ArticlePDF AvailableLiterature Review

The dopamine system and alcohol dependence

  • The First Affiliated Hospital of China Medical University (PRC)


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.
• 61 • Shanghai Archives of Psychiatry, 2014, Vol. 26, No. 2
doi: hp://
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
A full-text Chinese translaon will be available at on May 15, 2014.
Hui MA1,2 , Gang ZHU2,*
The dopamine system and alcohol dependence
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
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
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
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
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
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
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
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
The authors did not receive any financial support for
preparing this review.
本文全文中文版从 2014 515 日起在 供免费阅览下载
1. World Health Organizaon. Global status report on alcohol
2004. Geneva, Switzerland. 2004
2. Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani
H, et al. A comparave risk assessment of burden of disease
and injury attributable to 67 risk factors and risk factor
clusters in 21 regions, 1990-2010: a systemac analysis for
the Global Burden of Disease Study 2010. Lancet. 2012;
380(9859): 2224-2260. doi:
3. Chen F, Andrew JL, Liang JH. [Research progress in
central neurotransmitters related to alcohol abuse and
addiction]. Zhong Guo Yao Wu Yi Lai Xing Za Zhi. 2007;
16(1):5-11. Chinese. doi:
4. Tupala E, Tiihonen J. Dopamine and alcoholism:
neurobiological basis of ethanol abuse. Prog
Neuropsychopharmacol Biol Psychiatry. 2004; 28(8): 1221-
1247. doi: hp://
5. Wise RA. Roles for nigrostriatal--not just mesocorcolimbic-
-dopamine in reward and addiction. Trends Neurosci.
2009; 32(10): 517-524. doi:
6. Taber KH, Black DN, Porrino LJ, Hurley RA. Neuroanatomy
of dopamine: reward and addicon. J Neuropsychiatry Clin
Neurosci. 2012; 24(1): 1-4. doi:
7. Dichter GS, Damiano CA, Allen JA. Reward circuitry
dysfunction in psychiatric and neurodevelopmental
disorders and genec syndromes: animal models and clinical
findings. J Neurodev Disord. 2012; 4(1): 19. doi: http://
8. Charlet K, Beck A, Heinz A. The dopamine system in mediang
alcohol effects in humans. Curr Top Behav Neurosci. 2013;
13:461-488. doi: hp://
9. Yan QS. Extracellular dopamine and serotonin aer ethanol
monitored with 5-minute microdialysis. Alcohol. 1999; 19(1):
1-7. doi: hp://
10. Yim HJ, Gonzales RA. Ethanol-induced increases in dopamine
extracellular concentration in rat nucleus accumbens
are accounted for by increased release and not uptake
inhibion. Alcohol. 2000; 22(2): 107-115. doi: hp://dx.doi.
11. Yoshimoto K, McBride WJ, Lumeng L, Li TK. Alcohol
stimulates the release of dopamine and serotonin in the
nucleus accumbens. Alcohol. 1992; 9(1): 17-22. doi: hp://
12. Yim HJ, Schallert T, Randall PK, Gonzales RA. Comparison of
local and systemic ethanol eects on extracellular dopamine
concentration in rat nucleus accumbens by microdialysis.
Alcohol Clin Exp Res. 1998; 22(2): 367-374. doi: hp://dx.doi.
• 65 • Shanghai Archives of Psychiatry, 2014, Vol. 26, No. 2
13. Yoshimoto K, Ueda S, Kato B, Takeuchi Y, Kawai Y, Noritake K,
et al. Alcohol enhances characterisc releases of dopamine
and serotonin in the central nucleus of the amygdala.
Neurochem Int. 2000; 37(4): 369-376. doi: http://dx.doi.
14. Yim HJ, Robinson DL, White ML, Jaworski JN, Randall PK,
Lancaster FE, et al. Dissociaon between the me course of
ethanol and extracellular dopamine concentrations in the
nucleus accumbens aer a single intraperitoneal injecon.
Alcohol Clin Exp Res. 2000; 24(6): 781-788
15. Cowen MS, Lawrence AJ. The role of opioid-dopamine
interactions in the induction and maintenance of ethanol
consumpon. Prog Neuropsychopharmacol Biol Psychiatry.
1999; 23(7): 1171-1212. doi:
16. Spanagel R, Herz A, Shippenberg TS. Opposing tonically
acve endogenous opioid systems modulate the mesolimbic
dopaminergic pathway. Proc Natl Acad Sci USA. 1992; 89(6):
17. Adermark L, Clarke RB, Olsson T, Hansson E, Soderpalm B,
Ericson M. Implicaons for glycine receptors and astrocytes
in ethanol-induced elevation of dopamine levels in the
nucleus accumbens. Addict Biol. 2011; 16(1): 43-54. doi:
18. Weiss F, Parsons LH, Schulteis G, Hansson E, Söderpalm B,
Ericson M. Ethanol self-administraon restores withdrawal-
associated deficiencies in accumbal dopamine and
5-hydroxytryptamine release in dependent rats. J Neurosci.
