Alcohol: Mode of Actions and Clinical Perspectives

151 Pages·2001·0.54 MB·English

by  Albert Sun

Αλχοηολ:
Μοδε οφ Αχτιονσ ανδ
Χλινιχαλ Περσπεχτιϖεσ
Γυεστ Εδιτορσ
Αλβερτ Συν
ΚΑΡΓΕΡ
Alcohol:
Mode of Actions and
Clinical Perspectives
Guest Editors
Albert Sun,Columbia, Mo.
Ting-Kai Li, Indianapolis, Ind.
Shih-Jiun Yin, Taipei
Jang-Yen Wu,Lawrence, Kans.
58 figures, 4 in color, 18 tables, 2001
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Biomedical Vignette
In the current issue:
CYP2E1-Derived Oxidative Stress Structure and Function of Dopamine and Alcohol Relapse
Alcohol Dehydrogenases
It is believed that reactive oxygen spe- Relapse prevention is a major concern
cies produced by ethanol plays an impor- Mammalian alcohol dehydrogenase in therapeutic intervention of alcohol-de-
tant role in ethanol-induced hepatotoxici- (ADH) constitutes a complex system with pendent patients. Dopaminergic transmis-
ty [2, 3]. Mari et al. [20] reported that over- different forms and extensive multiplicity sion has been implicated in alcohol depen-
expression of cytochrome P450 2E1 (ADH1–ADH6) that catalyzes the oxidation dence and hence dopaminergic agents have
(CYP2E1) in HepG2-E47 cells increases to- and reduction of a wide variety of alcohols been regarded as putative therapeutics for
tal levels of antioxidants such as glu- and aldehydes [7, 8]. Höög et al. [14] re- preventing relapse [24, 26]. Walter et al.
tathione, and activity, protein or mRNA ported the functions of ADH1–ADH4 and [30] reported that flupenthixol, a D1, D2,
levels for other antioxidants such as cata- cautioned that rodents are poor model sys- and D3 antagonist, increases the relapse
lase and glutathione transferases. These tems for human ethanol metabolism since rate significantly. The authors further
findings may reflect an adaptive mecha- the rodent ADH2 enzymes almost lack showed that flupenthixol has detrimental
nism to remove CYP2E1-derived reactive ethanol-oxidizing capacity in contrast to effects only in types I and III and has no ef-
oxygen species through up-regulation of the human form. The authors further pro- fect in types II and IV based on the Lesch
these antioxidant genes. posed that, in contrast to the cytochrome typology. These findings demonstrate the
P450 system, the function of the entire value of the Lesch typology in the analysis
ADH system could be seen as a general of outcome of therapeutic intervention of
Oxidative Stress and Ethanol detoxifying system for alcohols and alde- alcohol relapse.
hydes without generating toxic radicals.
It is well known that production of ex-
cessive reactive oxygen species could lead NMDA Receptor and
to structural and functional changes in the P300 ERP and Alcoholism Pharmacological Intervention
body [10]. Among various reactive oxygen
species, nitric oxide (NO) appears to play a Increasing evidence supports a role for The central neurotoxic effects of alco-
central role in regulatory functions in the genetic factors in the susceptibility to alco- holism seem to be related to glutamate-in-
nervous, immune and cardiovascular sys- hol dependence [12, 23]. However, the duced excitotoxic damage and up-regula-
tems [17]. Zima et al. [38] reported in al- identification of specific genes that con- tion of NMDA receptor [9]. Acamprosate
coholics an increase in NO-stable metabo- tribute to this predisposition has proven is thought to have inhibitory activity on
lites-nitrites and nitrates, antiphospholipid elusive. Hesselbrock et al. [11] reported the NMDA receptors [37]. It can also affect tau-
antibodies or oxidized LDL and a decrease use of P300 wave amplitude as an alterna- rin and calcium channels. The preclinical
in some important enzymatic antioxidant tive approach to diagnose phenotype for al- study with the European Acamprosate Tri-
systems, including superoxide dismutase coholism susceptibility genes. The authors al project has shown excellent method-
and glutathione peroxidase. These results identify differences in P300 amplitude be- ological approach for relapse prevention
provide additional evidence to support the tween alcoholics and non-alcoholics, be- and therapy [16]. There is also evidence
long-suspected notion that free radicals tween unaffected relatives of alcoholics and that this compound can increase the sobri-
play an important role in the development relatives of controls, as well as between un- ety rates and has only few and mild side ef-
of alcoholic liver damage. affected offspring of alcoholic fathers and fects.
offspring of controls [11]. These results in-
dicate that P300 can be used as an en-
dophenotype for alcohol dependence.
