Center for the Neurobehavioral Study of Alcohol, Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
* Author to whom correspondence should be addressed at: Department of Pharmacology, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA. Tel.: +1 717 531 8285; Fax: +1 717 531 0419; E-mail: kvrana{at}psu.edu
(Received 4 August 2004; first review notified 17 August 2004; in revised form 2 September 2004; accepted 24 October 2004)
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ABSTRACT |
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INTRODUCTION |
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With the wealth of knowledge available, bioinformatic interpretation is pivotal to a well-executed study. There are several software programs that can facilitate the completion of this task. A program maintained by the National Institutes of Health, DAVID (Database for Annotation, Visualization and Integrated Discovery; http://apps1.niaid.nih.gov/david/), offers several features such as ontological, pathway and functional classifications (Dennis et al., 2003). A program that deals specifically with pathways, GenMapp (Gene Microarray Pathway Profilier; http://www.genmapp.org/), has been created by the Gladstone Institutes of the University of California at San Francisco. Both programs can identify genes within a pathway or with common function that could illuminate new research directions or further clarify current results.
However, before delving into this literature, it is important that we recognize that at several points there are seemingly opposite findings or counter-intuitive results. This is particularly important in the small, but growing literature on DNA microarrays, where there are relatively few situations wherein the studies illuminate common genetic pathways. This problem arises from the fact that there are both direct pharmacological effects of ethanol, as well as long-term compensatory changes that occur in response to those pharmacological effects. These need not agree in an obvious way and so the route of administration, animal model and time course of a specific study will have a dramatic impact on the results.
Animals models and mode of administration
There are numerous animal models that have been employed to study the effects of alcohol. A unique research tool in the ethanol field, for instance, is the creation of genetically selected lines of varying ethanol phenotypes. Several such lines have been addressed within the following review, including the Alko Accepting and Alko Non-Accepting lines (AA and ANA, respectively) created in Finland (Eriksson, 1968) and the alcohol Preferring and Non-Preferring (P/NP) and High Alcohol Drinking and Low Alcohol Drinking (HAD/LAD) rats from the NIAAA-funded centre in Indianapolis (Lumeng et al., 1977
; McBride and Li, 1998
). A popular mouse model involves the comparison of C57Black/6 and DBA/2 mice, inbred strains that show differential ethanol preference and the recombinant inbred lines (BXD) created from an original F1 cross of the C57 and DBA animals (McClearn and Rodgers, 1959
; Gora-Maslak et al., 1991
). Similarly, two mouse lines have been employed to great benefit in the field. Withdrawal-seizure prone and resistant mice (WSP/WSR) differ in the seizure producing consequences of chronic ethanol administration (Crabbe and Phillips, 1993
). In addition, the long sleep and short sleep (LS/SS) mice differ in their responses to the sedative effects of acute ethanol (McClearn and Kikihana, 1981
).
A major area of conflict, when it comes to comparing disparate findings from individual reports, is the mode of ethanol administration. There are several distinct methods of administration that have differing effects on gene expression and it is important to realize that they have different pharmacological profiles and so might produce disparate results for a given genetic system. Such varying systems include intraperitoneal injection (IP), intragastric gavage (IG), oral self-administration (induced in a variety of distinct behavioural methodologies), inhalation chamber administration (with and without pharmacological manipulation of metabolism) and enforced administration as part of a liquid diet. The various approaches have differing levels of administration, varying levels of attendant administration stress, differing pharmacodynamic characteristics and unique behavioural contingencies. To illustrate this point, the differences in IP, IG and liquid diet have been studied and shown to cause increases in gene expression of NGFI-B using IP and IG but not liquid diet (Ogilvie et al., 1997a). Although the IP and IG doses were matched for dose, there was a significant difference in NGFI-B gene expression levels. Moreover, a liquid diet generating blood alcohol levels of 0.060.14% w/v failed to cause a change in NGFI-B levels as it had with IP and IG administration (Ogilvie et al., 1997a
). It is therefore important to keep these issues in mind when comparing the results from different laboratories.
