bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Prenatal Exposure to Alcohol, Smoking, and Illicit Drugs on Postpartum Somatic Growth
Authors: Jacobson Joseph L. , Jacobson Sandra W. , Sokol Robert J.
Published: April 2006

The association of fetal growth retardation with prenatal exposure to alcohol, smoking, opiates, and cocaine is well documented, but relatively little is known about the effects of these exposures on postpartum growth. This study assessed physical growth from birth through 6.5 and 13 months in 412 black, inner‐city infants recruited on the basis of their mothers' use of alcohol and/or cocaine during pregnancy. Prenatal alcohol exposure was associated with a slower rate of growth during the first 6.5 postpartum months. This postnatal growth retardation was associated with maternal drinking during a critical period–the latter part of gestation–and was not related to drinking at the time of conception or to postnatal exposure to alcohol from breast‐feeding. By contrast, smoking and cocaine use during pregnancy were associated with faster postnatal weight gain. Although maternal smoking was correlated with shorter stature at 6.5 and 13 months, this effect was attributable to maternal drinking during pregnancy, suggesting that the association of maternal smoking with shorter childhood stature reported elsewhere may be due to prenatal alcohol exposure, which was not controlled in prior studies.
Eye Movement Effects of Diazepam in Sons of Alcoholic Fathers and Male Control Subjects
Authors: Cowley Deborah S. , Roy‐Byme Peter P. , Radant Allen , Hommer Daniel W. , Greenblatt David J. , Vitaliano Peter P. , Godon Carol
Published: April 2006

Both animal and human studies suggest that the GABA‐benzodiaze‐pine receptor complex may be involved in the acute effects of ethanol, as well as the development of tolerance and dependence with chronic ethanol use. The current study was performed to assess sensitivity to benzodiazepines, and thus the functional sensitivity of the GABA‐benzodiazepine receptor system, in subjects at high risk for alcoholism. Sons of alcoholic fathers (SOAs; n = 27) were com‐pared with male controls without a family history of alcoholism (n = 23) in response to diazepam versus placebo. SOAs and controls received four logarithmically increasing doses of intravenous diaze‐pam or placebo in randomized order on 2 days at least 1 week apart. Effects of diazepam were assessed using two eye movement tasks, peak saccadic eye movement velocity, and average smooth pursuit eye movement gain, which provide reliable, quantitative measures of benzodiazepine effects. In addition, memory, self‐rated sedation, and pleasurable drug effects were measured. In comparison with control subjects, SOAs displayed significantly less diazepam effects on peak saccade velocity, average smooth pursuit gain, memory, and self‐rated sedation, but significantly greater pleasurable drug effects. Differences in response to diazepam between SOAs and male controls may reflect altered functional sensitivity of the central GABA‐benzodiazepine receptor system or a more general difference between groups in the effects of CNS active or sedating drugs.
Ethanol Acutely Impairs the Renal Conservation of 5‐Methyltetrahydrofolate in the Isolated Perfused Rat Kidney
Authors: Muldoon R. T. , McMartin K. E.
Published: April 2006

The ethanol‐induced increase in urinary folate excretion has been shown to decrease plasma folate levels and may contribute to the development of folate deficiency associated with alcoholism. The mechanism for this effect remains to be elucidated. The present studies were designed to examine the direct effect of ethanol on the renal handling of 5‐methyltetrahydrofolate (5‐CH3‐H4PteGlu), the physiological folate. Rats were given four consecutive hourly doses of ethanol (1 g/kg) or isocaloric doses of glucose solution orally. This treatment generated an average plasma ethanol level of 305 mg/dl. Kidneys from male Sprague‐Dawley rats were removed 5 hr after initial treatment and perfused in vitro to eliminate any extrarenal effects that could confound interpretation of results. Ethanol was not added to the perfusate. These treatments had no effect on 5‐CH3‐H4PteGlu conservation by the isolated perfused rat kidney in comparison to experiments in which the animal received no treatment. Ethanol was then added directly to the perfusate to generate average concentrations of 293 mg/dl. The in vitro addition of ethanol significantly decreased the percentage reabsorption and increased the fractional excretion of 5‐CH3H4PteGlu in comparison to controls (kidneys perfused with or without an isocaloric dose of glucose). This effect did not become significant until the renal tissue was exposed to these levels of ethanol for 1 hr. These results indicate that ethanol directly impairs the renal conservation of 5‐CH3‐H4PteGlu.
Dietary Vitamin E Modulation of Cytokine Production by Splenocytes and Thymocytes from Alcohol‐Fed Mice
Authors: Wang Yuejian , Huang Dennis S. , Watson Ronald R.
Published: April 2006