1996; 16(10): 3474-3485
19. Rossetti ZL, Hmaidan Y, Gessa GL. Marked inhibition of
mesolimbic dopamine release: a common feature of
ethanol, morphine, cocaine and amphetamine absnence in
rats. Eur J Pharmacol. 1992; 221(2-3): 227-234. doi: hp://
20. Bustamante D, Quintanilla ME, Tampier L, et al. Ethanol
induces stronger dopamine release in nucleus accumbens
(shell) of alcohol-preferring (bibulous) than in alcohol-
avoiding (abstainer) rats. Eur J Pharmacol. 2008;
591(1-3): 153-158. doi:
21. Murphy JM, McBride WJ, Lumeng L, Li TK. Contents of
monoamines in forebrain regions of alcohol-preferring
(P) and -nonpreferring (NP) lines of rats. Pharmacol
Biochem Behav. 1987; 26(2): 389-392. doi: http://dx.doi.
22. Strother WN, Lumeng L, Li T-K, McBride WJ. Dopamine and
serotonin content in select brain regions of weanling and
adult alcohol drinking rat lines. Pharmacol Biochem Behav.
2005; 80(2): 229–237. doi:
23. Gongwer MA, Murphy JM, McBride WJ, Lumeng L, Li TK.
Regional brain contents of serotonin, dopamine and their
metabolites in the selectively bred high- and low-alcohol
drinking lines of rats. Alcohol. 1989; 6(4): 317-320. doi:
24. Quintanilla ME, Bustamante D, Tampier L, Israel Y, Herrera-
Marschitz M. Dopamine release in the nucleus accumbens
(shell) of two lines of rats selecvely bred to prefer or avoid
ethanol. Eur J Pharmacol. 2007; 573(1-3): 84-92. doi: hp://
25. Smith AD, Weiss F. Ethanol exposure differentially alters
central monoamine neurotransmission in alcohol-preferring
versus -nonpreferring rats. J Pharmacol Exp Ther. 1999;
288(3): 1223-1228
26. Tuomainen P, Patsenka A, Hyyä P, Grinevich V, Kiianmaa K.
Extracellular levels of dopamine in the nucleus accumbens in
AA and ANA rats aer reverse microdialysis of ethanol into
the nucleus accumbens or ventral tegmental area. Alcohol.
2003; 29(2): 117-124. doi: hp://
27. Katner SN, Weiss F. Neurochemical characteriscs associated
with ethanol preference in selected alcohol-preferring and
–nonpreferring rats: a quantitative microdialysis study.
Alcohol Clin Exp Res. 2001; 25(2): 198-205. doi: hp://dx.doi.
28. Kiianmaa K, Nurmi M, Nykänen I, Sinclair JD. Effect of
ethanol on extracellular dopamine in the nucleus accumbens
of alcohol-preferring AA and alcohol-avoiding ANA rats.
Pharmacol Biochem Behav. 1995; 52(1): 29-34. doi: hp://
29. Madras BK, Fahey MA, Bergman J, Canfield DR, Spealman
RD. Effects of cocaine and related drugs in nonhuman
primates. I. [3H] cocaine binding sites in caudate–putamen. J
Pharmacol Exp Ther. 1989; 251(1):131-141
30. Volkow ND, Wang GJ, Fowler JS, Logan J, Gatley SJ, Wong C,
et al. Reinforcing eects of psychosmulants in humans are
associated with increases in brain dopamine and occupancy
of D(2) receptors. J Pharmacol Exp Ther. 1999; 291(1): 409-
31. Setiawan E, Pihl RO, Dagher A, Schlagintweit H, Casey KF,
Benkelfat C, et al. Differential striatal dopamine responses
following oral alcohol in individuals at varying risk for
dependence. Alcohol Clin Exp Res. 2014; 38(1); 126-34. doi:
32. Stefanini E, Frau M, Garau MG, Garau B, Fadda F, Gessa GL.
Alcohol-preferring rats have fewer dopamine D2 receptors in
the limbic system. Alcohol. 1992; 27(2): 127-130
33. McBride WJ, Chernet E, Dyr W, Lumeng L, Li TK. Densities
of dopamine D2 receptors are reduced in CNS regions of
alcohol preferring P rats. Alcohol. 1993; 10(5): 387-390. doi:
34. Strother WN, Lumeng L, Li TK, McBride WJ. Regional CNS
densities of serotonin 1A and dopamine D2 receptors
in periadolescent alcohol-preferring P and alcohol-
nonpreferring NP rat pups. Pharmacol Biochem Behav.
2003; 74(2): 335-342. doi: hp://
35. Hietala J, West C, Syvälahti E, Någren K, Lehikoinen P,
Sonninen P, et al. Striatal D2 dopamine receptor binding
characteriscs in vivo in paents with alcohol dependence.
Psychopharmacology (Berl). 1994; 116(3): 285-290. doi:
Shanghai Archives of Psychiatry, 2014, Vol. 26, No. 2 • 66 •
36. Volkow ND, Wang GJ, Fowler JS, Logan J, Hitzemann R,
Ding YS, et al. Decreases in dopamine receptors but not in
dopamine transporters in alcoholics. Alcohol Clin Exp Res.