In general, this review of differential CNS gene expression in alcohol abuse and alcoholism is organized by neuropharmacological systems. Previously, studies have focused on those systems thought to be directly impacted by alcoholGABA, glutamate, opiates and dopamine. Therefore, there is a wealth of information evolving for these systems. Growing evidence also implicates signal transduction/transcription factor systems. Finally, we examine the wealth of information that is beginning to emerge from the use of multiplex DNA hybridization arrays (DNA macroarrays, microarrays and GeneChips). As an added bibliographic tool, all of the genes discussed in the review are provided in a public website with associated PubMed reference links and NCBI-supported genetic LocusLink (www.arraydata.org/AlcoholReview).
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GABA SYSTEM |
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Buck et al. (1991) found changes in GABAA receptor mRNA expression in WSP and WSR mice prior to and after ethanol administered in a liquid diet. In ethanol-naïve comparisons, the WSP mice demonstrate a decrease in
3 expression versus WSR strains. In contrast, after ethanol treatment, both lines show upregulation of the
3 subunit compared with ethanol-naïve animals. These investigators conclude that the
3 subunit may play a small role compared with the increased gene expression of the
1 subunit in contributing to the genetic difference between the two strains.
An in situ study of the 4 subunit reported changes in mRNA expression in several different brain regions, such as an increase in the thalamus, layers 2 and 3 of the cortex and the CA1, CA3 regions and dentate gyrus of hippocampus following 5 g/kg/day of IG ethanol (Mahmoudi et al., 1997
). Another
4 subunit study exposed rats to 5% ethanol in a liquid diet for 1 week, then 7.5% ethanol for 1 week followed by 1 day of withdrawal (Davis-Cox et al., 1996
). The animals demonstrated increases in
4 gene expression in the cortex as assessed by reverse transcriptasepolymerase chain reaction (RTPCR). Protein levels were increased in the cortex and hippocampus of rats after a BEC of 250 mg/dl over a range of 1440 days and withdrawal periods of 024 h (Devaud et al., 1997
; Matthews et al., 1998
). In contrast to these findings, a post-mortem human study found no change in
;4 gene expression using RTPCR (Mitsuyama et al., 1998
). All studies, with the exception of this human post-mortem investigation, reported an increase in expression for the
4 subunit gene. This type of consistency in results from different laboratories is relatively uncommon in the gene expression field and indicates a potentially important role of the
4 subunit. At the same time, however, the Mitsuyama et al. (1998)
study needs confirmation. If replicated, these human results force a re-examination of the relationships with rodent models.
The 5 and
6 subunits were both analysed as components of larger studies and showed differential expression in various regions of the brain. Eravci et al. (2000)
show downregulation of the
5 subunit in controlled consumers and behaviourally dependent rats (even following a month of enforced abstinence). The
6 subunit was decreased in whole brain of ethanol-naïve WSP compared with WSR mice, but WSR mice showed a decrease after ethanol treatment (Buck et al., 1991
). Finally, one study demonstrated a decrease in
5 subunit expression in the cortex after IG administration of 20% ethanol thrice daily for 6 days after both 1 and 24 h withdrawal, but an increase in
6 in the cerebellum was found on following the same protocol (Mhatre and Ticku, 1992
).
The ß subunits have had less attention but show gene expression responses to ethanol. The ß2 subunit mRNA expression was decreased in ethanol-naïve C57Black mice compared with DBA2 and treated C57Black mice compared with naïve C57Black mice in whole brains at low ethanol concentrations, whereas higher concentrations of ethanol showed an increase. The DBA2 mice showed an increase at intermediate and higher doses of ethanol compared with ethanol-naïve DBA2 mice (Reilly and Buck, 2000). One study noted decreases in the ß1 subunit in a behaviourally dependent cohort and decreases in the ß2 subunit in controlled consumers as well as behaviourally dependent animals (Eravci et al., 2000
), whereas others demonstrated increases in ß2 and ß3 subunit protein expression within the cortex after 14 days of a 67.5% liquid diet (Devaud et al., 1997
, 1998
). Another study, involving the ß3 subunit in human post-mortem samples, showed an increase in gene expression within the frontal cortex (Mitsuyama et al., 1998
).
