bluuebunny/crossref_metadata_2025_split huggingface dataset:
Grape Polyphenols Inhibit Chronic Ethanol‐Induced COX‐2 mRNA Expression in Rat Brain
Authors: Simonyi Agnes , Woods Danielle , Sun Albert Y. , Sun Grace Y. 
Published: April 2006

Background: Chronic ethanol has been shown to increase oxidative stress leading to neurodegenerative changes in the brain. Oxidative stress may up‐regulate extracellular signal regulated kinases (ERK1/2) and, subsequently, the arachidonic acid cascade mediated by phospholipase A2 (PLA2) and cyclooxygenase (COX‐2). Our earlier study showed that grape polyphenols (GP) could ameliorate oxidative damage to synaptic membrane proteins due to chronic ethanol treatment. This study was aimed at examining the effects of GP on mRNA expression of ERK1/2, cytosolic PLA2 (cPLA2), and COX‐2 in different brain regions after chronic ethanol treatment.Methods: Male Sprague‐Dawley rats were fed a Lieber‐DeCarli liquid diet with ethanol or isocaloric amount of maltose, with or without GP for 2 months. In situ hybridization was carried out using coronal brain sections through the hippocampus.Results: Quantitative in situ hybridization showed no changes in ERK1 and cPLA2 mRNA levels in cortical areas and hippocampus after ethanol and/or GP administration. However, a decrease in ERK2 and an increase in COX‐2 mRNA level was found in the hippocampus of ethanol‐treated animals. GP completely inhibited the increase in COX‐2 due to ethanol treatment.Conclusion: Increase in COX‐2 expression may be an underlying mechanism for the increase in oxidative stress induced by chronic ethanol administration. Dietary supplementation of GP may have a beneficial role in inhibiting certain alcohol effects.
Ethanol‐Enhanced Cytotoxicity of Alkylating Agents
Authors: Couch David B. , Baker Rodney C. 
Published: April 2006

Background: Although ethanol itself is not genotoxic, chronic alcohol consumption increases the risk of neoplastic disease. The mechanism by which ethanol exerts a cocarcinogenic effect is not well established, and the aim of this study was to determine whether exposure to ethanol increased the cytotoxicity of known carcinogens.Methods: To assess cell survival, the ability of Chinese hamster A10 cells, which express alcohol dehydrogenase, to form colonies was determined after exposure to ethanol and other substances, including both genotoxicants and non–DNA‐reactive cytotoxic agents.Results: 1‐Methyl‐3‐nitro‐1‐nitrosoguanidine (MNNG) is an alkylating agent that forms covalent bonds with DNA. The cytotoxicity of MNNG at concentrations of 0.17 to 0.68 μM was markedly enhanced when cells were also treated with 50 mM ethanol. When combined with 0.34 μM MNNG, concentrations of ethanol as low as 2 mM exacerbated the toxicity of this alkylating agent. When these experiments were repeated in the presence of 4‐methylpyrazole, an inhibitor of alcohol dehydrogenase, pretreatment with ethanol did not affect the toxicity of MNNG. When ethanol treatment was combined with exposure to other carcinogens, as well as agents that do not directly damage DNA, the cytotoxicity of the DNA‐reactive agents 4‐nitroquinoline‐N‐oxide, mitomycin C, and 6‐chloro‐9‐(3‐[2‐chloroethyl]aminopropylamino)‐2‐methoxyacridine was modestly enhanced, and that of a second alkylating agent, ethyl methanesulfonate, was markedly increased.Conclusions: The results are consistent with impairment of DNA repair processes, particularly base excision repair, by acetaldehyde, as a mechanism by which ethanol increases the genotoxicity of certain genotoxic agents.
Chronic Ethanol Treatment and Withdrawal Alter ACPD‐Evoked Calcium Signals in Developing Purkinje Neurons
Authors: Netzeband Jeffrey G. , Schneeloch Jaimes R. , Trotter Carol , Caguioa‐Aquino Jodilyn N. , Gruol Donna L. 
Published: April 2006