As vitamin E enhances immune responses, it may reduce dietary ethanol (EtOH)‐induced immune suppression, thereby favorably afffecting host disease resistance. The effects of dietary vitamin E at higher level in alcohol‐fed female C57BL/6 mice was determined via in vitro cytokine production by splenocytes and thymocytes, and some other immune functions. A 15‐fold increase of vitamin E (160IU/liter) in a liquid diet (National Council Research), with or without EtOH (4.5%, v/v), was fed to mice for 10 weeks. Vitamin E supplementation restored production of interleukin‐2, ‐5, ‐6, ‐10, and inter‐feron‐γ by concanavalin A (Con A)‐stimulated splenocytes and in terleukin‐6 and tumor necrosis factor‐a by lipopolysaccharide‐stimulated splenocytes, which were suppressed by dietary EtOH. However, it had no effect on interleukin‐4 secretion, which was also reduced by splenocytes from EtOH‐fed mice. Vitamin E supplementation also restored EtOH‐suppressed, mitogen‐induced splenocyte proliferation, but not thymocyte proliferation, although it slightly increased production of immunoglobulin A and G by lipopolysaccha‐ride‐stimulated splenocytes, which were suppressed by dietary EtOH. Dietary vitamin E, furthermore, significantly increased interleu‐kin‐2 and ‐6 secretion by Con A‐stimulated thymocytes, which were suppressed by dietary EtOH, although it had no effect on interleukin‐ 4 and interferon‐γ production by Con A‐stimulated thymocytes from EtOH‐fed mice. These data suggest that dietary vitamin E supple‐mentation can modulate dysregulation of cytokines initiated by dietary EtOH and restore immune dysfunctions induced by EtOH ingestion.
Consumption of Sweet, Salty, Sour, and Bitter Solutions by Selectively Bred Alcohol‐Preferring and Alcohol‐Nonpreferring Lines of Rats
Authors: Stewart Robert B. , Russell Rebecca N. , Lumeng Lawrence , Li Ting‐Kai , Murphy James M.
Published: April 2006

To determine whether selective breeding for high or low oral ethanol consumption is associated with different preferences for nonpharmacological solutions with various flavors, the oral intake of a range of concentrations of sucrose (0.5–64.0 g/100 ml), NaCl(0.025–3.2 g/100 ml), citric acid (0.008–2.048 g/liter), and sucrose octaacetate (0.002–0.512 g/liter) was studied in alcohol‐preferring (P) and alcohol‐nonpreferring (NP) rats. Separate groups of 7–8 rats from each line were tested for consumption of each of the four flavors. The flavored solutions were presented continuously with water and food always available, and the concentrations were doubled every 48 hr. Although rats from both lines showed a strong preference for the sucrose solutions, P rats consumed greater amounts than NP rats [F(7,98) = 5.57, p < 0.001], Rats of the P line drank less of the NaCl solutions than NP rats [F(7,98) = 3.88, p < 0.0011], but the effect was not as robust as the line differences seen with sucrose. The P and NP rats did not differ in citric acid or sucrose octaacetate intake at any of the concentrations tested. Selective breeding for high oral ethanol preference appears to be positively associated with consumption of sweet solutions and negatively associated with intake of salty solutions.
Temperature Dependence of Ethanol Depression in Mice: Dose Response
Authors: Finn Deborah A. , Syapin Peter J. , Bejanian Marina , Jones Brenda L. , Alkana Ronald L.
Published: April 2006

