The dopamine system and alcohol dependence

Abstract

summary
Alcohol dependence is a common mental disorder that is associated with substantial disease burden. Current efforts at prevention and treatment of alcohol dependence are of very limited effectiveness. A better understanding of the biological mechanisms underlying dependence is essential to improving the outcomes of treatment and prevention initiatives. To date, most of the efforts have focused on the key role of the dopamine system in the complex etiological network of alcohol dependence. This review summarizes current research about the relationships between alcohol consumption and the dopaminergic system. We find that many of the currently available studies have contradictory results, presumably due to differences in methodology, non-linear dosage effects, use of different samples, and the possible confounding effects of other neurotransmitter systems.

Full text

• 61 • Shanghai Archives of Psychiatry, 2014, Vol. 26, No. 2
doi: hp://dx.doi.org/10.3969/j.issn.1002-0829.2014.02.002
1 Center for Mental Health, Yanshan University, Qinhuangdao, Hebei Province, China
2 Department of Psychiatry, the First Aliated Hospital of China Medical University, Shenyang, Liaoning Province, China
*correspondence: gzhu@mail.cmu.edu.cn
A full-text Chinese translaon will be available at www.saponline.org on May 15, 2014.
Hui MA1,2 , Gang ZHU2,*
The dopamine system and alcohol dependence
•Review•
Summary: Alcohol dependence is a common mental disorder that is associated with substantial disease
burden. Current eorts at prevenon and treatment of alcohol dependence are of very limited eecveness.
A beer understanding of the biological mechanisms underlying dependence is essenal to improving the
outcomes of treatment and prevenon iniaves. To date, most of the eorts have focused on the key role
of the dopamine system in the complex eological network of alcohol dependence. This review summarizes
current research about the relaonships between alcohol consumpon and the dopaminergic system. We
nd that many of the currently available studies have contradictory results, presumably due to dierences
in methodology, non-linear dosage eects, use of dierent samples, and the possible confounding eects of
other neurotransmier systems.
Keywords: dopamine, alcohol dependence, neurobiochemistry, review
1. Introducon
Alcohol is one of the most widely used psychoactive
substances in the world. Alcohol-induced changes
in brain functions can lead to disordered cognitive
functioning, disrupted emotions and behavioral
changes. Moreover, these brain changes are important
contribung factors to the development of alcohol use
disorders, including acute intoxicaon, long-term misuse
and dependence. According to a survey sponsored by
the World Health Organization, approximately 50% of
the world adult population drank alcohol in 2004 and
76 million individuals met criteria for alcohol-related
mental or behavioral disorders listed in the 10th Revision
of the Internaonal Stascal Classicaon of Diseases
and Related Health Problems (ICD-10).[1] A report on
the relative contribution of different conditions to
the ‘global burden of disease’ (which considers both
premature mortality and disability) found that in 2010
alcohol ranked third out of the 25 major causes of the
global burden of disease. In high-income countries the
relave importance of alcohol-related health problems
compared to other health problems is usually greater
than in low- and middle-income countries.[2] Alcohol
dependence, one of the most important alcohol-related
conditions, is widely recognized as a growing global
problem with serious medical, economic and social
consequences.
Ethanol is a liposoluble neurotropic substance
which penetrates the blood-brain barrier and inhibits
central nervous system (CNS) functions; it is directly
toxic to the brain. The eology and pathology of alcohol
dependence is the outcome of a complex interplay
of biological, psychological and socio-environmental
factors. CNS neurotransmiers play an important role in
the development of alcohol addicon. Previous studies
identified a wide range of neurotransmitters related
to alcohol metabolism including dopamine, 5-HT,
γ-aminobutyric acid, glutamate, endogenous opioid
transmitter, acetylcholine and norepinephrine.[3] This
review summarizes research progress in understanding
the relationships linking the dopaminergic system and
alcohol consumpon.