1996; 20(9): 1594-1598. doi:
37. Kuikka JT, Repo E, Bergström KA, Tupala E, Tiihonen J. Specic
binding and laterality of human extrastriatal dopamine D2/
D3 receptors in late onset type 1 alcoholic paents. Neurosci
Lett. 2000; 292(1): 57-59. doi:
38. Tupala E, Hall H, Bergström K, Särkioja T, Räsänen P, Mantere
T, et al. Dopamine D2/D3-receptor and transporter densies
in nucleus accumbens and amygdala of type 1 and 2
alcoholics. Mol Psychiatry. 2001; 6(3): 261-267
39. Balldin JI, Berggren UC, Lindstedt G. Neuroendocrine
evidence for reduced dopamine receptor sensitivity in
alcoholism. Alcohol Clin Exp Res. 1992; 16(1): 71-74
40. Ng GY, O’Dowd BF, George SR. Genotypic dierences in brain
dopamine receptor function in the DBA/2J and C57BL/6J
inbred mouse strains. Eur J Pharmacol. 1994; 269(3): 349-
41. McBride WJ, Chernet E, Russell RN, Wong DT, Guan XM,
Lumeng L, et al. Regional CNS densities of monoamine
receptors in alcohol-naive alcohol-preferring P and
-nonpreferring NP rats. Alcohol. 1997; 14(2): 141-148
42. McBride WJ, Chernet E, Russell RN, Chamberlain JK, Lumeng
L, Li TK. Regional CNS densies of serotonin and dopamine
receptors in high alcohol-drinking (HAD) and low alcohol-
drinking (LAD) rats. Alcohol. 1997; 14(6): 603-609
43. Syvälahti EK, Pohjalainen T, Korpi ER, Pälvimäki EP, Ovaska
T, Kuoppamäki M, et al. Dopamine D2 receptor gene
expression in rat lines selected for dierences in voluntary
alcohol consumption. Alcohol Clin Exp Res. 1994; 18(4):
44. Tupala E, Hall H, Mantere T, Räsänen P, Särkioja T, Tiihonen
J. Dopamine receptors and transporters in the brain reward
circuits of type 1 and 2 alcoholics measured with whole
hemisphere autoradiography. Neuroimage. 2003; 19(1): 145-
45. Myers RD, Melchior CL. Alcohol drinking in the rat after
destrucon of serotonergic and catecholaminergic neurons
in the brain. Res Commun Chem Pathol Pharmacol. 1975;
10(2): 363-378
46. Ikemoto S, McBride WJ, Murphy JM, Lumeng L, Li TK.
6-OHDA-lesions of the nucleus accumbens disrupt the
acquision but not the maintenance of ethanol consumpon
in the alcohol-preferring P line of rats. Alcohol Clin Exp Res.
1997; 21(6): 1042-1046
47. Quarfordt SD, Kalmus GW, Myers RD. Ethanol drinking
following 6-OHDA lesions of nucleus accumbens and
tuberculum olfactorium of the rat. Alcohol. 1991; 8(3): 211-
217. doi: hp://
48. Yoshimoto K, Kawamura K, Yayama K, Fujimiya T, Uemura K,
Komura S. The effects of neurotoxins 6-hydroxydopamine
and 5,7-dihydroxytryptamine into the rat nucleus accumbens
on the alcohol drinking behavior. Nihon Hoigaku Zasshi.
1995; 49(1): 11-19
49. Yoshimoto K, Kaneda S, Kawai Y, Ueda S, Takeuchi
Y, Matsushita H, et al. Treating neonatal rats with
6-hydroxydopamine induced an increase in voluntary alcohol
consumpon. Alcohol Clin Exp Res. 1999; 23(4 Suppl): 2S-6S
50. Lanca AJ. Reduction of voluntary alcohol intake in the rat
by modulation of the dopaminergic mesolimbic system:
transplantation of ventral mesencephalic cell suspensions.
Neuroscience.1994; 58(2): 359-369. doi: http://dx.doi.
51. Hodge CW, Samson HH, Haraguchi M. Microinjections of
dopamine agonists in the nucleus accumbens increase
ethanolreinforced responding. Pharmacol Biochem Behav.
1992; 43(1): 249-54. doi:
52. Samson HH, Hodge CW. The role of the mesoaccumbens
dopamine system in ethanol reinforcement: studies using
the techniques of microinjecon and voltammetry. Alcohol
Alcohol Suppl 1993; 2: 469-274
53. Kaczmarek HJ, Kiefer SW. Microinjections of dopaminergic
agents in the nucleus accumbens affect ethanol
consumpon but not palatability. Pharmacol Biochem Behav.
2000; 66(2): 307-312. doi: hp://
54. Hodge CW, Samson HH, Chappelle AM. Alcohol self-
administraon: further examinaon of the role of dopamine
receptors in the nucleus accumbens. Alcohol Clin Exp Res.
1997; 21(6): 1083-1091. doi:
55. Zhong SR, Wu XH, Wang XJ, Bao JJ, Gao CQ, Wu WY, et al.
[Association analyses of DRD2 (TAQI A, TAQI B, -141CINS/
DEL), DRD4 and DAT genetic polymorphisms with alcohol
dependence syndrome in Yunnan Han population]. Zhong
Guo Yao Wu Yi Lai Xing Za Zhi. 2009; 18(4): 341-370. Chinese
56. Blum K, Noble EP, Sheridan PJ, Montgomery A, Ritchie
T, Jagadeeswaran P, et al. Allelic association of human
dopamine D2 receptor gene in alcoholism. JAMA. 1990;
263(15): 2055-2060. doi:
57. Berggren U, Fahlke C, Aronsson E, Karanti A, Eriksson M,
Blennow K, et al. The taqI DRD2 A1 allele is associated with
alcohol-dependence although its eect size is small. Alcohol.
