reflects high dopamine release. is, enhanced alcohol-induced dopamine release55 and
In response to an alcohol challenge in social drinkers, attenuated sensitivity to morphine58. This suggests that
evidence for alcohol-induced dopamine release in the the human OPRM1 118G allele is not only correlated
ventral striatum (which encompasses the human equiva- with these effects, but in fact causesthem.
lent of the rodent nucleus accumbens (NAc)) was only The human PET data combine with the microdialysis
detected in 118G carriers, whereas in subjects who were findings from the humanized mouse lines to form a con-
Linkage disequilibrium homozygous for the more common (major) 118A allele, sistent pattern with regard to the effect of OPRM1 118G
The degree with which a the data suggested reduced dopamine release following on alcohol-induced dopamine release. It seems that
certain combination of alleles the alcohol challenge55 (FIG. 3). 118G carriers activate dopaminergic reward circuitry in
at different chromosomal
Paralleling the human PET study, the consequences of response to alcohol, and that this activation is mediated
locations is encountered
together in a population, in A118G variation for alcohol-induced dopaminerelease through actions of endogenous opioids. Activation of
excess of what would be were investigated in two humanized mouse lines, in this cascade offers a target for naltrexone on the basis
expected by chance alone. which the mouse Oprm1 gene was replaced with the of the idea that naltrexone can inhibit alcohol-induced
human sequence. These two mouse lines carried two dopamine release by blocking the MOR upstream of the
Haplotype block
A block or stretch of DNA that
identical copies of the human OPRM1 sequence either dopamine neurons. Conversely, the data indicate that
encompasses polymorphisms with an A (OPRM1 118AA) or a G (OPRM1 118GG) administration of alcohol is largely without influence
that are in linkage in position 118, but were otherwise identical. Following on dopaminergic reward circuitry in 118A homozy-
disequilibrium. administration of alcohol, brain microdialysis experi- gotes, and that there is therefore nothing for naltrexone
ments showed a fourfold higher dopamine release in to block in these subjects.
Haplotype
A combination of alleles at the NAc of the 118GG line compared to the 118AA Importantly, OPRM1 118G carrier frequencies
different loci on the same line, indicating that the OPRM1 118AG substitution is vary across populations of different ancestry, with evi-
chromosome. sufficient to cause elevated alcohol-induced dopamine dence for recent positive selection. The frequency of
release in thisarea55. 118G (40D) carriers is less than 1 in 10 among African
Isoform
In relation to proteins, isoforms
Using a different targeting strategy, the functional Americans, about 1 in 3 among most white populations,
are different forms of a protein role of the human OPRM1 118AG SNP was inde- and about 1 in 2 among individuals of Asian descent59.
that arise from the same gene. pendently studied in another pair of mouse lines. In Some observations of population-specific effects suggest
these experiments, a 112AG mutation was introduced that an individuals genetic background can modify the
Reverse translational
directly into the genetic background of C57/BL6 mice, effects of the OPRM1 A118G variation. Thus, similarly
strategy
Applying findings from humans resulting in an ND substitution in amino acid posi- to subjects with a family history of alcoholism60, white
to model organisms. For tion 38 (N38D) of the mouse MOR that is thought to OPRM1 118G carriers showed elevated adrenocorti-
example, human genetic be functionally equivalent to the human N40D substitu- cotropic hormone (ACTH) and cortisol responses to a
variants are inserted into a tion56. No alcohol data are to our knowledge yet avail- challenge with the injectable naltrexone analogue nalox-
model organism, allowing their
functional role to be studied
able from the N38D model, but functional equivalence one compared to white individuals who are homozygous
under better controlled of the two mouse models is suggested by other observa- for 118A. By contrast, no such difference was found
conditions. tions. In both cases, introduction of the AG mutation among individuals of Asian descent 61,62. It is unclear

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C clinical naltrexone efficacy in all populations. However,

at least one study in patients of Asian ancestry did find
that OPRM1 118G carriers took longer to relapse when
treated with naltrexone, whereas no such effect was seen
in 118A homozygous participants64.
In summary, it seems that the small mean effect size
of naltrexone in a mixed patient population is likely to
represent a robust effect in the minority of patients who
are 118G carriers, and that this effect is diluted by the
absence of effects in the remaining patient population43.
Expressed differently, a biologically defined population
of individuals with alcohol addiction namely, those
individuals who are 118G carriers and therefore have
what could be termed endorphin-dependent alcoholism
(approximately one-third of alcohol-addicted individu-
als of European ancestry) stands to robustly benefit
from naltrexone, and should receive this treatment. Even
before pharmacogenetic tests become widely available in
clinical practice, behavioural phenotypes that are char-
acteristic of reward drinking, such as pronounced psy-
D E chomotor stimulation by alcohol21, may help to identify
patients with a high probability of being responsive to
2NCEGDQ
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sonalized treatments, in that reward drinking is likely to
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have a greater role in relatively early stages of the addic-

tive process. Patients with the right genetic make-up

who, in addition, are in these early stages may therefore

be particularly good candidates for naltrexone treat-
ment. Other medications will be needed for individuals