2. The dopamine system and brain reward circuitry
The dopamine (DA) system in the CNS includes the
nigrostriatal pathway, the mesolimbic pathway and
the tuberoinfundibular pathway. Dopamine is mainly

studies also found that alcohol withdrawal is related to
reduced release of DA in the striatal.[19] This suggests
that the negative mood during alcohol withdrawal is
related to the inhibion of DA in the limbic system and
that the voluntary alcohol intake of animals experiencing
withdrawal may be reinforced by restoration of DA
levels in relevant brain areas aer re-iniaon of alcohol
intake.
Researchers have successfully bred several lines of
rats to aid in research about alcohol use and alcohol
dependence[4,20]: (a) alcohol-preferring (P) / alcohol-
nonpreferring (NP) rats; (b) high-alcohol-drinking (HAD)
/ low-alcohol-drinking (LAD) rats; (c) University of Chile
bibulous (UChB) /University of Chile abstainer (UChA)
rats, (d) Alko alcohol (AA) / Alko non-alcohol (ANA) rats,
(e) Sardinian alcohol-preferring (sP) / Sardinian alcohol–
nonpreferring (sNP) rats, (f) high alcohol consuming
(HARF) / low alcohol consuming (LARF) rats and so forth.
Alcohol-preferring rats are of special importance for
research on the role of DA in alcohol preference because
rats highly susceptible to alcohol dependence have
defects of the DA system in the mesolimbic pathways.[4,20-
22] Using these rat models, researchers have located lower
extracellular baseline DA levels in the cerebral cortex
and NAc in P rats;[21,22] in the striatal, olfactory tubercle
and NAc in HAD rats;[22,23] and in the NAc in UChB rats.[24]
Smith and Weiss[25] injected ethanol intraperitoneally
to P rats, NP rats and genecally heterogeneous Wistar
rats for five consecutive days and found elevated
extracellular DA levels in P rats and Wistar rats but not
in NP rats. Bustamante and colleagues[20] found that
intraperitoneal injection of saline water to UChB and
UChA did not induce any changes in the extracellular
DA levels in the NAc, but injection of ethanol induced
significant increase in DA levels in both lines of rats.
Furthermore, ethanol affects the release of DA in the
CNS more in UChB rats than UChA rats. Tuomainen and
colleagues found[26] that microdialysis of ethanol (of
varying concentraons) in the NAc area induced dose-
related increases in extracellular levels of DA among AA
and ANA rats, and the inceases in AA rats were more
than those in ANA rats. Katner and Weiss[27] studied
HAD/LAD, AA/ANA, and Wistar rats, and found elevated
extracellular basal DA levels induced by intraperitoneal
injecon of ethanol; moreover, the degree of elevaon
of DA levels predicted subsequent alcohol drinking
behavior. In summary, these studies suggest that
ethanol-induced increases in extracellular DA in the CNS
NAc and amygdala play a role in ethanol preference.
Not all studies support this conclusion. Some
experiments found no difference in DA release in the
NAc aer intraperitoneal injecon of ethanol between
P and NP rats. For example, Yoshimoto and colleagues[11]
and Gongwer and colleagues[23] found that although
HAD and LAD rats differed in their basal level of
extracellular DA, they did not differ in CNS DA release
after intraperitoneal injection of ethanol. Similarly,
Kiianmaa and colleagues[28] found no differential
increase of extracellular DA concentration in the NAc
between AA and ANA rats aer microdialysis of ethanol.
produced in the substantia nigra, projected along the
nigrostriatal pathways and stored in the striatum. Five
subtypes of DA receptors have been identified and
cloned. All of them function both individually and
interacvely as G-protein coupled receptors.
There has been continuous research since the
1970s on the role DA plays in the brain reward system.