The subunits have received more attention since the discovery that the
2 short and long variants may have differential expression (Devaud et al., 1995
). Interestingly,
2s and
1 mRNA expression were found increased in cortex after 2 weeks of an ethanol-containing diet (Devaud et al., 1995
). Later, Devaud et al. (1997)
analysed
1 protein expression in the cortex, discovering an upregulation 0 and 8 h after removal from an ethanol liquid diet. Several studies have shown a decrease in gene expression in both the
2l and
2s subunits in the parieto-occipital cortex (POC) and cortex (Eravci et al., 2000
; Mhatre and Ticku, 1992
, respectively). Expression of
2l mRNA has also been reported as decreased in the dendritic and pyramidal layers of the CA1 region of the hippocampus (Petrie et al., 2001
).
The inhibitory GABA receptor is noteworthy for its complex modulation by several molecules, including the diazepam binding inhibitor (DBI). DBI acts as an inverse agonist that binds to the benzodiazepine site on GABA receptors (Ohkuma et al., 2001). One study focused on DBI in cultured cerebral cortical neurons of mice (Katsura et al., 1995a
). This study had two parts: the first experiment held the concentration of ethanol at 50 mM for 15 days, the second used concentrations of ethanol from 1 to 100 mM for 3 days. The end result was an increase in expression at all points for the first experiment and all but the 1 mM concentration for the second. Coincidently, this laboratory published whole animal studies in mice with an average BEC of 250 mg/dl over 8 days and showed that DBI mRNA was increased after 0 and 8 h of withdrawal (Katsura et al., 1995b
). A subsequent experiment by this group involved a project having a well-balanced mix of mRNA and protein level measures, conducted in mice subjected to inhalation chamber administration for 8 days, producing a BEC of
250 mg/dl (Katsura et al., 1998
). They found increases in gene expression after no withdrawal, 8 h, 1, 2, 3, 4, 5 and 7 days following the last treatment. Protein levels displayed a similar pattern beginning at the 8 h pointthis latter finding would be consistent with a functional lag between changes in mRNA and protein.
In summary, of the several subunits studied to date, the 4 and
2l subunits appear to be the most consistently regulated, indicating that they are of fundamental importance. These two subunits alone are the subject of eight individual studies covering 11 separate regions of the brain. The
4 subunit has been loosely associated with tolerance (Mahmoudi et al., 1997
), such that increasing this subunit may represent an attempt to normalize the genomic effects of alcohol. The
2l subunit has been associated with protein kinase C (PKC) and phosphorylation, indicating that ethanol may alter phosphorylation states and second messenger activity, possibly leading to increased receptor function. On the other hand, the GABAergic system is also very plastic, showing differential expression responses in numerous subunits, thereby making these subunits prime targets for development of pharmacotherapies. In addition, the inhibitory nature of GABA is in contrast to the excitatory nature of the glutamate system (discussed below) and provides an ideal environment for investigating a cause and effect relationship between these two systems.
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GLUTAMATE SYSTEM |
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The NMDA-sensitive receptors are, by far, the most frequently associated with ethanol effects. In the previously noted study with AMPA and kainate receptors in the POC, Eravci et al. (2000) reported decreases in the mRNA levels for NMDA1 and 2a subunits in the controlled consumers. Additionally, the 2a subunit was also decreased in the behaviourally dependent model. These animals had free access to ethanol or water for 9 months prior to 3 months abstinence, a 1 month testing period and 1 further month of abstinence. This depression agrees with Feuerstein and collaborators, who have shown a decrease in the 2b subunit in the CA region of the hippocampus as well as caudate putamen (Darstein et al., 2000
). Two groups have shown increases in 2b subunit expression: one demonstrated an increase in 2b mRNA in cultured mouse cortical neurons after 5 days of exposure to 50 mM ethanol (Hu et al., 1996
); the second showed that an inhalation chamber paradigm, producing a BEC of 200400 mg/dl, also increased 2b mRNA within the cortex (Hardy et al., 1999
). Moving to the 2d subunit, Naassila and Daoust (2002)
reported increases in gene and protein expression in the hippocampus in pups of ethanol-drinking dams. However, in a study of a selected line, ethanol-naïve Alcohol Tolerant (AT) rats showed no difference from Alcohol Non Tolerant (ANT) rats in 2a, 2b, 2c and 2d NMDA subunit gene expression (Toropainen et al., 1997
). This change was also noted in protein expression.