Manipulation of body temperature during intoxication significantly alters brain sensitivity to ethanol. The current study tested the generality of this effect within the hypnotic dose range. Drug naive, male C57BL/6J mice were injected with 3.2, 3.6, or 4.0 g/kg ethanol (20% w/v) and were exposed to 1 of 7 designated temperatures from 13° to 34°C to manipulate body temperature during intoxication. Rectal temperature at return of righting reflex (RORR) was significantly, positively correlated with loss of righting reflex (LORR) duration and significantly, negatively correlated with blood ethanol concentration (BEC) at RORR at all three doses. These results indicate that increasing body temperature during intoxication increased ethanol sensitivity in C57 mice at all three doses tested and demonstrate the generality of temperature dependence across hypnotic doses in these animals. Interestingly, the LORR duration was dose‐dependent at each ambient temperature, but the degree of body temperature change and the BEC at RORR were not dose‐dependent. Overall, these results emphasize the importance of body temperature as a variable in ethanol research.
Microheterogeneity of Serum Glycoproteins in Alcoholics: Is Desialo‐transferrin the Marker of Chronic Alcohol Drinking or Alcoholic Liver Injury?
Authors: Tsutsumi Mikihiro , Wang Jian‐Song , Takada Akira
Published: April 2006

The appearance of desialo‐transferrin (De‐TF) in serum has been reported to be a biochemical marker of chronic alcoholism. However, conclusive evidence of whether De‐TF is a marker for chronic alcohol drinking or for alcoholic liver disease (ALD) has not yet been obtained. Glycoproteins can be divided into two groups, a transferrin (TF) group and an al‐acid glycoprotein (Al‐AG) group, based on the characteristics of microheterogeneity (M‐HTG) of each protein. In the present study, the appearance of M‐HTG in serum TF and A1‐AG in alcohol drinkers was compared. In 96 patients with ALD, M‐HTG of TF was found in 66 patients (68.6%), and M‐HTG of A1‐AG was found in 61 patients (63.5%). In 20 patients with alcoholic pancreatitis, the detection rate of M‐HTG of A1‐AG was significantly higher than that of TF. In six patients with pancreatitis but not liver disease, M‐HTG of TF was not detected. In 14 alcoholics without liver or pancreas disease, M‐HTG of TF was not detected, whereas M‐HTG of A1‐AG was detected in 6 cases‐a significant difference. The amount of alcohol consumed was not different in patients with and without liver disease. In non‐ALD, M‐HTG of both proteins was detected only in patients with decompensated liver cirrhosis. The detection rate of M‐HTG in TF was significantly higher than in A1 ‐ AG. These results suggest that M‐HTG of serum TF is a marker of ALD and that of serum A1‐AG is a marker of chronic alcohol drinking.
Alcohol, Marijuana, and Tobacco: Effects of Prenatal Exposure on Offspring Growth and Morphology at Age Six
Authors: Day Nancy L. , Richardson Gale A. , Geva Diklah , Robles Nadine
Published: April 2006

Little is known about the long‐term effects of prenatal exposure to alcohol. There are even fewer reports on the longitudinal effects of exposure to either marijuana or tobacco during pregnancy. This study is on the 6‐year follow‐up of 668 children enrolled in the Maternal Health Practices and Child Development Project. Mothers were interviewed at the 4th and 7th months of pregnancy, and mothers and children were evaluated at delivery, 8, and 18 months, and 3 and 6 years postpartum. At 6 years of age, children who were exposed to alcohol prenatally were significantly smaller in weight, height, head circumference, and palpebral fissure width. These effects on size were mediated by the effect of prenatal alcohol exposure on the offspring at 8 months. Prenatal alcohol exposure was also significantly associated with maternal reports of the child's appetite at 6 years. There were no effects of prenatal marijuana or tobacco exposure on growth when the children were age 6. There were also no significant relationships between prenatal exposure to alcohol, marijuana, or tobacco and the rate of morphologic anomalies, including the features of the fetal alcohol syndrome.
Effects of Helicobacter pylori Infection and Gastritis on Gastric Alcohol Dehydrogenase Activity
Authors: Thuluvath Paul , Wojno Kirk J. , Yardley John H. , Mezey Esteban
Published: April 2006