2006; 41(5): 479-485. doi: hp://
58. Kraschewski A, Reese J, Anghelescu I, Winterer G, Schmidt
LG, Gallinat J, et al. Associaon of the dopamine D2 receptor
gene with alcohol dependence: haplotypes and subgroups
of alcoholics as key factors for understanding receptor
funcon. Pharmacogenet Genomics. 2009; 19(7): 513–527.
doi: hp://
59. Bulwa ZB, Sharlin JA, Clark PJ, Bhattacharya TK, Kilby
CN, Wang Y, et al. Increased consumption of ethanol
and sugar water in mice lacking the dopamine D2 long
receptor. Alcohol. 2011; 45(7): 631-639. doi: http://dx.doi.
• 67 • Shanghai Archives of Psychiatry, 2014, Vol. 26, No. 2
60. Gelernter J, Kranzler H. D2 dopamine receptor gene (DRD2)
allele and haplotype frequencies in alcohol dependent and
control subjects: no associaon with phenotype or severity
of phenotype. Neuropsychopharmacology. 1999; 20(6): 640-
649. doi: hp://
61. Blomqvist O, Gelernter J, Kranzler HR. Family-based study
of DRD2 alleles in alcohol and drug dependence. Am J
Med Genet. 2000; 96(5): 659-664. doi: http://dx.doi.
62. El-Ghundi M, George SR, Drago J, Fletcher PJ, Fan T, Nguyen
T, et al. Disrupon of dopamine D1 receptor gene expression
aenuates alcohol-seeking behavior. Eur J Pharmacol. 1998;
353(2-3):149-158. doi:
63. Ma H, Huang Y, Zhang B, Wang Y, Zhao H, Du H, et al.
Association Between Neurotensin Receptor 1 Gene
Polymorphisms and Alcohol Dependence in a Male Han
Chinese Population. J Mol Neurosci. 2013; 51(2): 408-415.
doi: hp://
64. Tampier L, Prado C, Quintanilla ME, Mardones J. Effect
of bromocriptine on acute ethanol tolerance in UChB
rats. Addict Biol. 1999; 4(3): 317-321. doi: http://dx.doi.
65. Lawford BR, Young RM, Rowell JA, Qualichefski J, Fletcher
BH, Syndulko K, et al. Bromocriptine in the treatment of
alcoholics with the D2 dopamine receptor A1 allele. Nat
Med. 1995; 1(4): 337-341. doi:
66. Shaw GK, Waller S, Majumdar SK, Alberts JL, Latham CJ,
Dunn G. Tiapride in the prevention of relapse in recently
detoxied alcoholics. Br J Psychiatry. 1994; 165(4): 515-523.
doi: hp://
67. Naranjo CA, Dongier M, Bremner KE. Long-acng injectable
bromocriptine does not reduce relapse in alcoholics.
Addiction. 1997; 92(8): 969-978. doi: http://dx.doi.
68. Bender S, Scherbaum N, Soyka M, Ruther E, Mann K,
Gatspar M. The ecacy of the dopamine D2/D3 antagonist
tiapride in maintaining abstinence: a randomized, double-
blind, placebo-controlled trial in 299 alcohol-dependent
paents. Int J Neuropsychopharmacol. 2007; 10(5): 653-660.
doi: hp://
69. Yahn SL, Watterson LR, Olive MF. Safety and efficacy of
acamprosate for the treatment of alcohol dependence.
Subst Abuse. 2013; 6: 1-12. doi: hp://
70. Jørgensen CH, Pedersen B, Tønnesen H. The efficacy of
disulram for the treatment of alcohol use disorder. Alcohol
Clin Exp Res. 2011; 35(10): 1749-1758. doi: http://dx.doi.
(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 •
... The emergence of these hallucinations is attributed to an autonomic hyperarousal conveyed by an increased dopamine activity found in both alcoholic intoxication and withdrawal [52], which explains the similarity of the hallucinatory experience in acute alcoholic intoxication with delirium ("pink elephants") and in alcoholic hallucinosis. Alcohol is known to increase the dopamine levels in certain brain structures, an effect that also seems to play an important part in the emergence of addiction [53]. In heavy drinkers, the sudden lack of alcohol leads to a decrease in dopamine activity following withdrawal [53]. ...
... Alcohol is known to increase the dopamine levels in certain brain structures, an effect that also seems to play an important part in the emergence of addiction [53]. In heavy drinkers, the sudden lack of alcohol leads to a decrease in dopamine activity following withdrawal [53]. The dopamine level increases again a few days later, probably in the context of an autonomic compensatory upregulation, and may thus induce hallucinations [54]. ...
Full-text available
Previous publications have discussed the occurrence of intracerebral hemorrhages, hallucinations and psychosis in COVID-19 patients. In this article, we have reviewed the literature on the subject while depicting the case of a 63-year-old female patient who suffered from an intracerebral hemorrhage in the right basal ganglia and thalamus two weeks after a COVID-19 diagnosis and who developed a visual hallucinosis shortly after. We concluded that, while there may be a correlation between COVID-19 and hallucinations according to current literature, more research is yet needed to clarify. In our case, we rather interpreted the hallucinations in the context of a peduncular hallucinosis related to the intracerebral hemorrhage. We compared our patient’s lesion localization to other 15 reported cases of peduncular hallucinations following intracerebral hemorrhages reported on Pubmed. In summary, the lesions were localized in the pons in 52.9% of the cases, 17.7% were in the thalamus and/or the basal ganglia, 17.7% in the mesencephalon and respectively 5.8% in the temporal and occipital lobe. The distribution pattern we found is consistent with the previously proposed mechanism behind peduncular hallucinations.