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Biomedical Vignette
Mode of Action of DETC-MeSO and Neuroprotection Alcohol and Brain Serotonin
Acamprosate and Neurotoxicity
S-methyl N,N-diethylthiolcarbamate It is commonly found that children of
Acamprosate (AC), N-acetyl-homotau- sulfoxide (DETC-MeSO), the active metab- women who were heavy drinkers during
rine, has recently been introduced for treat- olite of disulfiram, has recently been shown pregnancy exhibit mental retardation, hy-
ing alcohol craving and reducing relapses in to exert an antagonistic effect on brain glu- peractivity, cognitive deficit and behavioral
weaned alcoholics [27, 32]. However, its tamate receptors [21]. It is also possible that abnormalities [5, 28] . These psychological
mechanism remains elusive. Wu et al. [35] the clinical efficacy of disulfiram in the problems have long been suspected to be
proposed that AC might exert its action treatment of alcoholism is due, at least in related to central nervous system dysfunc-
through the taurine, rather than the gluta- part, to its effect on glutamate receptors. tion. Sari et al. [25] reported that alcohol
matergic or GABAergic system. Whereas The effect of DETC-MeSO on glutamate re- reduces the normal formation and growth
AC strongly inhibits the binding of taurine ceptors may also explain the synergistic ef- of serotonin (5-HT) neurons in the mid-
to taurine receptors, it has little effect on fect of acamprosate in combination with brain. Furthermore, the projection of 5-HT
glutamate or GABA receptors. In addition, disulfiram in the prevention of alcoholic re- fibers, in density as well as in distribution,
A
AC is neurotoxic, at least in neuronal cul- lapse [33]. Ningaraj et al. [22] reported that is reduced in the major trajectory bundle.
tures. The underlying mechanism of AC- DETC-MeSO has neuroprotective function These findings may provide an explanation
induced neuronal injury appears to be its against glutamate-induced excitotoxicity in for some of the syndromes associated with
action in increasing the intracellular calci- cultured neurons. Furthermore, the au- fetal alcohol syndrome.
um level, [Ca2+]. Both AC-induced neuro- thors showed that this neuroprotective
i
toxicity and elevation of [Ca2+] can be pre- function of DETC-MeSO is due to the re-
i
vented by taurine suggesting that AC may duction in glutamate-induced elevation of Ethanol and Signaling Pathways in
exert its effect through its antagonistic in- intracellular Ca2+. These observations point Astrocytes
teraction with taurine receptors. to an exciting possibility that DETC-MeSO
may be useful for treatment of alcoholism Chronic and excessive consumption of
as well as neurodegenerative diseases. alcohol in humans and animals causes cel-
lular damages in many body organs, in-
cluding neurons and glial cells in the cen-
Lipid Carrier Proteins tral nervous system [15, 18]. Wang and Sun
[31] reported that in astrocyte cultures,
Liver fatty acid binding protein is a lipid ethanol inhibits nitric oxide (NO) produc-
carrier protein that binds cholesterol, fat- tion as well as cytokine-induced release of
ty acids, fatty acyl-CoA, retinal-heme, he- secretory phospholipase A (sPLA). Fur-
2 2
matin, lysophospholipid, bilirubin, prosta- thermore, the inhibitory effect of ethanol
glandins and many other amphipathic on NO production corresponds well with
ligands. On the other hand, sterol carrier the decrease in iNOS protein and NOS en-
protein-2 is an intracellular protein that zyme activity but not with iNOS and sPLA
2
binds cholesterol and is involved in the in- mRNA nor binding of NF-(cid:1)B to DNA. These
tracellular trafficking of cholesterol [1]. results provide evidence for a post-tran-
Wood et al. [34] demonstrated that ethanol scriptional mode of ethanol action on the
alters the cholesterol transport mechanism, cytokine induction pathway for NO pro-
leading to the accumulation of cholesterol duction in astrocytes.
inside the cells. Since cholesterol accumu-
lation inside the cell may have great impact
on cell structure and function, the changes
in cholesterol homeostasis due to chronic
ethanol administration may lead to activa-
tion of Fas pathway and apoptosis [36].