Background: Alcohol exposure during human fetal development can result in fetal alcohol syndrome, a condition characterized by central nervous system dysfunction. Detailed studies in animal models of fetal alcohol syndrome show that the cerebellar region is particularly sensitive to alcohol exposure during early development; however, the cellular mechanisms underlying the alcohol sensitivity of the immature cerebellum are poorly understood.Methods: Primary neuronal cultures of cerebellar cells were prepared from embryonic day 20 rat pups. Cultures were exposed to ethanol (33 mM; 150 mg/100 ml) during the main period of morphological development of the Purkinje neurons, from 6 to 17 days in vitro. After the ethanol treatment, the response of Purkinje neurons to the selective metabotropic glutamate receptor (mGluR) agonist (1S,3R)‐1‐aminocyclopentane‐1,3‐dicarboxylic acid (ACPD; 300 μM) was examined in parallel fura‐2 Ca2+ imaging and current‐clamp experiments. In an additional set of experiments, ethanol‐treated cultures were allowed to withdraw from ethanol overnight before recordings were performed.Results: In Ca2+ imaging studies, the mean peak amplitude of ACPD‐evoked Ca2+ signals was depressed in the dendritic region of chronic ethanol–treated Purkinje neurons compared with control neurons (p < 0.05, unpaired t test), whereas there was no apparent difference in the somatic region. In contrast, peak ACPD‐evoked Ca2+ signals were enhanced in both the somatic and dendritic regions of withdrawn Purkinje neurons compared with control neurons. Parallel current‐clamp studies showed no consistent effect of chronic ethanol treatment or ethanol withdrawal on the membrane response to ACPD.Conclusions: These results show that prolonged ethanol exposure and early withdrawal lead to alterations in mGluR‐evoked Ca2+ signaling in cerebellar Purkinje neurons. Metabotropic GluRs in the Purkinje neuron play important roles in cerebellar development and function, suggesting that alterations of mGluR signaling pathways by ethanol may play a key role in the actions of ethanol on the developing cerebellum.
Effects of Combined Systemic Alcohol and Central Nicotine Administration into Ventral Tegmental Area on Dopamine Release in the Nucleus Accumbens
Authors: Tizabi Yousef , Copeland Robert L. , Louis Vely A. , Taylor Robert E. 
Published: April 2006

Background: Alcoholism is associated with a higher incidence of smoking. The mesolimbic dopaminergic pathway is believed to play an important role in the reinforcing effects of both ethanol and nicotine. This study was undertaken to determine whether simultaneous administration of systemic ethanol and microinjection of nicotine into the ventral tegmental area (VTA) would result in exaggerated release of dopamine (DA) in the shell region of nucleus accumbens.Methods: Microdialysis was applied in awake, freely moving adult male Wistar rats, and DA concentration in the dialysate was measured by HPLC‐electrochemical detectors.Results: Systemic administration of ethanol or microinjection of nicotine into VTA resulted in a dose‐dependent increase in DA release (extracellular DA concentration). Simultaneous administration of lower doses of nicotine and ethanol resulted in an additive effect on the released DA. This additive effect was not observed with higher doses of nicotine and ethanol. Administration of the nicotinic antagonist mecamylamine into VTA completely blocked ethanol‐induced DA release.Conclusions: These data support the hypothesis that the reinforcing effects of ethanol are at least partially mediated through the nicotinic receptors in the VTA. Furthermore, administration of selective nicotinic antagonists may be of therapeutic potential in reducing the rewarding effects of ethanol. The data also suggest that the combined effects of ethanol and nicotine on the “reward pathway” may be a contributing factor to the high incidence of smoking in alcoholics.
Locomotor Activity Induced by Noncompetitive NMDA Receptor Antagonists Versus Dopamine Transporter Inhibitors: Opposite Strain Differences in Inbred Long‐Sleep and Short‐Sleep Mice
Authors: Hanania Taleen , Zahniser Nancy R. 
Published: April 2006

Background: The actions of ethanol in the brain involve multiple neuroreceptor systems, including glutamatergic N‐methyl‐D‐aspartate receptor (NMDAR) channels. In a novel environment, both ethanol and the noncompetitive NMDAR antagonist MK‐801 stimulate locomotor activity to a lesser extent in inbred long‐sleep (ILS) mice compared with inbred short‐sleep (ISS) mice. The behaviorally activating effects of noncompetitive NMDAR antagonists are thought to involve increased monoamine neurotransmission. Thus, in this study, we sought to determine whether: (1) habituation to the behavioral environment alters the differential locomotor‐stimulant effects of noncompetitive NMDAR antagonists in ILS and ISS mice and (2) the differential behavioral sensitivity of ILS and ISS mice to noncompetitive NMDAR antagonists is mediated through direct inhibition of the dopamine transporter (DAT).Methods: Open field locomotor activity was measured following acute systemic injection of saline or drug. [3H]DA uptake parameters were determined in striatal synaptosomes prepared from drug‐naïve mice.Results: Habituation to the testing environment abolished the strain differences in saline‐induced locomotor activity. However, ethanol‐ as well as MK‐801‐treated ILS mice still exhibited reduced locomotor activity compared with ISS mice, suggesting that a drug‐environment interaction is not the primary explanation for the strain differences. The noncompetitive NMDAR antagonists phencyclidine and ketamine also induced significantly lower locomotor activity in ILS than in ISS mice. In contrast, the DAT inhibitors cocaine and GBR 12909 and the DA releaser amphetamine induced greater locomotor activity in ILS than in ISS mice, a strain difference opposite that of the noncompetitive NMDAR antagonists. Furthermore, the differential behavioral effect found with DAT inhibitors was not mediated by differences in the affinity nor number of striatal DATs between ILS and ISS mice.Conclusions: Our results support the conclusion that the differential locomotor‐stimulant effects of ethanol and noncompetitive NMDAR antagonists in ILS and ISS mice are not mediated through direct inhibition of DAT.
Prevention of Alcohol‐Related Deaths in Middle‐Aged Heavy Drinkers
Authors: Kristenson Hans , Österling Agneta , Nilsson Jan‐Åke , Lindgärde Folke 
Published: April 2006