with alcohol addiction who are unlikely to respond to

5CNKPG 0CNVTGZQPG #UP #UR naltrexone.
124/IGPQV[RG
Figure 2 | Efficacy of naltrexone is moderated by OPRM1 variation in rhesus Targeting brain stress systems
macaques and humans. Results from studies indicating that carriers of the minor Brain stress systems and relief-drinking. The use of
77G (rhesus) or 118G (human) alleles of OPRM1 (which encodes the mu-opioid receptor
0CVWTG4GXKGYU^0GWTQUEKGPEG alcohol to alleviate social anxiety at a party illustrates
(MOR)) are more sensitive to effects of naltrexone on alcohol preference and the well-known ability of this drug to suppress nega-
consumption than non-carriers. a | Set-up of an alcohol-preference test in monkeys. Each tive emotional states, such as anxiety or dysphoria. In a
monkey is tagged by a microchip in its collar. Alcohol is made available for 1 hour daily, 5
clinical context, this ability sets the scene for negatively
days a week. During this time, monkeys can walk up, place their head into one of the
several bar booths, be identified through the chip being read, and choose between an
reinforced alcohol use, an incentive that is clearly dis-
aspartame-sweetened alcohol solution or a solution of aspartame alone. b | Suppression tinct from that which is driven by activation of brain
of alcohol preference by naltrexone as a function of OPRM1 genotype. In rhesus 77G reward circuitry. Recent preclinical evidence has pointed
carriers (CG), which have a greater baseline alcohol preference, naltrexone suppressed to the potential for a vicious circle or rather a spiral
alcohol preference, whereas in rhesus subjects that are homozygous for the more in which negative reinforcement drives the progres-
common 77C allele (CC), naltrexone lacked effect. Data from REF. 50.c | Selective sive escalation of alcohol consumption over time. In this
increase in good clinical outcome after naltrexone treatment compared to placebo in process, withdrawal from an episode of heavy intoxica-
individuals with alcohol addiction carrying the 118G allele (Asp40), and lack of efficacy in tion leads to symptoms of anxiety. With repeated cycles
subjects who are homozygous for the more common 118A allele (Asn40). Good clinical of heavy intoxication and withdrawal, this negative emo-
outcome is a dichotomous composite measure of clinical efficacy that includes
tional state sensitizes or increases in strength ulti-
abstinence or absence of heavy drinking and improvement with regard to negative
consequences of drinking. Figure is modified, with permission, from REF. 43 (2009)
mately resulting in negative emotionality that persists
American Medical Association. and provides a powerful incentive for resumption of
alcohol intake (relapse)65.
The dynamics of this process closely parallel the
whether opioid antagonist effects on ACTH and corti- opponent process theory of affective regulation, which
sol responses are mechanistically related to therapeutic was originally proposed more than three decades ago66
efficacy in alcoholism, but they have been shown to be and has subsequently been applied to drug addiction67,68.
biomarkers of clinical naltrexone response63. The differ- In this conceptualization, drug use initially engages
ential effects of OPRM1 A118G genotype on naloxone- a group of processes that mediate pleasurable emo-
induced ACTH and cortisol responses in populations of tional states and therefore drive positively reinforced
different ancestry therefore suggests the possibility that drug seeking and taking. This triggers an activation of
variation at this locus may not be equally predictive of opponent processes in the CNS that mediate negative