The NMDA1 subunit has also been the focus of significant attention. Characterization of ethanol-naïve AA versus ANA rats demonstrated an increase in subunit variant 1-4 within the hippocampus of ANA rats (Winkler et al., 1999). This study also reported an increase in protein expression in the hippocampus from the alternative splice variant C-terminus subunit 1-3/1-4 after ethanol treatment in AA rats. A fetal alcohol syndrome model demonstrated increases in subunit 10xx in the cerebellum 1, 7 and 14 days post-parturition and 7 and 14 days in the hippocampus for both 10xx and 11xx splice variants (Naassila and Daoust, 2002
). Hardy et al. (1999)
reported an increased expression of the 10xx over the 11xx within the cortex at 0, 6, 12, 24 and 48 h after inhalation chamber administration of ethanol.
Receptors are not the only molecules that affect glutamatergic functionenzymes and transporters can also have an impact on the activity of this neurotransmitter system. Within the POC, mitochondrial and cytosolic aspartate aminotransferase gene expression was decreased in both controlled consumers and behaviourally dependent models (Eravci et al., 1999). This gene encodes a glutamate converting enzyme, changing glutamate into
-ketoglutarate and vice versa, although the thermodynamic balance is higher for degrading glutamate (McKenna et al., 2000
). Two other glutamate degrading enzymes include glutaminase and glutamine synthetase (Svenneby and Torgner, 1987
). Glutaminase was decreased in the behaviourally dependent rats in the POC, along with glutamine synthetase in both controlled consumers and behaviourally dependent rats. A hybridization array experiment also revealed an increased expression of the glutamate/aspartate transporter in the cingulate cortex (Rimondini et al., 2002
). Eravci and colleagues tested other glutamate-related enzymes as well, and showed a decrease in glutamate dehydrogenase in the POC in both ethanol self-administering models as well as a decrease in a GABA producing enzyme, glutamic acid decarboxylase 65 (GAD65), in the behaviourally dependent model. On the other hand, GAD65 expression is increased in the controlled consumers and behaviourally dependent rats within the limbic forebrain (Eravci et al., 1999
). Two other unique NMDA receptor-like molecules, glutamate- and glycine-binding subunits, originally discovered in synaptic membrane preparations, were demonstrated to be increased in cortical cultures after 3 days of treatment with 100 mM ethanol (Bao et al., 2001
).
Similar to the GABAergic system, the glutamate system demonstrates more robust receptor changes rather than ligand or metabolic effects. Examples include increased gene expression in nearly all NMDA receptor subunits, such as NR1-3, NR1-4, NR2A, NR2B and NR2D but with few changes in glutamate degrading enzymes, such as decreases in glutaminase, glutamine synthase and GAD65. This may reflect the ubiquitous nature of glutamate, requiring that regulatory responses reside within the receptors. Moreover, the common theme of receptor regulation within GABAergic and glutamatergic systems, along with the unique relationship of GABA activity robustly opposing glutamate function in the presence of ethanol, make these two systems particularly interesting.
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OPIATE SYSTEM |
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The µ and receptors were both evaluated in several regions of the brain in a single paper by Winkler et al. (1998b)
beginning with comparisons in ethanol-naïve C57Black versus DBA2 mice (Winkler et al., 1998b
). These two mouse lines exhibit markedly different sensitivities and self-administration behaviours for ethanol. These investigators reported no changes in gene expression level between the two strains. However, using the C57Black, they showed a decrease in the µ receptor in the hypothalamus after ethanol treatment. The mice self-administered 10% ethanol for 28 days consuming average values of ethanol of 8.8 and 3 g/kg/day for the C57Black and DBA2 mice, respectively. RTPCR was performed after withdrawal periods of 0, 3 and 21 days to evaluate mRNA levels for the opiate receptors. The DBA2 mice also showed a decrease in the hypothalamus after no withdrawal, but not after 3 or 21 days post ethanol. Winkler addressed the
receptor in a separate study and showed an increase receptor mRNA expression in the DBA2 mice in the regions of the hypothalamus and striatum (Winkler et al., 1998a
). The
and µ receptors were also increased in the ANA compared with AA and Wistar rats as assessed by receptor binding studies, whereas RTPCR demonstrated increases in pro-enkephalin, pro-dynorphin, and POMC (Marinelli et al., 2000
).