The reward reinforcement circuitry is part of the limbic
system that includes the ventral tegmental area (VTA),
nucleus accumbens (NAc), ventral striatum, bed nucleus
of the stria terminalis, hippocampus, amygdale, and
other brain structures. DA is the main neurotransmier
of this system.[4-8] The reward system modulates primary
physiological funcons related to survival including the
intake of food and water and sexual behavior. It is also
the target of psychoacve substances including alcohol,
cocaine, amphetamine and opioids. The mesolimbic DA
pathway (the NAc is the central regulaon structure for
the reward eect) and the mesocorcal pathway are the
key structures that modulate the reward reinforcement
circuitry.[4-8]
3. Inuence of alcohol consumpon on the
dopaminergic system
Several studies have confirmed a dose-response
relationship between alcohol intake and DA release
in the NAc.[9-11] Other experiments have also found
that injection of ethanol in the NAc induces local
DA release in a dose-response fashion.[11-12] In 2000
Yoshimoto and colleagues[13] reported a dose-
related elevation of extracellular DA levels in the
amygdala after intraperitoneal injection of ethanol
and a delayed elevation of DA after ethanol injection
in the central amygdaloid nucleus via a microdialysis
membrane.[13] These results suggest that the amygdala,
part of the reward circuitry, plays a central role in
the alcohol-induced effects on the brain. Yim and
colleagues[14] documented the process of DA release
in the brain induced by various doses of ethanol (0-2.0
g/kg). They found that extracellular DA levels did not
respond to ethanol in a linear fashion with high doses (1
and 2 g/kg); the DA level returned to baseline within 90
minutes while the ethanol level was sll elevated.[14] This
suggests acute tolerance to ethanol-induced DA release
in the NAc and that ethanol-induced DA release is
dependent on the concentraon of ethanol. Research by
Yim and Gonzales[10] exploring the underlying mechanism
of ethanol-induced DA release using animal models
found that ethanol increases DA via the promotion
of synaptic terminal DA release rather than via the
inhibion of DA transporters.[10] Other studies found that
ethanol can also indirectly increase DA levels by aecng
GABAergic neurons and opioid receptors in the NAc.[15-17]
Other lines of research related to alcohol withdrawal
reinforce this model of alcohol-related changes in DA.
Electrophysiological studies found that acute ethanol
intake can increase DA neuron discharge in the nigra and
VTA; this discharge is reduced during alcohol withdrawal
and restored after restarting ethanol intake.[18] Animal
Shanghai Archives of Psychiatry, 2014, Vol. 26, No. 2 • 62 •

These varying results may be due to the use of dierent
animal models or dierent research protocols.
Methylphenidate (MP) is a smulant that inhibits the
DA transporter and increases the level of extracellular
DA;[29] some researchers suggest that this is associated
with the subjective feeling of being ‘high’.[30] Positron
emission tomography (PET) using radiolabelled
raclopride (11C-RAC)—a D2 antagonist that competes
with endogenous DA – can be used to observe changes
in extracellular DA levels. Using this method, MP was
found to decrease the binding of 11C-RAC to receptors
in a dose-responsive fashion which indirectly suggested
an increased binding of DA to receptors; moreover,
the magnitude of DA release was positively correlated
with the intensity of MP-induced subjective feeling of
being ‘high’.[30] Recently, Seawan and colleagues have
found decreased binding of 11C-RAC to DA receptors
(which suggest increased extracellular DA levels) among
youths at high risk for alcohol dependence.[31] This
nding in humans parallels the animal studies by Katner
and Weiss;[27] both sets of studies provide support for
a quantitative dose-response relationship between
DA functioning and the intensity of the reward effect
after the intake of psychoactive substances (including
alcohol).
In addition to the effect of ethanol on DA release,
it can also affect the functioning of DA receptors,
particularly D2 and D1 receptors. The D1 receptor
binds with excitatory G protein and acvates adenylate
cyclase (AC) via Gs; AC catalyzes the producon of cAMP
and cAMP regulates cAMP-dependent protein kinases
to open calcium ion channels. D2 receptors bind with
inhibitory G protein and thus reduce the producon of
AC and resulng cAMP.