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Figure 3 | Dopamine release in the ventral striatum in response to alcohol is restricted to OPRM1 118G carriers.
0CVWTG4GXKGYU^0GWTQUEKGPEG
The effect of alcohol on activation of the dopaminergic brain reward circuitry in carriers of the OPRM1 118G allele, as
assessed using positron emission tomography (PET) and [ C]-raclopride displacement. Alcohol given to male social
11
drinkers under closely controlled conditions induced a robust dopamine release (detected as reduced binding potential
of the radioligand) in minor 118G allele carriers (AG), whereas no measurable release was observed in subjects
homozygous for the major 118A allele (AA). The units in the PET scan represent the change in binding potential (nCi ml1).
AVS, anterior ventral striatum; PVS, posterior ventral striatum. Figure is modified, with permission, from REF. 55 (2011)
Macmillan Publishers Ltd. All rights reserved.
emotional states, such as dysphoria and anxiety, in an principle that neuropeptides are commonly released at
attempt to bring emotional homeostasis back to its nor- high neuronal firing frequencies and act as alarm sys-
mal level. With repeated drug use, the opponent pro- tems76. This suggests that CRF1 antagonists may have
cesses increase in strength and duration, and ultimately little if any invivo activity unless central stress systems
remain activated. This in turn results in an emotional are activated, and would therefore have an advantageous
setpoint shift, or allostasis, such that negative emotion- safety and tolerability profile. Animal experiments sup-
ality is experienced in the absence of the drug and drives port this notion74,77.
negatively reinforced drug seeking and use. A progres- Alcohol withdrawal is a highly stressful state. Rats
sive increase in the activity of brain systems that mediate do not typically self-administer alcohol in amounts that
behavioural stress responses is a crucial process behind result in physical dependence and in withdrawal symp-
this allostatic setpoint shift. The transition to negatively toms upon cessation of alcohol intake unless they have
reinforced drug use is what has become known as the been genetically selected for high alcohol preference.
dark side of addiction69. However, physical alcohol dependence can be induced
in rats, for example, by allowing them to consume a liq-
Corticotropin-releasing factor and relief drinking. uid alcohol diet or breathe alcohol vapour. Studies in rats
Extrahypothalamic CRF systems are crucial for the pro- made dependent on alcohol in this manner have shown
cess described above. CRF is a 41 amino acid peptide that CRF is released in the CeA during acute alcohol
that is highly expressed within neurons of the hypotha- withdrawal and mediates anxiety-like behaviour 7880.
lamic paraventricular nucleus (PVN). These neurons Behavioural withdrawal signs in rats peak after about
release CRF into the portal vein system, which runs 12hours, and are gone within 48 to 72hours into with-
along the pituitary stalk and delivers CRF to the ante- drawal. However, if the alcohol-dependent state is main-
rior pituitary. In the pituitary, CRF acts as the releasing tained for a month or more (before withdrawal), and
factor for ACTH, which in turn stimulates the release in particular if the exposure to alcohol is in the form
of cortisol from the adrenal glands70. CRF-positive cells of repeated intoxication and withdrawal cycles, more
are, however, also present in extrahypothalamic struc- persistent behavioural consequences of withdrawal are
tures, including the central nucleus of the amygdala observed. Under these conditions, behavioural stress
(CeA), the bed nucleus of stria terminalis (BNST) and sensitivity remains upregulated long after acute with-
the brainstem71. These extrahypothalamic CRF cells also drawal signs have subsided, and this emotional dysreg-
release CRF in response to stress and mediate a broad ulation is accompanied by escalated voluntary intake
range of behavioural (rather than endocrine) stress of alcohol18,65. At this stage, the increased behavioural
responses, primarily through actions at CRF receptor stress sensitivity reflects a shift in responsiveness rather
1 (CRF1; also known as CRFR1 and CRHR1), a seven than an increase in baseline anxiety. For example, during
transmembrane domain G s-coupled receptor of the protracted abstinence from alcohol, rats with a history
secretin receptor family 72,73. CRF1 is an attractive thera- of dependence showed no increase in baseline anxiety-
peutic target because its endogenous ligand CRF is not like behaviour in the elevated plus-maze, a pharmaco-
typically released in extrahypothalamic areas under logically validated animal model of anxiety. However,
basal, unstressed conditions. Instead, extrahypothalamic when these animals were challenged with a stressor
CRF systems become activated in response to sustained, before testing, anxiety-like behaviour was markedly
high-intensity, uncontrollable stress74,75, illustrating the accentuated compared to animals without a history of