Sex and age differences in gastric alcohol dehydrogenase activity in relation to abnormalities of gastric histology and Helicobacter pylori infection were determined in 63 patients (32 men and 31 women) undergoing upper endoscopy for gastrointestinal symptoms. No sex difference was found in gastric alcohol dehydrogenase activity. Males older than 50 years had lower enzyme activity than younger males. Patients with H. pylori and/or moderate to severe chronic and acute inflammation and epithelial mucin depletion had lower alcohol dehydrogenase activity in the antrum, but not in the fundus. H. pylori was found more frequently in the older male patients. Antral alcohol dehydrogenase was most decreased in older patients of both sexes with H. pylori infection. In conclusion, H. pylori infection and/or chronic active gastritis are important causes of low gastric alcohol dehydrogenase activity.
Individual, Family, and Peer Affiliation Factors Predisposing to Early‐Age Onset of Alcohol and Drug Use
Authors: Blackson Timothy C. , Tarter Ralph E.
Published: April 2006

In this study, a multifactorial model of liability to early‐age alcohol and drug use was elucidated on a sample of sons of substanceabusing fathers (n= 59) and sons of normal fathers (n= 71) at time 1 when the boys were 10–12 years of age. Three hierarchical regression analyses were computed to test models to identify salient risk characteristics associated with sons' perception of family dysfunction, unconventional activities among peers, and affiliation with peers engaged in delinquent behaviors. The respective models explained 28% of the variance on sons' Dysfunctional Family Index scores, 21% of the variance on sons' Conventional Activities of Friends Scale scores, and 53% of the variance was accounted for on sons' Peer Delinquency Scale scores. In subsequent logistic regression analyses, a multifactorial model comprised of individual, family, and peer risk characteristics obtained at time 1 correctly predicted 83.7% of sons who had used alcohol and/or drugs by time 2 when they were 12–14 years old. The findings also suggest that temperament phenotype influences family interaction patterns that in turn influence the psychosocial development of the child.
Neuroendocrine Evidence for Reduced Serotonergic Neurotransmission During Heavy Drinking
Authors: Balldin Jan , Berggren Ulf , Engel Jörgen , Eriksson Matts
Published: April 2006

A fenfluramine (60‐mg oral dose) challenge test was performed in 19 male heavy drinkers (mean daily consumption 88 g of pure alcohol). Twelve healthy males served as controls. The prolactin and temperature responses to fenfluramine were significantly reduced in the group of heavy drinkers. The results suggest impaired central serotonergic neurotransmission in alcoholism, possibly involving subsensitivity in various serotonin receptor subtypes.
Remission of Late‐Life Drinking Problems: A 4‐ Year Follow‐up
Authors: Schutte Kathleen K. , Brennan Penny L. , Moos Rudolf H.
Published: April 2006

This 4‐year follow‐up study compared stably remitted late‐life problem drinkers to nonremitted problem drinkers and nonproblem drinkers. At time 1, to‐be‐remitted drinkers reported less alcohol consumption and fewer drinking problems, more depression and less self‐confidence, less spousal support and approval of drinking from friends, and more help‐seeking than did to‐be‐nonremitted drinkers. Remitted drinkers showed improvement in functioning and life context at the 4‐year follow‐up, but compared with nonproblem drinkers some deficits persisted. Stable remission and abstinence among late‐onset drinkers were closely tied to receiving less spousal support and approval from friends for drinking at time 1, whereas helpseeking was a strong predictor of stable remission and abstinence among early‐onset problem drinkers. For both late‐ and early‐onset drinkers, abstinence was predicted by initially having more drinking problems, depression, and health stressors.
Anxiety and Drinking Behavior: Moderating Effects of Tension‐Reduction Alcohol Outcome Expectancies
Authors: Kushner Matt G. , Sher Kenneth J. , Wood Mark D. , Wood Phillip K.
Published: April 2006