... Moreover, fatty acids are neuroprotective (Parga et al., 2018), and aldehyde dehydrogenase, which is involved in DA metabolism and associated with DAn generation, is a key enzyme in the ethanol degradation IV pathway (Villa et al., 2009;Grünblatt and Riederer, 2016;MetaCyc, 2021). Ethanol is known to have an effect on DAn (Melis et al., 2009;Ma and Zhu, 2014). As well, the nuclear factor erythroid 2-related factor 2 (NFE2L2/ NRF2)-mediated oxidative stress response and BAG family molecular chaperone regulator 2 (BAG2) signaling pathways have both been implicated in PD (Jazwa et al., 2011;Che et al., 2013;Qin et al., 2016;Todorovic et al., 2016) (Figure 2D). ...
Full-text available
Parkinson’s disease (PD) is an age-associated neurodegenerative disorder for which there is currently no cure. Cell replacement therapy is a potential treatment for PD; however, this therapy has more clinically beneficial outcomes in younger patients with less advanced PD. In this study, hVM1 clone 32 cells, a line of human neural stem cells, were characterized and subsequently transplanted in middle-aged Parkinsonian mice in order to examine cell replacement therapy as a treatment for PD. In vitro analyses revealed that these cells express standard dopamine-centered markers as well as others associated with mitochondrial and peroxisome function, as well as glucose and lipid metabolism. Four months after the transplantation of the hVM1 clone 32 cells, striatal expression of tyrosine hydroxylase was minimally reduced in all Parkinsonian mice but that of dopamine transporter was decreased to a greater extent in buffer compared to cell-treated mice. Behavioral tests showed marked differences between experimental groups, and cell transplant improved hyperactivity and gait alterations, while in the striatum, astroglial populations were increased in all groups due to age and a higher amount of microglia were found in Parkinsonian mice. In the motor cortex, nonphosphorylated neurofilament heavy was increased in all Parkinsonian mice. Overall, these findings demonstrate that hVM1 clone 32 cell transplant prevented motor and non-motor impairments and that PD is a complex disorder with many influencing factors, thus reinforcing the idea of novel targets for PD treatment that tend to be focused on dopamine and nigrostriatal damage.
... While psychosocial [3] and pharmaceutical [4] treatment options exist for this disorder, outcomes are moderate at best [5,6], signifying the need for improved treatment options. The dopamine system has been implicated in AUD with the dopamine D2 receptors (DRD2) as the historical target of research [7]. Previous animal studies show that chronic consumption of alcohol reduces the expression of DRD2s [8,9]. ...
Preclinical studies support an important role of dopamine D3 receptors (DRD3s) in alcohol use disorder (AUD). In animals, voluntary alcohol consumption increases DRD3 expression, and pharmacological blockade of DRD3s attenuates alcohol self-administration and reinstatement of alcohol seeking. However, these findings have yet to be translated in humans. This study used positron emission tomography (PET) and [11C]-(+)-PHNO to compare receptor levels in several dopamine D2 receptor (DRD2) and DRD3 regions of interest between AUD subjects in early abstinence (n = 17; 6.59 ± 4.14 days of abstinence) and healthy controls (n = 18). We recruited non-treatment seeking subjects meeting DSM-5 criteria for AUD. We examined the relationship between DRD2/3 levels and both alcohol craving and alcohol motivation/wanting, using a cue reactivity procedure and an intravenous alcohol self-administration (IVASA) paradigm, respectively. [11C]-(+)-PHNO binding levels in AUD subjects were significantly lower than binding in HCs when looking at all DRD2/3 ROIs jointly (Wilk’s Λ = .58, F(6,28) =3.33, p = 0.013, η2p = 0.42), however there were no region-specific differences. Binding values demonstrate −12.3% and −16.1% lower [11C]-(+)-PHNO binding in the SMST and SN respectively, though these differences did not withstand Bonferroni corrections. There was a positive association between [11C]-(+)-PHNO binding in the SN (almost exclusively reflective of DRD3) and alpha (lower values reflect higher alcohol demand) in the APT after Bonferroni corrections (r = 0.66, p = 0.0080). This demonstrates that AUD subjects with lower DRD3 levels in the SN exhibit increased demand for alcohol. These results replicate previous findings demonstrating reduced DRD2/3 levels while also supporting a lack of DRD3 upregulation and potential downregulation in early abstinent AUD. Furthermore, the finding that binding in the SN is associated with alcohol demand warrants further examination.
... The reinforcing effects of opioids are mediated by increases in dopamine levels in certain brain regions (Cao et al., 2021;Nisell et al., 1994;Wiss et al., 2018). In addition to opioids, sucrose, saccharin and alcohol, as well as other drugs of abuse, increase dopamine release in the nucleus accumbens (NAc) and this increase in dopamine levels has been correlated to development of preference in mice (Ma and Zhu, 2014;Yoshimoto et al., 1992). ...