Several animal studies report reduced D2 receptor
concentraon among P rats compared to NP rats in the
olfactory tubercle, caudate putamen, NAc, VTA, and
the cortex.[32-34] Based on these findings, researchers
have inferred a connection between the reduced D2
receptor density in the limbic system and preference for
alcohol. This hypothesis has been supported by clinical
studies using PET scans that report a 20% reduction
in striatal D2 receptor efficiency (i.e., the ratio of D2
receptor density and anity) in individuals with alcohol
dependence compared to controls.[35-36] Another study
using single-photon emission computed tomography
(SPECT) found low D2/D3 receptor affinity in the left
temporal cortex among individuals with Type I alcohol
dependence.[37] Using whole-hemisphere autoradiography
(WHA), researchers found that compared to controls
individuals with Type I alcohol dependence had a 20%
reducon of D2/D3 receptor anity in the NAc region
and a 41% reducon in the amygdala.[38] Results from an
endocrinological study also showed decreased CNS D2
anity in alcohol dependence.[39]
Studies about the relationship of D1 receptors
and affinity for alcohol have had inconsistent results.
A study reported higher striatal D1 receptor efficiency
among alcohol preferring C57BL/6J mice compared
to non-alcohol preferring DBA/2J mice.[40] Other
studies using autoradiography techniques found no
stascally signicant dierences in D1 receptor anity
at multiple sites in the mesolimbic and nigrostriatal
regions between P and NP rats[41], between HAD and
LAD rats[42] or between AA and ANA rats.[43] A clinical
study using autoradiography found a 23% reducon in
D1 receptor anity in the NAc region among individuals
with Type I alcohol dependence and a 14% reduction
in D1 receptor affinity among individuals with Type II
alcohol dependence compared to controls, but these
dierences showed no stascal signicance.[44] Clearly,
more research is needed to clarify the relationship
between the D1 receptor and alcohol dependence.
4. Inuence of dopaminergic system to alcohol
consumpon
Several studies have shown that changes in the DA
system in the CNS can influence drinking behaviors
both in animals and in humans. Early animal
models have shown that injection of the neurotoxin
6-hydroxydopamine (6-OHDA) in the ventricle or in other
brain regions destroys dopaminergic neurons. In 1975,
Myers and Melchior found that CNS DA level decreased
and rats showed a lower preference for alcohol after
bilateral cerebral ventricle injecon of 6-OHDA.[45] More
recently, Ikemoto and colleagues[46] found that bilateral
injecon of 6-OHDA in the NAc area of alcohol-naïve rats
(compared with sham-operated controls) induced a 60%
decline in alcohol consumpon a week later and a 30%
decline three weeks later. On the other hand, Quarfordt
and colleagues found that selective destruction of
the NAc and tuberculum olfactorium using 6-OHDA
increased drinking behavior in rats.[47] Yoshimoto and
colleagues found similar results in rats aer injecon of
6-OHDA in the NAc[48] and ventricle.[49] The subsequent
increase in alcohol consumption after injection of
6-OHDA in these studies may either be the result of
direct destruction of the mechanism that results in
tolerance or the result of compensatory drinking due
to 6-OHDA-induced damage to DA neurons. In order to
pinpoint the specic mechanism, Lanca performed fetal
dopaminergic transplants of ventral mesencephalon and
found increased DA levels and a 40 to 50% reduction
in voluntary alcohol intake; in contrast, this effect was
not observed in rats receiving a sham-operation with
dopamine-poor transplants.[50] These studies clarified
the inverse relationship between DA activities and
alcohol consumpon, supporng the hypothesis which
suggests that increased alcohol intake after 6-OHDA-
induced damage is compensang for the damage to DA
neurons.