We evaluated whether alcohol outcome expectancies moderate the association between measures of anxiety and alcohol use. Student subjects completed questionnaires related to their level of anxiety, recent alcohol‐use patterns, and outcome expectancies for alcohol to be tension reducing. Interviews were used to determine the presence or absence of alcohol dependence in subjects and in their first‐ and second‐degree relatives. Consistent with predictions, male subjects with high tension‐reduction alcohol outcome expectancies showed a stronger positive correlation between measures of anxiety and drinking behavior than did male subjects with low tensionreduction outcome expectancies. However, this effect was not found for female subjects. We note past studies showing similar gender effects, and relate the overall study findings to the tension‐reduction hypothesis of stress‐induced drinking.
Double‐Blind Study of Alprazolam, Diazepam, Clonidine, and Placebo in the Alcohol Withdrawal Syndrome: Preliminary Findings
Authors: Adinoff Bryon
Published: April 2006

Both a reduction in the inhibitory effects of GABA (disinhibition) and activation of the sympathetic nervous system are manifested during the alcohol withdrawal syndrome. This study was designed to explore the relative efficacy of medications that differentially affects these two biological systems: the benzodiazepines, which attenuate GABAergic disinhibition, and the α2‐adrenergic receptor agonists, which decrease sympathetic activation. The benzodiazepine diazepam (n= 6), the α2‐receptor agonist clonidine (n= 7), the benzodiazepine alprazolam (that is also purported to have α2‐receptor agonist properties) (n= 6), and placebo (n= 6) were evaluated in their effectiveness in decreasing signs and symptoms of alcohol withdrawal. Drug‐free, alcohol‐dependent patients were administered 1 of the 4 medications in a double‐blind design until symptoms of withdrawal, as measured by the Clinical Instrument Withdrawal Assessment for Alcohol‐Revised, were successfully treated. Alprazolam was significantly more efficacious than both clonidine and placebo in decreasing withdrawal symptoms. Diazepam was more effective than clonidine and placebo on some measures of withdrawal. Clonidine decreased systolic blood pressure significantly more than the other two active drugs and placebo, but was no more effective than placebo in decreasing other symptoms of withdrawal. Alprazolam did not significantly decrease blood pressure compared with diazepam or placebo. Despite the small sample size, these preliminary findings suggest that the efficacy of alprazolam in the treatment of alcohol withdrawal is related to its effect at the benzodiazepine receptor and not its α2‐receptor agonist properties.
Clinical Efficacy of the 5‐HT3 Antagonist Ondansetron in Alcohol Abuse and Dependence
Authors: Sellers Edward M. , Toneatto Tony , Romach Myroslava K. , Somer Gail R. , Sobell Linda C. , Sobell Mark B.
Published: April 2006