Full-text available
As a result of the opioid epidemic, there is a desire to identify new targets for treating opioid use disorder. Previous studies showed that fibroblast growth factor 21 (FGF21) decreased alcohol and sweet preference in mice. In this study, FGF21-transgenic (FGF21-Tg) mice, expressing high FGF21 serum levels, and wildtype (WT) C57BL/6J littermates were treated with morphine and saline to determine if differences exist in their physiological and behavioral responses to opioids. FGF21-Tg mice displayed reduced preference for morphine in the conditioned place preference assay compared to WT littermates. Similarly, FGF21-Tg mice had an attenuation of the magnitude and rate of acute morphine antinociceptive tolerance development, and acute and chronic morphine physical dependence, but exhibited no change in chronic morphine antinociceptive tolerance. The ED50 values for morphine-induced antinociception in the 55-degree C hot plate and the 55-degree C warm-water tail withdrawal assays were similar in both strains of mice. Likewise, FGF21-Tg and WT littermates had comparable responses to morphine-induced respiratory depression. Overall, FGF21-Tg mice had an attenuated preference for morphine, a reduced development of morphine-induced dependence, and a reduction in the development of acute morphine antinociceptive tolerance. FGF21 and its receptor have therapeutic potential for reducing opioid withdrawal symptoms and craving, and augmenting opioid therapeutics for acute pain treatment.
Resumen Objetivo Exponer a través de un caso clínico el uso de tiapride para la desintoxicación de alcohol en un paciente con diagnóstico de trastorno por el uso de alcohol. Caso clínico Una mujer de 50 años, en seguimiento en la Unidad de Conductas Adictivas desde septiembre de 2016 hasta la actualidad, con diagnósticos de trastorno de adaptación con alteración mixta de las emociones, trastorno por consumo de alcohol y descompensación maniforme, ante lo cual se le instaura el tratamiento con tiapride. Resultados Los estudios consultados demuestran la eficacia y seguridad de tiapride para el síndrome de abstinencia al alcohol, tanto en el ámbito ambulatorio como hospitalario, en monoterapia o en politerapia con benzodiacepinas y/o antiepilépticos, siendo usado también en la agitación y/o sintomatología psicótica. Conclusiones En el síndrome de abstinencia al alcohol se ha observado que el tiapride es eficaz, pudiendo incluso tenerlo en cuenta como un tratamiento coadyuvante a las benzodiacepinas o los anticonvulsivantes. Con vistas al futuro, se deberían tener en cuenta la farmacogenética que afecta al trastorno por consumo de alcohol, con lo que se podría beneficiar, con menores efectos adversos, a una terapia personalizada individualizada.
The number of people who suffer from a substance abuse disorder has continued to rise over the last decade; particularly, the number of drug-related overdose deaths has sharply increased during the COVID-19 pandemic. Converging lines of clinical observations, supported by imaging and neuropsychological performance testing, have demonstrated that substance abuse-induced dysregulation of neurotransmissions in the brain is critical for development and expression of the addictive properties of abused substances. Recent scientific advances have allowed for better understanding of the neurobiological processes that mediates drugs of abuse and addiction. This chapter presents the past classic concepts and the recent advances in our knowledge about how cocaine, amphetamines, opioids, alcohol, and nicotine alter multiple neurotransmitter systems, which contribute to the behaviors associated with each drug. Additionally, we discuss the interactive effects of HIV-1 or COVID-19 and substance abuse on neurotransmission and neurobiological pathways. Finally, we introduce therapeutic strategies for development of pharmacotherapies for substance abuse disorders.
Circadian genes, including Per1, in the medial shell region of nucleus accumbens (mNAcSh), regulate binge alcohol consumption. However, the upstream mechanism regulating circadian genes-induced alcohol consumption is not known. Since activation of dopamine D2 receptors (D2R) increases Per1 gene expression, we hypothesised that local infusion of quinpirole, a D2R agonist, by increasing Per1 gene expression in the mNAcSh, will increase binge alcohol consumption in mice. We performed two experiments on male C57BL/6J mice, instrumented with bilateral guide cannulas above the mNAcSh, and exposed to a 4-day drinking-in-dark (DID) paradigm. The first experiment determined the effects of bilateral infusion of quinpirole (100 ng/300 nl/site) or DMSO (Vehicle group) in the mNAcSh on Per1 gene expression and alcohol consumption. The second experiment determined the effect of antisense-induced downregulation of Per1 in the mNAcSh on the quinpirole-induced increase in alcohol consumption. Control experiments were performed by exposing the animals to sucrose (10% w/v). After the experiment, animals were euthanised, brains removed and processed for localisation of injection sites and analysis of Per1 gene expression in the mNAcSh. As compared with the DMSO, local bilateral infusion of quinpirole significantly increased the expression of Per1 in the mNAcSh along with an increase in the amount of alcohol consumed in mice exposed to DID paradigm. In addition, local antisense-induced downregulation of Per1 significantly attenuated the effects of intro-accumbal infusion of quinpirole on alcohol consumption. Our results suggest that Per1 in the mNAcSh mediates D2R activation-induced increase in alcohol consumption
Full-text available
Neurološke bolesti uzrokovane alkoholizmom.
Because of increased opioid misuse, there is a need to identify new targets for minimizing opioid tolerance, and physical and psychological dependence. Previous studies showed that fibroblast growth factor 21 (FGF21) decreased alcohol and sweet preference in mice. In this study, FGF21-transgenic (FGF21-Tg) mice, expressing high FGF21 serum levels, and wildtype (WT) C57BL/6J littermates were treated with morphine and saline to determine if differences exist in their physiological and behavioral responses to opioids. FGF21-Tg mice displayed reduced preference for morphine in the conditioned place preference assay compared to WT littermates. Similarly, FGF21-Tg mice had an attenuation of the magnitude and rate of acute morphine antinociceptive tolerance development, and acute and chronic morphine physical dependence, but exhibited no change in chronic morphine antinociceptive tolerance. The ED50 values for morphine-induced antinociception in the 55 °C hot plate and the 55 °C warm-water tail withdrawal assays were similar in both strains of mice. Likewise, FGF21-Tg and WT littermates had comparable responses to morphine-induced respiratory depression. Overall, FGF21-Tg mice had a decrease in the development of acute analgesic tolerance, and the development of physical dependence, and morphine preference. FGF21 and its receptor have therapeutic potential for reducing opioid withdrawal symptoms and craving, and augmenting opioid therapeutics for acute pain patients to minimize tolerance development.