Research about the influence of DA receptor
agonists and antagonists on alcohol consumption
has had inconsistent results. Some studies find that
injecon of d-amphetamine (a non-specic DA receptor
agonist) or quinpirole (a specific D2/D3 receptor
agonist) in the NAc area can increase the frequency of
alcohol-related reinforcement behaviors.[51] And local
• 63 • Shanghai Archives of Psychiatry, 2014, Vol. 26, No. 2

injection of raclopride (RAC, a specific D2/D3 receptor
antagonist) reduces alcohol-related reinforcement
behaviors.[52] These results both support hypotheses
about the positive correlation between DA activity
and alcohol reinforcement. However, other studies
using microinjecon have found that both DA receptor
agonists and antagonists can reduce voluntary alcohol
intake in animal models.[52-54] For example, Samson and
Hodge[52] found that administration of the antagonist
RAC in the NAc reduced voluntary drinking in a dose-
response fashion, while local injection of the agonist
quinpirole in the VTA also reduced voluntary drinking.
Kaczmarek and Kiefer found that local injection
of amphetamine or RAC in the NAc both reduced
ethanol intake in rats.[53] Hodge and colleagues found
a bidirectional effect of quinpirole injected in the NAc
area on voluntary alcohol intake: quinpirole increased
alcohol intake at lower dosages and decreased alcohol
intake at higher dosages.[54] The underlying mechanism
of this bidirectional effect may be that presynaptic
receptors are only acvated when quinpirole reaches a
certain concentraon, aer which point there is a dose-
related inhibion of DA. This highlights the importance
of dosage when studying the relationship between
drinking and DA receptor agonists and antagonists.
5. Gene variants related to DA systems and alcohol
dependence
Twin studies, linkage studies and large-sample
prospecve populaon studies have found that genec
factors play important roles in the development of
alcohol dependence. Two groups of genes have been
related to alcohol dependence. One group of genes
encode enzymes involved in alcohol metabolism,
including alcohol dehydrogenase, aldehyde dehydro-
genase and cytochromes P4502E1. The second group of
genes encode neurotransmiers (and the receptors for
these neurotransmiers) that respond to alcohol and its
metabolites, (e.g., DA, GABA, 5-HT, and opium).[55] D1,
D2 and D4 receptors and DA transporter polymorphisms
have been shown to play a role in alcohol dependence,
but there remains controversy about the pathways via
which these effects are produced. In 1990 Blum and
colleagues first proposed that: “the D2 receptor A1
allele is closely related to the development of alcohol
dependence”. They found that the D2 receptor A1 allele
was associated with a 8.7 higher odds of developing
alcoholism.[56] This nding has been replicated by many
case-control studies and other works have shown that
gene polymorphisms that inhibit the expression of
the D2 receptor are associated with increased risk of
alcohol dependence.[57,58] In support of this hypothesis,
a recent study found increased alcohol intake among
D2L receptor knock-out mice.[59] In contrast, other
studies failed to find any association between the D2
receptor and alcohol dependence.[60,61] Possible reasons
for these contradictory findings include differences in
sample characteriscs (e.g., types of alcohol dependence,
selection of controls, and race/ethnicity) and other
methodological differences across studies. Parallel
work with D1 receptors by El-Ghundi and colleagues
found lower alcohol preference and intake among D1
knockout mice compared to wild-type mice.[62] Using
a case-control design, Zhong and colleagues studied
three genetic polymorphisms of D2 (TAQI A, TAQI B,
-141CINS/DEL), the 48bp variable number tandem
repeat (VNTR) of the 3rd exon of the D4 receptors, and
the 40bp VNTR of the non-coding region at the end of
the DA transporter gene 3’ in a sample of Chinese Han
individuals living in Yunnan province. They found that
the D2 TaqIB genotype and allele frequencies were
associated with alcohol dependence and that carriers of
the B2 allele had a lower risk of alcohol dependence, but
no dierences were found for the other polymorphisms
between cases and controls.[55]
6. Summary and prospect
Anatomy, physiology, pharmacology, and behavior
studies have found ample evidence for the connecon
between the neurotensin (NT) and DA systems. A case-
control study conducted by our research team[63] in
a sample of Chinese Han individuals found that the
GG genotype of the single nucleotide polymorphism
(SNP) rs6011914C/G and the G allele and GG genotype
of the SNP rs2427422A/G of the NTR1 receptor
were associated with alcohol dependence; linkage
disequilibrium was found between rs6090453C/G,
rs6011914C/G and rs2427422A/G; and the haplotypes
rs6090453C/rs6011914C/rs2427422A and rs6090453C/
rs6011914C/rs2427422G were found associated with
alcohol dependence.[63] These findings suggest that
the NT system may affect the development of alcohol
dependence via the dopaminergic system and shed
some new light on the mechanism linking the DA system
funconing to alcohol dependence.