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Biomedical Vignette
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Review
J Biomed Sci 2001;8:7–19
Role of Glutamatergic and GABAergic
Systems in Alcoholism
KathleenM.Davis Jang-YenWu
Departments of Molecular Biosciences and Medical Chemistry, University of Kansas, Lawrence, Kans., USA
Key Words ‘Alcoholism is a disorder of great destructive power’
L-GlutamateW GABAW AlcoholismW Glutamate receptorsW [213]. It is one of the world’s leading health problems,
GABA receptorsW Decarboxylase costing the United States alone an estimated $150 billion
annually [156]. Prior to the 1970s, it was generally
accepted that the central effects associated with alcohol
Abstract abuse were the result of fluidization of neuronal mem-
The pharmacological effects of ethanol are complex and branes [189]. It has also been suggested that ethanol
widespread without a well-defined target. Since gluta- inflicts its damage by producing free radicals [129], and
matergic and GABAergic innervation are both dense and by interfering with the supply of oxygen and glucose to the
diffuse and account for more than 80% of the neuronal brain [181]. More recently it was found that the major
circuitry in the human brain, alterations in glutamatergic effect of ethanol is not lipid bilayer disruption [54, 56,
and GABAergic function could affect the function of all 166] but modification of the proteins in the lipid mem-
neurotransmitter systems. Here, we review recent pro- branes [166]. It is now apparent that ethanol can alter
gress in glutamatergic and GABAergic systems with neurotransmission in the central nervous system (CNS)
a special focus on their roles in alcohol dependence by modifying neurotransmitter enzymes and receptors,
and alcohol withdrawal-induced seizures. In particular, and it is generally accepted that alcohol abuse and depen-
NMDA-receptors appear to play a central role in alcohol dence has a biochemical basis related to abnormal neuro-
dependence and alcohol-induced neurological disor- transmitter function [158, 184]. Many neurotransmitter
ders. Hence, NMDA receptor antagonists may have mul- systems have been studied including Á-aminobutyric acid
tiple functions in treating alcoholism and other addic- (GABA) [68]; glutamate (Glu) [210, 212]; dopamine [105,
tions and they may become important therapeutics for 161]; serotonin [33, 125, 194]; acetylcholine [7, 13, 137,
numerous disorders including epilepsy, Parkinson’s dis- 204]; and endogenous opioids [38, 74, 158]. Neurochemi-
ease, amyotrophic lateral sclerosis, Huntington’s chorea, cal systems which have received the most attention have
anxiety, neurotoxicity, ischemic stroke, and chronic pain. been glutamate, GABA, serotonin, dopamine, and the
One of the new family of NMDA receptor antagonists, opioid peptides.
such as DETC-MESO, which regulate the redox site of GABA and Glu are the major inhibitory and excitatory
NMDA receptors, may prove to be the drug of choice for neurotransmitters, respectively, and greater than 80% of
treating alcoholism as well as many neurological dis- the neurons in the brain utilize these neurotransmitters
eases. [54]. The neuroadaptive changes that occur in these sys-
Copyright © 2001 National Science Council, ROC and S. Karger AG, Basel
ABC © 2001 National Science Council, ROC Dr. Jang-Yen Wu
S. Karger AG, Basel Department of Molecular Biosciences
Fax [phone] Haworth Hall, University of Kansas
E-Mail [email protected] Accessible online at: Lawrence, KS 66045-2106 (USA)
www.karger.com www.karger.com/journals/jbs Tel. [phone], Fax [phone], E-Mail [email protected]
tems therefore have primary relevance to the neurochemi- The NMDA receptors are coupled to a voltage-sensi-
cal and behavioral effects associated with ethanol depen- tive ion channel and permeable to calcium and monova-
dence. The glutamatergic and the GABAergic systems lent cations (Na+; K+). The binding of glutamate and gly-
have been implicated as target sites of brain adaptation cine to the NMDA receptor results in the opening of the
after chronic exposure to ethanol [3, 103, 131, 140, 159, ion-permeable channels [82]. Compared to the glutamate
201, 205]. In this review, we focus on recent advances in response at other receptor subtypes, the response of the
Glu and GABA systems with special focus on their roles NMDA receptor is relatively slow and results in a large
in alcohol dependence and alcohol-withdrawal-induced amount of Ca2+ entering the cell through the activated
seizures. NMDA receptor [79, 93]. This influx of Ca2+ mediated by
NMDA receptors is important for synaptic plasticity and
memory [10, 11, 89, 219]. When the receptor is excessive-
Glutamatergic System ly stimulated, the influx of Ca2+ can lead to excitotoxicity
[41, 123]. Thus the function of NMDA receptors has been
Glutamate receptors in the mammalian CNS have implicated in both health and disease, such as the devel-
been divided into two major families, namely, ionotropic opment of epileptiform seizures [27, 46, 132], neurotoxic-
and metabotropic receptors [34, 142]. The ionotropic ity [41, 94, 123], alcohol craving [128, 210, 231], Parkin-
receptors exhibit the best evidence for the alcohol effects son’s disease [73, 120, 215], Alzheimer’s disease, psy-
on the CNS [158]. Ionotropic receptors can be categorized chiatric syndromes, alcoholism, ischemic stroke [73],
as responding to N-methyl-D-aspartate (NMDA), kainate amyotrophic lateral sclerosis, Huntington’s chorea, anxi-
(KA), or ·-amino-3-hydroxy-5-methyl-4-isoxazolepropi- ety [110, 136] and chronic pain [12, 51, 130, 186].