In another series of experiments, Jamensky and Gianoulakis (1999) reported an increase in naïve C57Black versus DBA2 opiate system mRNA expression levels using in situ hybridization. The increases were noted for POMC in the arcuate hypothalamic nucleus and pro-enkephalin in the caudate putamen and nucleus accumbens. POMC was also increased after an IP administration of ethanol (Krishnan-Sarin et al., 1998
; Kinoshita et al., 2000
) and administration through a liquid diet (Angelogianni et al., 1993
; Chen et al., 2004
). Contrary to the Krishnan-Sarin studies, several groups have demonstrated decreases in POMC following an inhalation chamber paradigm, liquid diet and intragastric administration (Scanlon et al., 1992
; Aird et al., 1997
; Zhou et al., 2000
). These studies demonstrate that POMC regulation is dependent on the type of administration and the region of the brain, but is likely to play an important physiological role in response to ethanol.
In a series of experiments led by de Gortari et al. (2000), rats were intragastrically administered once with 2.5 g/kg of ethanol and allowed to withdraw for 1, 4 or 24 h after the single injection. Levels of pro-enkephalin were found decreased in hippocampal regions at the early time point and were reduced at longer withdrawal periods in the frontal cortex and nucleus accumbens. However, enkephalin mRNA was increased at later time points in hippocampal regions, mammillary bodies of the hypothalamus and nucleus accumbens. Another pro-enkephalin study showed no change in expression using in situ hybridization in the rostral striatum after chronic ethanol consumption (Tajuddin and Druse, 1998
). Pro-dynorphin, on the other hand, was increased in whole brains of withdrawal-seizure prone mice 6 h after ethanol inhalation (Beadles-Bohling et al., 2000
). The mice had an average BEC of 150 mg/dl for the 3 day treatment period. Plotkin et al. (1997)
conducted a whole-brain study that examined met-enkephalin and PPE in mice treated with a 5% ethanol liquid diet for 10 days. Although the PPE mRNA levels did not change, the met-enkephalin protein levels measured by radioimmunoassay, increased immediately after treatment, at 10 h and at 8 days post treatment. Concussion and ethanol consumption was the model used to query PPE mRNA levels after a 2.4 g/kg IP dose of ethanol (Sall et al., 1996
). These investigators set out to test the hypothesis that alcohol consumption alters PPE levels, leading to increased neuronal injury and death. Prior to concussion, PPE levels in the frontal cortex and olfactory bulb were found to be decreased 24 h after the neuronal injury. PPE was decreased in the concussion model with ethanol injection 10 min prior to injury in piriform/amygdala cortex and also increased in the same model in the olfactory bulb. This change within the olfactory bulb is opposite to the regulation seen in the ethanol-only treated rats, indicating the influence of trauma in that region. A comparison of naïve ethanol-preferring Fawn-Hooded and non-preferring KyotoWistar rats revealed an increase in PPD in the hippocampus and a decrease in PPE in the nucleus accumbens and striatum, as seen using in situ hybridization (Cowen et al., 1998
).
An additional PPE study analysed P and NP rats that are ethanol-naïve or treated with 2.5 g/kg of ethanol (IG) and allowed to withdraw for 1, 4 or 8 h (Li et al., 1998). PPE mRNA was found to be increased in ethanol-naive P over NP rats in the anterior hypothalamus, as well as the posterior and medial striatum, 4 h after saline treatment. After 8 h, the increase was seen in the medial shell of the nucleus accumbens. Four hours after ethanol treatment, PPE was increased again in the posterior striatum and the amygdala in the P versus the NP lines. Within-line comparisons were also performed. The P rats showed increased PPE levels 1 h after ethanol exposure in three regions of the nucleus accumbens: the whole accumbens, the lateral core and the medial shell. Eight hours after exposure, the naïve P rats had higher PPE levels in the medial shell and whole accumbens. In a similar manner, 8 h after treatment, the naïve NP rats had higher gene expression than exposed NP rats in the lateral core, medial shell and whole accumbens.