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alcohol dependence. This anxiety-like response to stress of alcohol self-administration is induced by yohimbine98.
was blocked by intracerebroventricular administration Finally, the CRF system may become engaged in earlier
of the non-selective CRF receptor antagonist DPhe stages of the addictive process than previously thought if
CRF1241 (REF. 81). Similar findings of increased behav- alcohol consumption occurs in a binge-like pattern101,102.
ioural sensitivity to stress in rats with a prolonged history In summary, work in animal models shows that
of alcohol dependence have been obtained using several increased activity of the CRF system is associated with
other models8286. A parallel of these findings in humans both escalated voluntary alcohol intake and increased
is suggested by the observation that brain responses to sensitivity to stress-induced relapse. It can be speculated
aversive visual stimuli, as measured by the blood oxy- that different populations of CRF neurons differentially
gen level-dependent (BOLD) response, were elevated contribute to these behaviours, with the amygdala driv-
in patients with alcohol addiction during protracted ing escalated consumption and the BNST and MRN
abstinence. Here, the greatest differences were found in being involved in relapse. However, the precise contri-
a network of cortical structures, presumably reflecting bution of these brain structures to the respective effects
the different nature of the stressor, species differences, remains to be determined. Nevertheless, the findings
or both87. Based on these and other observations, it with CRF1 antagonists together suggest that CRF1 is an
has been proposed that repeated cycles of intoxication attractive treatment target for alcohol addiction.
and withdrawal drive a progression to sensitized stress
responses and escalation of alcohol intake, and that Genetic variation within the CRF system and alcohol-
upregulated expression of Crfr1 (also known as Crhr1), related behaviours in animal studies. We have so far
the gene that encodes the CRF1 receptor, has a major role described findings that establish a role for central CRF
in this process18,82,88. signalling in escalated alcohol intake and stress-induced
The CRF system plays a part in relapse. Relapse is a relapse once this system has been sensitized through a
key element of addictive disorders and can be modelled prolonged history of exposure to cycles of alcohol intoxi-
in laboratory animals89. When alcohol self-administra- cation and withdrawal. These findings also predict that
tion is established in rats and then extinguished over an individual with innate or stress-induced upregula-
the course of several weeks, relapse to alcohol seeking tion of central CRF activity would be at higher risk for
is reliably triggered by footshock stress, even if there escalated alcohol use and stress-induced relapse than an
was no prior physical dependence and the animal did individual who is genetically protected against such an
not show any withdrawal signs90. Blockade of CRF1 in upregulation. By the same token, it would be expected
the brain blocks this stress-induced relapse to alcohol that individuals with upregulated CRF function would
seeking 77,9193, but the exact neurocircuitry that medi- be more responsive to CRF1 antagonism as a therapy for
ates this activity is not clear. Many anti-stress actions of alcohol addiction. Data are beginning to emerge in sup-
CRF1 antagonists have been mapped to the amygdala, port of these predictions.
and this structure, along with the BNST, is also impli- The first indication that genetic variation within the
cated in relapse to drug-seeking 94. In addition, however, CRF system might moderate alcohol intake and stress-
blockade of stress-induced relapse is in part mediated by induced relapse came from experiments with genetically
CRF1 blockade in the median raphe nucleus (MRN)95. selected Marchigian-Sardinian alcohol-preferring (msP)
Projections from the MRN are largely restricted to rats93. These rats have an innate behavioural sensitivity to
midline subcortical structures and do not include the stress and high voluntary alcohol intake in the absence of
amygdala or the BNST96. This suggests that CRF activ- prior exposure to alcohol. They are thus partial pheno-
ity may contribute to stress-induced relapse at multiple copies of rats in which the same traits emerge and persist
sites along the complex neurocircuitry that drives this following a prolonged period of alcohol dependence, as
behaviour 94. described above. A differential gene expression screen
In addition to stress, relapse can be triggered by revealed that expression of Crfr1 was increased in several
exposure to alcohol-associated cues or alcohol itself brain regions, including the amygdala, of alcohol-naive
(priming)89. CRF1 antagonism does not block cue- or msP rats compared to alcohol-naive animals of the paren-
priming-induced relapse to alcohol seeking. Conversely, tal Wistar strain93. The increased expression was accom-
naltrexone blocks relapse induced by both alcohol- panied by increased receptor density and signalling, and
associated cues and alcohol priming, but leaves stress- may be due to a Crfr1 promoter variant that is unique
induced relapse unaffected92,97. This suggests that it to the msP line. Rats with a history of dependence show
may be possible to target these two mechanisms in an similarly increased Crfr1 expression in the amygdala82
additive manner for clinical treatment. CRF1 block- (FIG. 4). When msP rats are given free access to alcohol,
ade also blocks relapse to alcohol seeking induced by a Crfr1 expression in the amygdala is downregulated to the
pharmacological stressor, the 2-adrenergic antagonist level of non-dependent, non-selected animals, suggesting
yohimbine98. Furthermore, non-selective CRF receptor the possibility that msP rats drink alcohol to normalize
antagonists or CRF1selective antagonists decrease the their CRF function103. In addition, both in rats with a
escalated levels of alcohol self-administration that are history of alcohol dependence and in msP rats, stress-
observed in rats following a prolonged period (a month induced relapse is blocked by systemic administration of
or longer) of alcohol dependence, and this decrease is the prototypical CRF1 antagonist antalarmin in doses that
mediated through actions in the amygdala77,99,100. The are insufficient to block this behaviour in non-selected
same effect of CRF1 antagonism is seen when escalation animals without a history of dependence93 (FIG. 5).

REVIEWS
C 5EJGOCVKENQECNK\CVKQP D %QPVTQNPQPUGNGEVGFTCV but to show normal levels of alcohol consumption oth-

erwise. In agreement with this prediction, alcohol con-
sumption in late adolescence and young adulthood in
284T carriers reared under normal conditions did not
differ from that of 284C homozygotes with the same
rearing history. By contrast, 284T carriers that had been
reared under conditions of high adversity had markedly
elevated HPA axis responses to stress and increased vol-
untary alcohol consumption compared to 284C carri-
ers also reared under high adversity 105. Thus, an early life
exposure to a sustained stressor seems to set the gain for
E #NEQJQNFGRGPFGPVPQPUGNGEVGFTCV F #NEQJQNRTGHGTTKPIOU2TCV acute stress responses later in life as a function of CRF
284C/T genotype, and this in turn is linked to the level
of voluntary alcoholintake.
$.# Human genetic variation within the CRF system and