Background: Alcohol as a cause of death in middle‐aged patients is well‐known from clinical studies. A similarly important correlation in the general population of urban middle‐aged men is highly underestimated. Health screening investigations have shown that mortality related to alcohol is five times more common in nonparticipants than in participants. From the mid‐70s, the Malmoe Screening and Intervention Study (MSIS) commenced screening investigations including a large number of residents of Malmoe. One goal was to find intervention programs for individuals in an early development of problem drinking, thereby preventing development of serious complications of endstage alcoholism. Herein, we report on the mortality of heavy drinkers (drinking more than 40 g alcohol/day) who were randomized to an intervention or control procedure and whose median survival was 13 years postentry into the MSIS.Methods: Health‐screened men, aged 45–49 years at the initial screening examination and displaying serum gamma‐glutamyltransferase (GT) in the top decentile of the GT distribution, were included. A total of 978 out of 11,257 participants met this criteria. A randomized intervention and control study was performed for four years and consisted of men (n= 667) who were born between 1927–1937 and who had two consecutive high GT values within 3 weeks along with heavy alcohol consumption. Half the individuals were informed of the test results and invited for further assessment by a senior physician (n= 365). The principles for brief intervention (DiClemente et al.,1991; Miller and Sanchez, 1993; National Institute of Alcohol Abuse and Alcoholism, 1999) were applied. The other half of the men (n= 302) were left with the information that they had a high GT value and were followed up with laboratory checkups every 2nd year. Mortality was followed up until 1991 and information on deaths was obtained from hospital and police records, necropsy reports, and death certificates.Results: Long‐term follow‐up of mortality for 10–16 years (median, 13 years) showed that 124 of the 978 men had died (12.7%). Autopsy was performed in 96.5% of the cases. In 59 men (48%), death was alcohol‐related. In the intervention group (n= 365), 38 (10.4%) men were dead and in the control group (n= 302), 42 (13.9%) men had died. There was a statistically significant difference (p= 0.026), with advantage for treatment. Less alcohol‐related deaths and deaths occurring later during follow‐up were found in the intervention group compared with the control group. The difference between the groups in total mortality, coronary heart disease, and cancer death was not statistically significant.Conclusions: These findings support previous results from the MSIS study indicating that long‐term intervention in urban males with alcohol‐induced GT increases may be beneficial in terms of survival.
Changes in Serum Apolipoprotein and Lipoprotein Profile After Alcohol Withdrawal: Effect of Apolipoprotein E Polymorphism
Authors: Gueguen Sonia , Herbeth Bernard , Pirollet Pascal , Paille François , Siest Gérard , Visvikis Sophie 
Published: April 2006