Animal studies have found that selecve D2 receptor
agonist bromocriptine can reduce alcohol intake and
acute ethanol tolerance in alcoholic rats.[64] Clinical studies
also found that bromocripne can relieve symptoms of
alcohol dependence and related problems in humans.[65]
In contrast, another study reported the treatment eect
of tiapride, a selective D2/D3 receptor antagonist, in
alcohol dependence.[66] Other double-blinded placebo-
controlled studies did not find any treatment effect
of either DA agonist[67] or antagonist [68] compared to
placebos, and documented some serious side effects
of the drugs. Given these contradictory findings,
dopaminergic drugs have not been recommended for
the clinical treatment of alcohol dependence. Currently,
the United States Food and Drug Administration
(FDA) has approved acamprosate, tetraethylthiuram
disulde (TETD, disulram) and naltrexone as treatment
mediaons for alcohol dependence and alcohol misuse.
The mechanism of action of these agents is related to
their eects on the CNS glutamatergic system.[69,70]
All psychoacve drugs can acvate the mesolimbic
DA system, but the DA system is not the only system
involved in the positive reinforcement network in the
NAc. Previous research about the neurobiochemisty
Shanghai Archives of Psychiatry, 2014, Vol. 26, No. 2 • 64 •

of alcohol dependence has focused on the DA system,
but many of the findings have been contradictory.
This may be related to varying methodologies, to non-
linear dosage effects, to non-transferability of animal
results to humans, to different target groups (most
previous studies have used samples from Western
countries), and to the possible confounding effects of
other inter-related neurotransmitter systems. Further
research aimed at clarifying the interaction between
the DA system, the glutamatergic system and other
neurotransmitter systems is needed before it will be
possible to improve the effectiveness of interventions
for prevenng and treang alcohol dependence.
Conict of interest
Authors declare no conflict of interest related to this
manuscript.
Funding
The authors did not receive any financial support for
preparing this review.
摘要：酒精依赖是一种常见的精神疾病，社会危害大，
疾病负担重。目前致力于酒精依赖的预防和治疗的研
究取得的成果比较有限。为了进一步完善酒精依赖的
治疗和预防措施，有必要对酒精依赖潜在的生物学机
制进行深入探究。迄今为止，针对酒精依赖错综复杂
的病因学的研究，大部分聚焦于多巴胺系统的关键作
用。本综述总结了目前国内外对饮酒行为与多巴胺能
系统之间关系的研究，发现研究结果并不一致，甚至
相互矛盾，可能是由于方法学的差异、非线性的剂量
效应、样本的选取差异以及多巴胺系统与其它神经递
质系统之间可能存在交互作用等因素造成。
关键词：多巴胺，酒精依赖，神经生化，综述
本文全文中文版从 2014 年5月15 日起在 www.saponline.org 可供免费阅览下载
多巴胺系统和酒精依赖
马慧，朱刚
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(received: 2013-11-03; accepted: 2014-01-20)
Hui Ma graduated from China Medical University with a bachelor’s degree in Clinical Medicine in
2000. She obtained her master’s degree in Medical Psychology in 2003 and is currently enrolled in the
PhD program in Psychiatry (projected to graduate in June 2014) at China Medical University. She is
currently an associate professor at the Center for Mental Health in Yanshan University where she has
being working since 2003. Her research interests include psychiatric genecs, biological psychiatry and
psychological assessment.
Shanghai Archives of Psychiatry, 2014, Vol. 26, No. 2 • 68 •