Unlike the inhibitory (GABA) and excitatory (glutamate) neurotransmitter systems discussed above, the opiates tend to have more emphasis on precursor molecules rather than receptor changes. This is reflected by an increase observed in 62% of the ligands tested in several regions of the brain. Presumably, the change in ligand amount would directly reflect action at receptors, leading to increased or decreased opioid function.
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ALTERNATIVE NEUROTRANSMITTER, HORMONE AND TRANSCRIPTION FACTOR SYSTEMS |
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The serotonin 1a and 1b receptors were investigated at the level of mRNA and protein (Nevo et al., 1995). The 1a receptor mRNA demonstrated no change 18 h after withdrawal following 2 weeks of a 10% ethanol liquid diet and an additional 5 g/kg of IG dose of ethanol. The 1a receptor protein, however, increased expression (based on autoradiography studies) in the dorsal raphe and decreased expression in the dentate gyrus, entorhinal cortex and layer IV of the frontal cortex. The same investigators went on to show an increase in serotonin 1b receptor mRNA expression within the striatum and protein expression within the globus pallidus.
The rate-limiting step of dopamine biosynthesis is tyrosine hydroxylase (TH). In fact, as the key regulator for all catecholamine synthesis, this enzyme (and its gene) has been shown to be subject to nearly every form of regulation (Kumer and Vrana, 1996). Szot et al. (1999)
have demonstrated a decrease in gene expression for TH in the ventral tegmental area of offspring of dams treated on day 21 of pregnancy through birth with 12 g/kg of ethanol in a liquid diet. This is intriguing considering that theories of dopamine-related reward revolve around the change in dopamine access or production in the synapse as seen in cocaine studies (Drago et al., 1998
). The dopamine D3 receptor exhibits decreased expression in the limbic forebrain in controlled consumers and behaviourally dependent rats and in the hippocampus of controlled consumers (Eravci et al., 1997
). Dopamine transporter gene expression in the ventral tegmental area and substantia nigra pars compacta is also decreased in the offspring of rats treated with 12 g/kg of ethanol from day 21 through the end of pregnancy (Szot et al., 1999
).
As summarized above, the monoaminergic transmitter systems demonstrate mixed responses, although both dopamine and serotonin systems show a trend for downregulation of gene expression. The few studies on these systems also make it difficult to draw conclusions about an overall effect of ethanol. However, there is consistent downregulation of the dopamine D3 autoreceptor and dopamine transporter, indicating a possible method for increasing synaptic dopamine.
In addition to these alternative neurotransmitter systems, a variety of hormone and transcription factors have been implicated in alcohol abuse and alcoholism. In the interests of space, these genes and gene products are summarized in Tables 1 and 2.
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ARRAY MANUSCRIPTS |
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Thibault et al. (2000) have also provided evidence, with cAMP and ethanol demonstrating a similar regulation on a subset of neuroblastoma genes responsive to ethanol. Selected targets from this work were confirmed using other methods, such as RTPCR, which is proving to be the normal practice in the array field. A single myelin-associated gene, myelin basic protein, appeared in other array work. This is not surprising considering the use of cultured human neuroblastoma cells in this manuscript versus the human post-mortem samples used by Lewohl et al. (2000)
and Mayfield et al. (2002)
.
Saito et al. (2002) moved to the rat model and identified another 165 differentially-expressed genes. This laboratory identified two general physiological systems that are affected by ethanoloxidative stress and membrane trafficking. This study was performed on hippocampal regions and in an entirely different species, so the lack of matching expression patterns is not necessarily a point of concern.
Another array format manuscript, performed by Rimondini et al. (2002), reported changes in rats after three weeks of exposure to ethanol. They focused on the cingulate cortex and amygdala, noting changes of gene expression in three main areasneurotransmission, synaptic plasticity and signal transduction. The difference in ethanol treatment and administration may be responsible for the lack of replicated genes between this and the study of Saito et al. (2002)
discussed previously.
The message regarding array work is two-fold: (i) several models can independently demonstrate a large number of changes in gene expression; and (ii) different models are important for ethanol research but may identify different results. The different models will each give details on specific aspects of the disease, and large-scale gene studies reflect changes in those aspects. Therefore, inconsistent data, although troubling, increases the base of knowledge that others may build upon.
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CONCLUSIONS |
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ACKNOWLEDGEMENTS |
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