alcohol-related phenotypes. An association between
/G# genetic variation at the human CRFR1 gene locus and
alcohol-related phenotypes was first reported in the
Mannheim Study of Risk Children (MARC), a cohort
enriched for individuals who had been exposed to adver-
sity early in life106. At the time of the last assessment, the
Figure 4 | Innate or acquired hyperactivity of extrahypothalamic CRF systems is subjects in this cohort were still in adolescence. After
0CVWTG4GXKGYU^0GWTQUEKGPEG determining haplotype structure based on 14 markers
associated with high alcohol preference. a | Schematic localization on a coronal
section of the rat brain. The red box indicates the area that approximately corresponds to within the CRFR1 gene, the authors selected haplotype
the subsequent insitu expression panels. b | Low expression of Crfr1 in a control rat (not tagging SNPs (htSNPs) rs1876831 and rs242938
genetically selected for high alcohol preference and without a history of alcohol that tag two separate blocks of CRFR1 and examined
exposure). c | Markedly upregulated Crfr1 expression (darkened areas) in the medial their association with drinking phenotypes. Both htSNPs
nucleus of the amygdala (MeA) and basolateral nucleus of the amygdala (BLA) of an were independently associated with binge drinking and
unselected rat that was exposed for 7weeks to intoxicating blood alcohol levels, 3weeks lifetime prevalence of intoxication, indicating that vari-
after exposure to alcohol was terminated. d | Similarly upregulated Crfr1 expression in the ation affecting either haplotype block could influence
BLA of a Marchigian-Sardinian alcohol-preferring (msP) rat, observed in the absence of
these behaviours. No evidence for an interaction of the
any alcohol exposure. These findings show that increased expression of Crfr1 in the BLA
can result from a kindling process induced by exposure to cycles of alcohol intake and two markers was found106. In the same study, an associa-
withdrawal, but it can also be an innate trait that is present in the absence of any alcohol tion of rs1876831 with high alcohol consumption was
exposure, such as in the msP rat line, which has been genetically selected for high alcohol found in an independent sample of adult individuals
preference. Part a reproduced, with permission, from REF. 157 (2005) Elsevier. Parts b with alcohol addiction. Most importantly, a follow-up
and d reproduced, with permission, from REF. 93 (2006) National Academy of Sciences. analysis from the MARC cohort showed that an inter-
Part c reproduced, with permission, from REF. 82 (2008) Elsevier. action between adverse life events and rs1876831 influ-
ences alcohol-related phenotypes, with the minor (less
common) allele being protective107.
These data are consistent with subsequent findings The latter finding was subsequently replicated and
in non-human primates. A screen of genetic variation extended in a large independent sample108. Together with
within the CRF (also known as CRH) gene in rhesus several other genes, CRFR1 is located in a large haplo-
macaques identified a CRF 284CT SNP. This vari- type block on chromosome 17 that may have resulted
ant renders hypothalamic CRF expression insensitive from a local chromosomal inversion. The minor allele of
to end-product feedback inhibition by cortisol acting at rs1876831 is within the H2 haplotype at this locus. An
glucocorticoid response elements in the CRF promoter. AustralianAmerican study examined the possible inter-
This means that under stress conditions, when cortisol action between genotype at this locus and the effects on
Haplotype tagging levels are high, CRF levels remain elevated in 284T car- alcohol-related behaviour of childhood sexual abuse a
The concept that most of the
alleles and haplotypes (allele
riers and continue to drive a hypercortisolemic state. In type of adversity known to constitute a risk factor for
combinations) in a particular contrast to CRF expression in the PVN, CRF expression alcohol use disorders109. More than 1,100 participants
chromosomal region can be in the amygdala and the BNST is thought to be under in the Australian Nicotine Addiction Genetics project
captured by genotyping a positive regulation by cortisol104, and so the unrestrained were assessed for alcohol dependence, lifetime alcohol
small number of markers.
activity of the hypothalamuspituitaryadrenal (HPA) consumption and exposure to childhood sexual abuse.
Chromosomal inversion axis in 284T carriers would be expected to result in fur- A history of childhood sexual abuse was associated with
A chromosome rearrangement ther upregulation of CRF activity in these structures. As significantly higher lifetime alcohol consumption and
in which a segment of a a functional consequence of the continuing high levels of increased risk for alcohol dependence108. Furthermore,
chromosome is reversed from CRF, 284T carriers are predicted to have increased alco- childhood sexual abuse was found to interact with the
end to end. An inversion occurs
when a single chromosome
hol intake (compared to subjects that are homozygous rs1876831 genotype both for measures of alcohol con-
undergoes breakage and for the more common allele) following sensitization of sumption and for a diagnosis of alcohol dependence.
rearrangement within itself. the stress systems by sustained and uncontrollable stress, Specifically, the presence of the H2 haplotype, which is

V ItEion
WS
1RGTCPVUGNH 'ZVKPEVKQP (QQVUJQEM 4GKPUVCVGOGPV selecting patients for CRF1 antagonist treatment. Along
CFOKPKUVTCVKQP
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OKP UGUUKQP the way, this will also be important during clinical devel-
opment of CRF1 antagonists, because demonstrating
their efficacy will be difficult if an effect in a genetically
defined subpopulation of subjects is diluted by a lack of
0WODGTQHTGURQPUGUKPOKP
effect in other study participants110.

The prospects of CRF1 antagonists as therapeutics for
alcohol addiction. CRF1 antagonists were originally
developed for the treatment of depression and anxiety.

For a long time, the discovery of safe, orally available
and brain-penetrant CRF1 antagonists proved challeng-
ing. The first such molecule R121919 given to