The harmful consumption of ethanol is associated with significant health problems and social burdens. This drug activates a complex network of reward mechanisms and habit formation learning that is supposed to contribute to the consumption of increasingly high and frequent amounts, ultimately leading to addiction. In the context of fetal alcohol spectrum disorders, fetal alcohol syndrome (FAS) is a consequence of the harmful use of alcohol during pregnancy, which affects the embryonic development of the fetus. FAS can be easily reproduced in zebrafish by exposing the embryos to different concentrations of ethanol in water. In this regard, the aim of the present review is to discuss the late pathological implications in zebrafish exposed to ethanol at the embryonic stage, providing information in the context of human fetal alcoholic spectrum disorders. Experimental FAS in zebrafish is associated with impairments in the metabolic, morphological, neurochemical, behavioral, and cognitive domains. Many of the pathways that are affected by ethanol in zebrafish have at least one ortholog in humans, collaborating with the wider adoption of zebrafish in studies on alcohol disorders. In fact, zebrafish present validities required for the study of these conditions, which contributes to the use of this species in research, in addition to studies with rodents. This article is protected by copyright. All rights reserved
Full-text available
Neurotensin (NT) is a 13-amino acid multifunctional neuropeptide. Previous studies have demonstrated the roles of NT and its high-affinity receptor 1 (NTR1) in genetically mediated differential sensitivities to alcohol. However, no studies have investigated the association between NTR1 gene single-nucleotide polymorphisms (SNPs) and alcohol dependence (AD). We therefore examined this link. We genotyped three SNPs (rs6090453C/G, rs6011914C/G, and rs2427422A/G) of NTR1 gene in 127 AD patients and 131 healthy controls drawn from Han Chinese males. Allele and genotype frequencies were compared, and linkage disequilibrium and haplotype analysis were performed. For rs6011914C/G, the frequencies of GG genotypes in AD patients showed an increased trend compared with controls (p = 0.057), and the ratio of GG/(CG + CC) for dominant model in AD patients was significantly higher (p = 0.024). For rs2427422A/G, both the frequencies of G alleles and GG genotypes and the ratio of GG/(AG + AA) for dominant model in AD patients were significantly higher compared with controls (p = 0.003, 0.006, 0.002, respectively). There was no significant difference in the frequencies of alleles, genotypes, and dominant or recessive model for rs6090453C/G (all p > 0.05). There were three pairs of SNP linkage disequilibriums, and the haplotype frequencies differed significantly between patients and controls for the CCA (p = 0.005, less frequent in the patients) and CCG (p = 0.002, more frequent in the patients) haplotypes. The current study supported an association between NTR1 gene variants and AD in the Han Chinese population.
Full-text available
Acamprosate (calcium acetylhomotaurine) is an amino acid modulator that has displayed efficacy in some clinical trials in reducing craving and promoting abstinence in alcohol dependent patients following detoxification. While acamprosate is safe and generally well-tolerated, not all studies have demonstrated clinical efficacy that is superior to placebo. In addition, the precise neurochemical mechanisms of action of acamprosate have still not yet been identified. In this review, we summarize current clinical data on the safety, efficacy, and pharmacokinetic properties of acamprosate, as well theories on its potential mechanism of action. We also discuss tolerability and patient preference issues and conclude with a discussion of the place of acamprosate in addiction medicine and therapy.