Medications that act on the serotonergic system have been found to be of benefit in the treatment of alcohol‐dependent individuals. In a randomized, placebo‐controlled study, the efficacy of 6 weeks of ondansetron, a 5‐HT3 antagonist (0.25 mg bid or 2.0 mg bid), in the treatment of 71 nonseverely alcohol‐dependent males was tested. The results showed reduction of drinking differences were steadily increasing toward the end of the treatment period approached significance at week 7 in the 0.25 mg group (p= 0.06). Twice as many patients in this group showed >2 standard deviations decrease in drinking compared with the other groups. When patients drinking >10 drinks/drinking day at baseline (n= 11) were excluded from the analysis, significant group differences were found at both treatment and follow‐up, with the lower ondansetron dose producing the greatest reduction from baseline (i.e., 2.8 standard drinks; –35% compared with baseline and –21% compared with placebo; p < 0.02–0.001). Within this group, there was an almost 4‐fold greater number of patients showing a clinically meaningful decrease in drinking. Lower baseline drinking and higher level of education were significant and strong predictors of drinking reduction during treatment. Ondansetron was very well tolerated; hence, further long‐term studies with 5‐HT3 antagonists alone or in combination with other treatment components may offer promise for treatment of alcoholism.
Carbohydrate‐Deficient Transferrin as an Alcohol Marker among Female Heavy Drinkers: A Population‐Based Study
Authors: Löf Kari , Seppä Kaija , Itälä Liisa , Koivula Timo , Turpeinen Ursula , Sillanaukee Pekka
Published: April 2006

Carbohydrate‐deficient transferrin (CDT) has previously been reported to be an excellent marker of male alcoholics. Less is known of its efficiency among women and especially of early‐phase alcohol abuse in nonselected populations. The present population‐based study examined the diagnostic value of CDT among consecutive women, including 13 teetotallers, 135 social drinkers (mean alcohol consumption 45 ± 34 g/week), and 57 nonalcoholic heavy drinkers (197 ± 97 g/week). Sixty‐two women with a well‐documented history of chronic alcoholism (942 ± 191 g/week) were also studied, as well as 36 pregnant women used as a reference group. Two weeks of abstinence among 11 alcoholics was followed. The CDT (containing part of isotransferrin with pl = 5.7, 5.8, and 5.9) was separated by anion exchange chromatography and assayed by radioimmunoassay. In the whole material, CDT correlated significantly with alcohol consumption (r= 0.43, p < 0.001) but not with conventional markers (γ‐glutamyltransferase, AST, ALT, and mean corpuscular volume). The CDT values of alcoholics (34 ± 20 units/liter) were significantly (p < 0.001) higher than those of teetotallers (19 ± 6 units/liter), social drinkers (20 ± 6 units/liter), or pregnant women (16 ± 13 units/ liter). Heavy drinkers also had higher values (25 ± 13 units/liter), but the difference did not reach statistic significance. The specificity of CDT was on the level of conventional markers when the cut‐off value was increased from 26 to 29 units/liter. At a specificity of 95%, CDT found 19% of the heavy drinkers and 52% of the alcoholics; the best traditional marker, AST, with a specificity of 97%, found 7% and 56%, respectively. CDT was useful for follow‐up of alcohol withdrawal when its initial value was elevated. In general, CDT (as well as conventional laboratory markers) does not seem to be sensitive enough in the detection of alcohol abuse in the female population. This is especially clear among nonalcoholic female heavy drinkers. CDT gives, however, additional information about alcohol abuse, and it may be recommended for parallel use with conventional markers in clinical use.
Zinc Deficiency and Corticosteroids in the Pathogenesis of Alcoholic Brain Dysfunction—A Review
Authors: Menzano E. , Carlen P. L.
Published: April 2006

Chronic alcoholism is associated with hypercortisolemia and low serum zinc (Zn). Hypercortisolernia could be responsible for alcoholic cerebral atrophy and is also associated with enhanced NMDA neurotoxicity. It is hypothesized that low brain Zn, noted in chronic alcoholics, enhances NMDA excitotoxicity and ethanol withdrawal seizure susceptibility. Also, Zn deficiency can produce neuronal damage through increased free radical formation. Clinically, Zn replacement therapy may be a rational approach to the treatment of alcohol withdrawal seizures and alcohol‐related brain dysfunction.
Changes in Cytochromes P‐450, 2E1, 2B1, and 4A, and Phospholipases A and C in the Intragastric Feeding Rat Model for Alcoholic Liver Disease: Relationship to Dietary Fats and Pathologic Liver Injury
Authors: Nanji Amin A. , Zhao Shuping , Lamb Robert G. , Dannenberg Andrew J. , Sadrzadeh S. M. Hossein , Waxman David J.
Published: April 2006