'ZV 'ZV humans in an open label, uncontrolled trial in patients
#PVCNCTOKP
OIMIs with depression seemed promising 111, but the trial was
7PUGNGEVGFTCVU OU2TCVU terminated owing to evidence of treatment-emergent
hepatotoxicity. Compounds with better properties have
Figure 5 | CRF1 antagonism suppresses stress-induced relapse-like behaviour in since been developed, but trials that tested these com-
msP rats. In the stress-induced relapse model, animals are first trained to establish pounds for use in the treatment of anxiety and depres-
0CVWTG4GXKGYU^0GWTQUEKGPEG
operant self-administration of alcohol. Once stable self-administration rates are sion have been disappointing 112,113. Failure to take into
achieved, this behaviour is extinguished by removing alcohol as reinforcer, after which
account the genotype of patients may have contributed
lever-pressing rates decline to low levels over the course of about 2weeks (Ext). Exposure
to a stressor a 10minute footshock reinstates response rates on the previously to these negative results. As indicated above, the central
alcohol-reinforced lever, even though alcohol continues to be absent. Antalarmin, a cor- CRF system is quiescent under non-stressed conditions,
ticotropin-releasing factor receptor 1 (CRF1) antagonist, blocks stress-induced and pathological activation of this system may be a fea-
relapse-like behaviour in Marchigian-Sardinian alcohol-preferring (msP) rats at doses ture in some, but not in other cases of depression and
that are ineffective in rats that are not selected for high alcohol preference. This shows anxiety. By contrast, as reviewed above, given sufficient
that the CRF1 receptor is crucial for stress-induced relapse, and that the activity of the duration of alcohol exposure, the brain CRF system
CRF system is higher in msP rats compared to non-preferring rats. Figure is reproduced, does seem to be consistently activated in animal models.
with permission, from REF. 93 (2006) National Academy of Sciences. This may make alcohol addiction the most promising
indication for CRF1 antagonists.
tagged by the minor allele of rs1876831, was protective. Functional loci at genes other than CRFR1 have also
In these subjects, childhood sexual abuse exposure was been implicated in the modulation of stress responses
not associated with increase in risk for any of the out- and resilience, and could therefore interact with, or act
come measures108. in parallel with, the CRF system to modulate alcohol-
An attractive interpretation of these data is that H2 induced plasticity of brain stress systems. Putative
carrier status is protective because it prevents a func- stress-modulatory functional polymorphisms have been
tional upregulation of CRF system activity that would found in the genes that encode FK506 binding protein
be caused by exposure to sustained, uncontrollable stress 5 (FKBP5)114, neuropeptide Y (NPY)115117, the serotonin
such as childhood sexual abuse, prolonged heavy alcohol transporter (SLC6A4)118 and catecholO-methyltrans-
use, or both. In studies that have examined populations ferase(COMT)119. It is outside the scope of this Review to
of European ancestry, about one-third of subjects are describe in detail the role of genetic factors in stress resil-
carriers of the minor rs1876831 allele that tags the H2 ience in general. It is, however, noteworthy that although
haplotype. A challenge posed by these findings is that several lines of evidence exist for a stress-modulatory
none of the markers within the H2 haplotype examined role of these functional loci, findings in traditional case
so far seems to be positioned to change the function of control association studies have been controversial
CRF1. For instance, rs1876831 is intronic. In fact, because this is perhaps best illustrated by the contradictory data
Intronic the extended linkage disequilibrium block at this locus regarding the possible interaction between SLC6A4 vari-
Located in a stretch of DNA encompasses additional genes, it cannot currently be ation and stress to produce depression120. As pointed out
between exons; although excluded that genes other than CRFR1 account for or recently 121, this may reflect limitations to approaching
regulatory elements can reside
within introns, genetic variation
contribute to the observed effects. Nevertheless, the hypotheses of geneenvironment interactions using
within introns is often without hypothesis that patients with alcohol addiction who are association studies alone, and highlights the comple-
functional consequences. not H2 carriers engage the central CRF system under mentary value of experimental approaches that utilize
conditions of stress or heavy alcohol use and would intermediate phenotypes and animal modelling. This is
Intermediate phenotypes
therefore be predicted to respond to CRF1 antagonist echoed by the progress made in the case of OPRM1 and
A genetically influenced trait
that is less complex and more therapy is an attractiveone. CRFR1 using the approaches reviewedabove.
proximal to the genetic The animal and human genetic data reviewed above CRF1 antagonists may become clinically available for
information than the actual suggest the possibility that pharmacogenetic variation the treatment of alcoholism before pharmacogenetic
behavioural trait of interest, will be found in the response to treatments that tar- tests become widely available in clinical practice. In a
and is informative of the more
distal complex trait while being
get the CRF system. This hypothesis has not yet been parallel to what has already been stated for the opioid
possible to measure with less addressed in clinical trials, but if it is confirmed, it will antagonist naltrexone, careful clinical assessment may go
variance. be crucial to take CRFR1 genotype into account when a long way towards identifying patients with phenotypes