Background: Apolipoprotein (Apo) E genotype and alcohol consumption or withdrawal strongly affect lipoprotein (Lp) metabolism and, as with any genetic and environmental factors, they might interact. The aim of this study was to investigate this gene/environment interaction by analyzing the effect of the apoE genotype on the alcohol withdrawal–induced alterations in the serum Apo and Lp profile.Methods: ApoE genotypes and concentrations of serum cholesterol, triglyceride, and Lps containing apoA‐I, A‐II, B, E, and C‐III were determined in 84 male alcohol abusers before and after 3 weeks of abstinence.Results: After withdrawal, concentrations of serum apoA‐I, LpA‐I, LpA‐I/A‐II, apoC‐III, LpC‐III‐non‐B, apoE, and LpE‐non‐B significantly decreased, whereas those of triglycerides and apoB increased; levels of cholesterol, LpC‐III:B, and LpB:E were not affected. ANOVA shows that apoE polymorphism effects were quite similar before and after alcohol withdrawal on all serum Apos and Lps (the interaction term between withdrawal and apoE genotype was not significant). The only interaction term that was borderline significant (p≤ 0.10) concerned the apoB concentration. Before withdrawal, no association between apoB level and apoE polymorphism was observed, whereas after abstinence, a borderline significant (p≤ 0.10) gradient of concentration across the three groups of subjects (ε2 carriers < ε3/ε3 < ε4 carriers) was noticed.Conclusions: Alcohol abstinence causes major changes in the antiatherogenic Apos and Lps and may increase those known to be atherogenic. Heavy alcohol consumption seems to alter the effect of apoE polymorphism on apoB levels, and further investigations are needed to clarify the mechanisms involved in this phenomenon: a defect in sialylation of apoE, formation of acetaldehyde adducts on apoB, or both.
Fracture Healing and Bone Mass in Rats Fed on Liquid Diet Containing Ethanol
Authors: Elmali Nurzat , Ertem Kadir , Ozen Süleyman , Inan Muharrem , Baysal Tamer , Güner Güntekin , Bora Arslan 
Published: April 2006

Background: Studies in animal models for alcohol abuse have suggested that ethanol inhibits bone growth, decreases bone formation, and increases fracture risk.Methods: Experimental tibia fracture healing in rats fed a liquid diet containing 7.2% ethanol for 8 weeks was investigated with histological and osteodensitometric studies with respect to the control group. After 4 weeks of vitamin A– and sucrose‐enriched milk containing 7.2% ethanol feeding, we created closed tibia fractures, which were then fixed with intramedullary nails, in 10 rats. After a follow‐up time of 4 weeks, the rats were killed for examination. The same procedure was performed in another 10 rats, which were fed on the same diet (isocaloric modified liquid diet) but without ethanol and used as the control group. A histological scoring system was developed for fracture healing.Results: Histological evaluation of fracture region revealed an average fracture healing score of 1.9 in the ethanol‐fed group versus 2.6 in the control group (p= 0.014). In the test group, dual‐energy x‐ray absorptiometry measurements in the fracture region showed a mean bone mineral density of 0.11 ± 0.03 g/cm2, whereas it was 0.130 ± 0.051 g/cm2 in the control group (p= 0.000). The mean bone mineral content in the fracture region was 0.103 ± 0.08 g/cm3 in the test group versus 0.128 ± 0.06 g/cm3 in the control group (p= 0.000). A significant correlation was found among histological scores, bone mineral density (r= 0.64, p= 0.04), and bone mineral content (r= 0.63, p= 0.04).Conclusions: This study showed that rats fed on a diet mixed with ethanol have a histologically delayed fracture healing associated with decreased bone density and mineral content. Besides the negative effects of ethanol on bone metabolism, it also interferes with the fracture‐healing process.
Effects of In Vitro Ethanol on Tumor Necrosis Factor‐α Production by Blood Obtained From Simian Immunodeficiency Virus–Infected Rhesus Macaques
Authors: Stoltz David A. , Nelson Steve , Kolls Jay K. , Zhang Ping , Bohm Rudolf P. , Murphey‐Corb Michael , Bagby Gregory J. 
Published: April 2006

Background: Tumor necrosis factor‐α (TNF‐α), a product of monocytes and macrophages, functions as an important proinflammatory cytokine in the host's response to invading pathogens.Methods: Because both alcohol abuse and human immunodeficiency virus infection affect TNF‐α production and are known to frequently coexist, this study examined the effects of simian immunodeficiency virus (SIV) infection and in vitro alcohol exposure on the lipopolysaccharide (LPS)‐induced TNF‐α response in blood obtained from SIV‐negative and ‐positive animals at the asymptomatic and terminal stages of infection.Results: Spontaneous TNF‐α production was undetectable or low in all groups examined. LPS‐induced TNF‐α production was increased in blood obtained at the asymptomatic (746 ± 226 pg/ml) and terminal (1945 ± 1013 pg/ml) stages, compared with that from SIV‐negative animals (210 ± 28 pg/ml), whereas TNF‐α messenger RNA content did not differ in LPS‐stimulated blood obtained from SIV‐negative, asymptomatic SIV‐positive, or terminal SIV‐positive animals. Ethanol treatment suppressed TNF‐α protein production in all groups, whereas TNF‐α messenger RNA levels remained unchanged in blood obtained from animals not infected with SIV.Conclusions: Blood cellular elements remain responsive to LPS stimulation with respect to TNF production even into the acquired immunodeficiency syndrome stage of SIV disease. However, intoxicating doses of alcohol suppress this response, and this may contribute to the immunocompromised state of the host.
Chronic Daily Ethanol and Withdrawal: 3. Forebrain Pro‐Opiomelanocortin Gene Expression and Implications for Dependence, Relapse, and Deprivation Effect
Authors: Rasmussen Dennis D. , Boldt Brian M. , Wilkinson Charles W. , Mitton Dennis R. 
Published: April 2006