onic acid (AMPA). NMDA receptors are sensitive to low Native NMDA receptor-channel complexes are
concentrations of ethanol (5–50 mM) and respond quick- thought to be heteromeric pentamers. There are at least
ly to the action of ethanol [117, 121, 122]. The acute five genes (NR1, 2A, 2B, 2C, 2D) encoding various sub-
action of ethanol has been reported to be more potent at units that have been cloned. NR1 is thought to be the
the NMDA receptor than at other glutamate-activated essential subunit since it forms a functional channel by
ligand-gated channels, and does not appear to be second- itself [48, 115], and the NR2 subunits are believed to
ary to other electrophysiological consequences of ethanol modulate the properties of the channel [48]. In addition to
application [123]. Thus it seems that ethanol acts directly these subunits, other proteins, which bind different
on NMDA receptors. KA-receptor-mediated currents are NMDA ligands, have been reported and may function as
also significantly inhibited by ethanol concentrations of receptor-associated proteins or subunits [142]. The gluta-
50 mM or more [36]. Contrary to most studies, it has been mate binding protein has been cloned [101].
reported that concentrations as low as 20 mM significant- In situ hybridization and immunocytochemical studies
ly and reversibly depressed KA excitatory postsynaptic have shown that NMDA receptor subunits show a high
currents and suggested that ethanol may have an even degree of regional and individual variability with some
greater inhibitory effect on glutamatergic synaptic trans- regions showing a strong preference for a particular sub-
mission mediated by KA receptors than NMDA receptors unit [64, 104, 153]. The NR1 subunits are found in the
in rat hippocampal CA3 pyramidal neurons [221]. It has majority of central neurons. There are two NR1 splice
been shown that AMPA receptors are inhibited by phar- variants, NR1a and NR1b. The NR1a isoform is present
macological-relevant concentrations of ethanol, however in the majority of NMDA receptors and the NR1b variant
these receptors, unlike NMDA receptors, do not undergo is present at high levels in the cortex and dentate gyrus of
adaptation with chronic ethanol exposure (CEE) suffi- the hippocampus [139]. NR2 subunits are large glycopro-
cient to induce physical dependence [63]. It has been teins whose specific expression profiles in the brain are
hypothesized that NMDA receptors mediate the common developmentally and regionally regulated [108]. The
adaptive processes, which are involved in the develop- NR2A-D and 3A subunits show distinct expression pat-
ment and maintenance of drug and alcohol addiction. We terns in the mammalian brain, suggesting that NMDA
will focus on the NMDA glutamate receptor since this receptor composition is unique to each region of the brain
receptor is most likely a pivotal ethanol target, which [64, 104, 172]. Immunological studies show that NR2A is
leads to changes in many other neurotransmitter sys- located throughout adult rat brain, NR2B primarily in the
tems. forebrain, NR2C primarily in the cerebellum and NR2D
is found mainly in the thalamus, midbrain and brainstem.