REVIEWS
conveniently grouped under the relief drinking label, subjects were genotyped for rs279858, a SNP marker
who might be particularly good candidates for CRF1 informative of the GABRA2 haplotype that had been
antagonist treatment. Much of the literature reviewed by identified as a susceptibility factor in association stud-
us also suggests that an important role for relief drinking ies122127. Subjects who were homozygous for the major
will be particularly likely in later stages of the addictive A allele at this locus reported markedly higher psycho-
process. By extension, it can be expected that patients motor stimulant-like effects on the ascending limb of
in those stages of the addictive process will be the most the blood alcohol concentration curve compared to AG
likely to benefit from CRF1 antagonist treatment. or GG subjects, and this was largely blocked by finas-
teride. By contrast, finasteride had no effect on the psy-
Other neurotransmitter systems chomotor response to alcohol in AG or GG subjects129.
With the decreasing cost of genotyping, it will become The moderating effects of this GABRA2 haplotype on
progressively easier to conduct unbiased genome-wide subjective alcohol effects have been replicated in an
searches for pharmacogenetic predictors of alcoholism independent sample130. Furthermore, a recent imaging
treatment responses. It is, however, important to rec- genetics study 131 showed that the same GABRA2 haplo-
ognize that this will require stringent statistical thresh- type moderates insula activity during outcome anticipa-
olds, and this necessitates the collection of very large tion in a monetary incentive delay task, an established
samples of participants that are consistently recruited, imaging-based measure of brain reward system activa-
treated and evaluated. In addition, the cost of the clini- tion132,133. Thus, genetic variation in GABRA2 seems to
cal studies will remain a challenge. Meanwhile, studies influence alcoholreward.
that are designed to target particular genes based on The molecular mechanism for the interaction
strong biological hypotheses are statistically advisable between GABRA2 genotype and alcohol effects is not
and potentially fruitful. Two additional neurotransmit- clear, because none of the markers in the susceptibil-
ter genes that have been implicated in alcohol addiction ity haplotype of GABRA2 examined so far seems to be
based on function are 5HT3A (also known as HTR3A), functional. For instance, although rs279858 is located
which encodes the ionotropic 5HT3 receptor for sero- within exon 4 of GABRA2, it is synonymous. If functional
tonin, and GABRA2, which encodes the 2-subunit of polymorphisms in significant linkage disequilibrium
the GABAA receptor. GABRA2 has been implicated on with rs279858 can be identified, however, an appealing
the basis of both its function and previous alcoholism hypothesis emerges. Psychomotor stimulant effects are
linkage studies. The findings reviewed below are largely highly correlated with activation of mesolimbic dopa-
exploratory at this point, but are presented to illustrate mine transmission, and dopamine neurons originating
the general approach and opportunities for translational in the VTA are under tonic GABAergic inhibition. It
and experimental medicine for alcohol addiction. can therefore be speculated that GABRA2 variation
or variations that alter the function of one of the other
GABAergic transmission and the GABRA2 gene. Among GABAA subunit genes found nearby in the gene cluster
its wide range of CNS effects, alcohol potently influences in which GABRA2 is located moderates the ability
GABAergic transmission in multiple ways, including of alcohol to disinhibit these dopamine cells through
modulation of presynaptic GABA release as well as post- effects on GABAergic transmission, ultimately result-
synaptic chloride flux. These actions are thought to con- ing in altered alcohol reward and psychomotoreffects.
tribute to some of the subjective effects of alcohol, such as In summary, the work reviewed above provides some
behavioural disinhibition at lower doses and sedation and additional support for a role of neurosteroids in alcohol
ataxia at higher doses26. It is therefore perhaps not surpris- responses, a role that has been proposed on the basis
ing that the first robust finding of a nervous system-related of animal studies128. However, these data suggest that if
genetic susceptibility factor in alcoholism was GABRA2, drugs targeting the neurosteroid response to alcohol are
the gene that encodes the 2-subunit of the ionotropic developed for therapeutic use in alcoholism, subjects will
GABAA receptor. Several markers within a haplotype of need to be selected for treatment on the basis of their
this gene have in multiple studies been associated with GABRA2 genotype. In fact, this may also apply more
attenuated P300 event-related potentials, an established broadly to therapeutics that target dopaminemediated
marker of familial risk for alcoholism. Associations have alcohol reward, as dopaminemediated alcohol reward
also been found directly with a diagnosis of alcoholism is influenced by GABA transmission at VTA synapses.
and with various drinking variables122127.
Experiments in animal models suggest that the Serotonergic transmission, serotonin transporter gene
Exon effects of alcohol on GABAergic transmission are in part variation and ondansetron. The development of selec-
A stretch of DNA that will be mediated by neuroactive steroids128. An elegant labora- tive serotonin reuptake inhibitors (SSRIs), such as fluox-
represented in the mature,
tory study set out to examine whether this translates to etine (Prozac; Eli Lilly), has made the role of serotonergic
spliced messenger RNA
(mRNA). the human situation129. This study used finasteride, a transmission in psychiatric disorders the subject of great
5steroid reductase inhibitor that blocks the synthesis interest, not only among scientists but also among the
Synonymous of several neuroactive steroids. Pretreatment with high- general public. Because SSRIs have been effective in a sur-
A coding sequence variant dose finasteride potently interacted with the participants prisingly wide range of conditions, they were evaluated
that, owing to the redundancy
of the genetic code, does not
genotype at markers within the GABRA2 gene to mod- as a potential treatment for alcoholism in multiple tri-
result in an amino acid erate subjective alcohol responses such as stimulation, als, but overall were not found to be effective134. Another
substitution. sedation and desire to obtain more alcohol. Specifically, serotonergic medication, however, yielded promising