Background: Although forebrain pro‐opiomelanocortin (POMC)–producing neurons seem to mediate or modulate many responses to ethanol consumption, changes in activity of this opiomelanocortinergic system in response to chronic ethanol consumption, withdrawal, and subsequent abstinence remain unresolved.Methods: We investigated the effects of chronic daily ethanol consumption, withdrawal, and subsequent abstinence on adult male Sprague‐Dawley rat forebrain opiomelanocortinergic activity as reflected by changes in hypothalamic POMC messenger RNA (mRNA) content by using a well characterized liquid diet model that we have previously demonstrated to accurately simulate not only daily oral ethanol consumption quantity and pattern, but also both neuroendocrine and behavioral changes characteristic of actively drinking and subsequently abstinent alcoholics.Results: After 7 weeks of daily ethanol consumption at night and withdrawal during the day, evening mediobasal hypothalamus POMC mRNA concentrations were suppressed versus both ad libitum–fed and pair‐fed controls. Morning POMC mRNA concentrations were also suppressed versus ad libitum–fed controls and tended to be decreased versus pair‐fed controls. Three weeks after gradual removal of ethanol from the diet, mediobasal hypothalamus POMC mRNA concentrations were increased relative to ad libitum–fed and pair‐fed controls. Plasma concentrations of corticosterone, testosterone, and leptin were also altered by the daily ethanol/withdrawal treatment and by subsequent abstinence.Conclusions: Because each of these hormones has been demonstrated to modify forebrain POMC gene expression under some conditions, the overall changes in forebrain opiomelanocortinergic regulation in response to chronic daily ethanol/withdrawal and subsequent abstinence probably reflect, at least in part, regulation by multiple endocrine mechanisms, together with responses to stress, development of tolerance during chronic daily ethanol consumption, and rebound of function after termination of this consumption. Overall, the demonstrated changes in forebrain POMC gene expression are consistent with significant roles for forebrain opiomelanocortinergic regulation in mediating alcohol dependence, propensity to relapse, and the alcohol deprivation effect.
Cortical Gray Matter Loss in Treatment‐Naïve Alcohol Dependent Individuals
Authors: Fein G. , Di Sclafani V. , Cardenas V. A. , Goldmann H. , Tolou‐Shams M. , Meyerhoff D. J. 
Published: April 2006

Background: Most studies of the impact of alcohol dependence on the brain have examined individuals in treatment. Such samples represent a small proportion of alcoholics in the general population. Such samples may embody a bias (Berkson's fallacy) if the association between variables (for example, alcoholism and cortical gray matter loss) differs between the population of alcoholics in treatment and alcoholics in the general population. Our objective was to determine if treatment‐naïve alcoholics show structural brain changes versus controls and to compare our findings with reports evaluating alcoholic samples drawn from treatment populations.Methods: Structural MRI was used to assess whole brain and regional volumes of cortical gray matter and white matter in 24 young to middle‐aged treatment‐naïve alcohol‐dependent males versus 17 controls.Results: Cortical gray matter volumes in alcohol‐dependent individuals were negatively associated with age and lifetime duration of alcohol use (which were highly confounded). These subjects showed reduced whole brain (p < 0.05), prefrontal (p < 0.01), and parietal (p < 0.05) cortical gray matter compared with controls. White matter and temporal cortex, tissues that usually show volume reductions in samples drawn from treatment, did not differ between treatment‐naïve alcoholics and controls (all p > 0.40).Conclusions: Our findings are consistent with the hypothesis that structural brain changes in treatment‐naïve alcoholics are less severe than those reported in clinical samples of alcoholics, perhaps due to less concomitant psychopathology and a reduced severity of alcoholism in treatment‐naïve alcoholics. However, caution must be taken when comparing our findings with results from clinical samples, as we did not directly compare treatment‐naïve alcoholics with treated alcoholics and our treatment‐naïve sample tended to be younger than the (clinical) samples reported in the literature. Nevertheless, we suggest that most of the reports of the central nervous system consequences of alcoholism may not accurately describe the majority of alcoholic‐dependent individuals.