8 J Biomed Sci 2001;8:7–19 Davis/Wu
In the rat brain, NR2A and NR2C increase during postna- NMDA or hyperbaric conditions [155]. Additionally di-
tal development, whereas NR2B and NR2D are abundant sulfiram has been shown to markedly enhance the anti-
at birth and declined with age [108]. Splice variants of the craving activity of acamprosate [14], suggesting that
NR2C subunit have also been reported [172]. DETC-MeSO may also have anti-craving activity. In this
The electrophysiological and pharmacological proper- issue, we have further demonstrated that DETC-MeSO
ties of the NMDA receptor complex are largely deter- specifically antagonizes NMDA receptors without signifi-
mined by the combination of the NR2 subunits. Peak cantly affecting either KA or AMPA receptors [160].
channel open probability is twofold to fivefold higher for These findings suggest that NMDA may play a role in
NMDA receptors composed of NR1A/NR2A than alcohol dependence and alcohol-withdrawal-induced sei-
NR1A/NR2B subunits. Thus a change in relative expres- zures.
sion levels of NR2A and NR2B can regulate the open/ The above notion is compatible with earlier observa-
close kinetics of the NMDA ion channels [29]. Therefore, tions that acute effects of ethanol disrupt glutamatergic
unique combinations of subunits can determine NMDA neurotransmission by inhibiting the response of the
receptor function [22, 87, 169, 188], and selected antago- NMDA receptor [76]. It has been reported that ethanol, at
nists and agonists would have varying effects on particu- concentrations corresponding to those achieved in the
lar NMDA receptors. Selectivity to particular subunits blood after moderate ethanol intake, reduces NMDA-
can be seen with infenprodil, an NMDA receptor NR2B- active ion currents, inhibits NMDA-evoked electrophysi-
specific antagonist [168]. Therefore, subunit composition ological responses, and decreases glutamate binding in the
may determine vulnerability to ethanol and may explain hippocampus and cortex, thus acting as an NMDA antag-
why there is a differential effect of ethanol on various onist [99]. Patch-clamp electrophysiological studies in
regions of the brain [102]. It has been reported that the Xenopus oocytes have also shown direct ethanol-protein
NR1/NR2A and NR1/NR2B combinations are preferen- interaction for the NMDA receptor [225].
tially sensitive to ethanol inhibition [224], although it has No specific site of action for ethanol on the NMDA
also been reported that ethanol sensitivity of the NMDA receptor has been found. Ethanol has been reported to
receptor in primary cultured cerebellar granule cells is not interact with an allosteric site that reduces agonist efficacy
related to subunit composition [168]. It is likely though by modulating the kinetics of channel gating [225]. It may
that CEE may alter the subunit composition of the interact with a discrete hydrophobic pocket within the
NMDA receptor, resulting in changes in binding of some receptor protein [166], thus modifying intermolecular
ligands and not others [82, 206]. In fact, chronic ethanol forces and bonds leading to a conformational change
treatment of rat cortical neuronal cultures leads to pro- [114, 121, 124, 166], thereby affecting the kinetics of
gressive increases in NR1, NR2A, NR2B and AMPA sub- channel opening and closing [39]. A possible interaction
units GluR2/3 and decreases in the NMDA receptor sub- of ethanol with the phencyclidine site has been reported
unit NR2D [26]. It also upregulates NMDA and AMPA [45], although other laboratories have reported that etha-
receptor subunits but not KA receptor subunit proteins nol does neither appear to interfere with the action of
[26]. The increases in subunit expression are probably an phencyclicine or Mg2+ [150], nor directly interact with the
adaptive response to the inhibitory effects of ethanol and agonist binding, either at the glutamate recognition site of
implicate both NMDA and AMPA receptors in the adap- the receptor, or at any other known multiple modulatory
tation of the CNS to chronic ethanol [26]. sites, such as the glycine or polyamine site [45, 170, 224].
In cerebellar granule cells though, ethanol has been re-
ported to reduce the potency of glycine to act as a co-
Ethanol and NMDA Receptors agonist at the NMDA receptors and this inhibitory effect
can be overcome by high concentrations of glycine [206].
Disulfiram, which has been used as a therapeutic agent In addition, antagonists which act at the glycine site of the
for treating alcoholic patients for the last 50 years, is NMDA receptor have been reported to control ethanol
believed to exert its effect by inhibiting acetaldehyde withdrawal seizures [196], suggesting an interaction with
dehydrogenase. However, recently we have shown that the glycine site. It has also been suggested that ethanol
the active metabolite of disulfiram, DETC-MeSO, not sensitivity of the receptor may be affected by intracellular
only inhibits acetaldehyde dehydrogenase but also partial- C-terminal receptor domains that regulate the calcium-
ly blocks glutamate receptors [155]. Furthermore, DETC- dependent inactivation of the receptor [6]. Ethanol has
MeSO is quite effective in preventing seizures induced by also been reported to decrease extracellular glutamate in
Glutamate, GABA and Alcoholism J Biomed Sci 2001;8:7–19 9