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results. Ondansetron, an antagonist of the ionotropic strategy, tailored treatments that target subpopulations
5HT3 receptor, was reported to reduce heavy drink- of patients with addictive disorders are particularly
ing in individuals with early-onset alcoholism, a clini- endangered.
cal subtype characterized by the onset of the disorder We believe that these challenges should prompt some
before the age of 25, and often during the teenage years. rethinking in industry, academic institutions and gov-
Secondary analyses indicated that reductions in craving ernment of the approach to the development of medi-
and improvement of mood disturbances might contrib- cations for addictive disorders. Small, mechanistic,
ute to the reduction in heavy drinking 135137. The thera- experimental medicine studies that use intermediate
peutic actions of 5HT3-receptor antagonists in people phenotypes as surrogate markers of clinical efficacy have
with alcoholism might be due to the presence of 5HT3 the potential to help guide development efforts, and to
receptors on dopamine terminals in the NAc and their make these efforts more cost effective. These experimen-
ability to modulate dopamine release138. tal medicine studies can use insights from preclinical
The serotonin transporter, which is encoded by research to guide their selection of subjects and outcome
SLC6A4, is a key element of serotonergic transmission. A measures, increasing the probability of detecting a drug
variable-length polymorphism in the promoter region of effect in limited-size studies. For instance, when devel-
this gene known as 5HTTLPR (serotonin-transporter- oping CRF1 antagonists, it might be beneficial to recruit
linked polymorphic region) results in differential tran- genetically susceptible, anxious individuals with alcohol
scriptional activity 139 and has been extensively studied addiction, and to measure stress-induced alcohol crav-
for association with a wide range of behavioural and ing. This type of approach can be adapted to a range of
clinical phenotypes that are beyond the scope of this diverse mechanisms, in what has been called a Rosetta
Review 121. A recent randomized controlled treatment Stone approach144.
study showed that individuals who are homozygous We also think that there is reason to rethink the
for the higher expression (LL) allele of the 5HTTLPR clinical outcomes that are pursued. The search for novel
had a better treatment response to the 5HT3-receptor treatments has largely been focused on finding medica-
antagonist ondansetron, measured both as the mean tions that would be effective as measured by their abil-
number of drinks per drinking day and as the percent- ity to lead to complete abstinence. This is, for instance,
age of days of total abstinence. Combining the analy- the position currently held by the US Food and Drug
sis of 5HTTLPR genotype with a SNP located in the 3 Administration when evaluating novel addiction thera-
untranslated region of the serotonin transporter tran- peutics for approval. However, the science clearly shows
script, rs1042173, further strengthened this pharmaco- that complete abstinence, although desirable, is not the
genetic effect140. Additional support for the reduction of only worthwhile outcome. Even in the absence of com-
drinking by ondansetron among alcohol-dependent indi- plete abstinence, reductions in heavy drinking can have
viduals with the 5HTTLPR LL genotype comes from a substantial clinical benefits145.
study that was carried out in non-treatment-seeking vol- We have largely structured our presentation of the
unteers, and used alcohol self-administration under labo- available empirical data by neurobiological system. This
ratory conditions as a measure of outcome141. Although is convenient for the purpose of a scientific review, but
the exact mechanism mediating these effects remains to clinical realities are clearly more complex. The patho-
be determined, 5HTTLPR is clearly functional in that it physiology of addiction may engage shifting combina-
regulates transcriptional activity of the serotonin trans- tions of mechanisms, not only in different individuals
porter, whereas rs1042173 might be related to micro- but also in different stages of the disease process. In some
RNA-mediated regulation of transcript stability 142. Both stages, reward- and relief-drinking-related mechanisms
are therefore well positioned to moderate the effects of a may combine, calling for combination treatment. At
therapeutic acting on serotonergic transmission. other times, one type of mechanism may dominate.
Thus, if ondansetron or other 5HT3-receptor antag- In this sense, optimally personalized treatment will
onists are developed for the treatment of alcohol addic- always remain a moving target. This prompts the need
tion, their efficacy should be tested in patients who for developing clinical assessments ideally based on
have been selected on the basis of their genotype at the the use of biomarkers that will allow treatment to be
SLC6A4locus. tailored on an ongoingbasis.
In conclusion, treatments that on average seem to
Conclusions produce only small improvements in alcoholics may
Addressing the extensive unmet medical needs related result in considerable clinical benefits in subpopulations
to alcohol addiction will require that novel pharmaco- of patients that are better defined with regard to their
therapies be developed. Numerous mechanisms that biology. We predict that genetic variation will emerge as
could potentially be targeted have been discovered by one of the most important categories of biological fac-
basic addiction neuroscience, but clinical translation tors that will need to be considered in this context, but
remains a challenge19. Developing therapeutics that that awareness of disease progression will also be crucial
target these mechanisms will require a considerable for improving treatments. Rather than finding a cure,
investment, at a time when the willingness of the phar- we look forward to the addition of multiple, appropri-
maceutical industry to invest in drug development for ately targeted novel treatments that will incrementally
behavioural disorders has diminished143. When search- improve outcomes and help to reduce the devastating
ing for blockbuster drugs has become the dominant consequences of alcohol addiction.

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Disability-adjusted life years

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Box 1 | Alcohol addiction is an end-stage disease

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#NEQJQN of alcoholism is associated with clinical improvement in

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Box 2 | The development of naltrexone as a medication for alcohol addiction

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$.# Human genetic variation within the CRF system and

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%% naltrexone. Furthermore, disease progression is likely

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C 5EJGOCVKENQECNK\CVKQP D %QPVTQNPQPUGNGEVGFTCV but to show normal levels of alcohol consumption oth-