Full-text available
Quantification of the disease burden caused by different risks informs prevention by providing an account of health loss different to that provided by a disease-by-disease analysis. No complete revision of global disease burden caused by risk factors has been done since a comparative risk assessment in 2000, and no previous analysis has assessed changes in burden attributable to risk factors over time. METHODS We estimated deaths and disability-adjusted life years (DALYs; sum of years lived with disability [YLD] and years of life lost [YLL]) attributable to the independent effects of 67 risk factors and clusters of risk factors for 21 regions in 1990 and 2010. We estimated exposure distributions for each year, region, sex, and age group, and relative risks per unit of exposure by systematically reviewing and synthesising published and unpublished data. We used these estimates, together with estimates of cause-specific deaths and DALYs from the Global Burden of Disease Study 2010, to calculate the burden attributable to each risk factor exposure compared with the theoretical-minimum-risk exposure. We incorporated uncertainty in disease burden, relative risks, and exposures into our estimates of attributable burden. FINDINGS In 2010, the three leading risk factors for global disease burden were high blood pressure (7·0% [95% uncertainty interval 6·2-7·7] of global DALYs), tobacco smoking including second-hand smoke (6·3% [5·5-7·0]), and alcohol use (5·5% [5·0-5·9]). In 1990, the leading risks were childhood underweight (7·9% [6·8-9·4]), household air pollution from solid fuels (HAP; 7·0% [5·6-8·3]), and tobacco smoking including second-hand smoke (6·1% [5·4-6·8]). Dietary risk factors and physical inactivity collectively accounted for 10·0% (95% UI 9·2-10·8) of global DALYs in 2010, with the most prominent dietary risks being diets low in fruits and those high in sodium. Several risks that primarily affect childhood communicable diseases, including unimproved water and sanitation and childhood micronutrient deficiencies, fell in rank between 1990 and 2010, with unimproved water and sanitation accounting for 0·9% (0·4-1·6) of global DALYs in 2010. However, in most of sub-Saharan Africa childhood underweight, HAP, and non-exclusive and discontinued breastfeeding were the leading risks in 2010, while HAP was the leading risk in south Asia. The leading risk factor in Eastern Europe, most of Latin America, and southern sub-Saharan Africa in 2010 was alcohol use; in most of Asia, North Africa and Middle East, and central Europe it was high blood pressure. Despite declines, tobacco smoking including second-hand smoke remained the leading risk in high-income north America and western Europe. High body-mass index has increased globally and it is the leading risk in Australasia and southern Latin America, and also ranks high in other high-income regions, North Africa and Middle East, and Oceania. INTERPRETATION Worldwide, the contribution of different risk factors to disease burden has changed substantially, with a shift away from risks for communicable diseases in children towards those for non-communicable diseases in adults. These changes are related to the ageing population, decreased mortality among children younger than 5 years, changes in cause-of-death composition, and changes in risk factor exposures. New evidence has led to changes in the magnitude of key risks including unimproved water and sanitation, vitamin A and zinc deficiencies, and ambient particulate matter pollution. The extent to which the epidemiological shift has occurred and what the leading risks currently are varies greatly across regions. In much of sub-Saharan Africa, the leading risks are still those associated with poverty and those that affect children. FUNDING Bill & Melinda Gates Foundation.
Full-text available
This review summarizes evidence of dysregulated reward circuitry function in a range of neurodevelopmental and psychiatric disorders and genetic syndromes. First, the contribution of identifying a core mechanistic process across disparate disorders to disease classification is discussed, followed by a review of the neurobiology of reward circuitry. We next consider preclinical animal models and clinical evidence of reward-pathway dysfunction in a range of disorders, including psychiatric disorders (i.e., substance-use disorders, affective disorders, eating disorders, and obsessive compulsive disorders), neurodevelopmental disorders (i.e., schizophrenia, attention-deficit/hyperactivity disorder, autism spectrum disorders, Tourette's syndrome, conduct disorder/oppositional defiant disorder), and genetic syndromes (i.e., Fragile X syndrome, Prader-Willi syndrome, Williams syndrome, Angelman syndrome, and Rett syndrome). We also provide brief overviews of effective psychopharmacologic agents that have an effect on the dopamine system in these disorders. This review concludes with methodological considerations for future research designed to more clearly probe reward-circuitry dysfunction, with the ultimate goal of improved intervention strategies.
In a blinded experiment, we report the first allelic association of the dopamine D2 receptor gene in alcoholism. From 70 brain samples of alcoholics and nonalcoholics, DNA was digested with restriction endonucleases and probed with a clone that contained the entire 3' coding exon, the polyadenylation signal, and approximately 16.4 kilobases of noncoding 3' sequence of the human dopamine D2 receptor gene (λhD2G1). In the present samples, the presence of A1 allele of the dopamine D2 receptor gene correctly classified 77% of alcoholics, and its absence classified 72% of nonalcoholics. The polymorphic pattern of this receptor gene suggests that a gene that confers susceptibility to at least one form of alcoholism is located on the q22-q23 region of chromosome 11.
The neurobiology of risk for alcohol use disorders (AUDs) remains poorly understood. Individual differences in vulnerability, though, have been indicated by subjective responses to alcohol ingestion and personality traits. To investigate the relationship between these features and striatal dopamine (DA) responses to alcohol, we studied 26 healthy young social drinkers (21.3 ± 3.0 years old; 10.7 ± 8.8 drinks/wk) at varying risk for alcoholism. Each participant received 2 positron emission tomography [(11) C]raclopride scans after administration of either placebo or oral alcohol (1 ml/kg body weight of 94% alcohol, 0.75 g/kg) in a randomized and counterbalanced design. Subjects with high-risk subjective responses to alcohol had more family members with AUDs, greater alcohol use problems, and, in response to the alcohol challenge, significant decreases in [(11) C]raclopride binding indicative of increased extracellular DA. In contrast, low-risk subjects exhibited increases in [(11) C]raclopride binding in response to alcohol. The results were similar when risk groups were based on personality traits, although statistically less robust. Changes in striatal DA in response to alcohol ingestion may be a neurobiological marker of vulnerability to AUDs.
In a blinded experiment, the authors report the first allelic association of the dopamine Dâ receptor gene in alcoholism. From 70 brain samples of alcoholics and nonalcoholics, DNA was digested with restriction endonucleases and probed with a clone that contained the entire 3â² coding exon, the polyadenylation signal, and approximately 16.4 kilobases of noncoding 3â² sequence of the human dopamine Dâ receptor gene (λhD2G1). In the present samples, the presence of A1 allele of the dopamine Dâ receptor gene correctly classified 77% of alcoholics, and its absence classified 72% of nonalcoholics. The polymorphic pattern of this receptor gene suggests that a gene that confers susceptibility to at least one form of alcoholism is located on the q22-q23 region of chromosome 11.