The influence of dietary fat and alcohol on hepatic microsomal levels of cytochromes P‐450 2E1, 2B, and 4A; phospholipases A and C; and UDP‐glucuronosyltransferase was studied in the intragastric feeding rat model for alcoholic liver injury. Eight groups of animals were evaluated. Control and ethanol fed rats received either saturated fat or corn oil and were killed after 2 weeks and 1 month of feeding. All animals were pair‐fed by continuous infusion of liquid diet through permanently implanted gastric cannulas. Alcoholic liver injury developed only in the corn oil‐ethanol‐fed groups and was manifest by 1 month. Livers were subjected to the following analyses: pathologic evaluation of liver injury; levels of cytochromes P‐450 2E1, 2B, and 4A protein and mRNA; aniline hydroxylase activity; and phospholipase A and C and UDP‐glucuronosyltransferase activities. Ethanol‐induced increases in cytochromes P‐450 2E1 and 2B protein determined by Western blotting were greatest in the corn oil‐ethanol‐fed group, which developed pathologic changes in the liver. Cytochromes P‐450 2E1 and 2B1 mRNA levels were unaffected, suggesting that posttranscriptional mechanisms are responsible for the increase in the corresponding P‐450 proteins. In contrast, cytochrome P‐450 4A levels were higher in the saturated fat‐ethanol groups compared with the corn oil‐ethanol groups. Phospholipase A and phospholipase C levels were higher in the corn oil‐ethanol groups compared with pair‐fed dextrose controls and the saturated fat‐ethanol groups. UDP‐glucuronosyltransferase levels declined with time in the ethanol‐fed groups. These observations are discussed in the context of a model whereby the induction of phospholipases A and C and cytochromes P‐450 2E1 and 2B1 in corn oil‐ethanol‐fed rats provide arachidonic acid substrate and induce lipid peroxidation, respectively. These changes may account for the more severe pathologic changes that develop in corn oil‐ethanol‐fed animals compared with animals fed saturated fat and ethanol.
Effects of Ethanol, MK‐801, and Chlordiazepoxide on Locomotor Activity in Different Rat Lines: Dissociation of Locomotor Stimulation from Ethanol Preference
Authors: Criswell Hugh E. , Overstreet David H. , Rezvani Amir H. , Johnson Kevin B. , Simson Peter E. , Knapp Darin J. , Moy Sheryl S. , Breese George R.
Published: April 2006

Several lines of research have suggested a link between the reward value of a drug and its ability to stimulate locomotion. One goal of the present study was to determine whether ethanol preferentially stimulates locomotor activity in lines of rat that show a preference for ethanol. A secondary goal was to determine the extent to which the benzodiazepine‐like and NMDA antagonistic action of ethanol accounted for its effect on locomotor activity. To meet these goals, the effects of varying doses of ethanol (0.125‐1.0 g/kg), MK‐801 (0.1‐0.3 mg/kg), and chlordiazepoxide (0.3‐3 mg/kg) on locomotor activity were studied in several lines of rats that had been habituated to the testing procedure. The effect of low doses of ethanol on motor activity in the Alcohol‐Preferring (P) and Fawn‐Hooded rats, which show a strong ethanol preference, were similar to those of the alcohol‐nonpreferring (NP), Flinders Sensitive Line, and Flinders Resistant Line rats. Only the Flinder Resistant Line rats showed a small, but significant increase in locomotor activity after the administration of ethanol. The highest dose of ethanol (1.0 g/kg) produced locomotor depression in all lines except the P and NP lines, which were not tested at this dose. These findings do not support a link between locomotor stimulation by ethanol and ethanol preference. In contrast, all lines exhibited locomotor stimulation after moderate (0.1‐0.3 mg/kg) doses of MK‐801, but did not exhibit increases in activity following any dose of chlordiazepoxide. These data indicate that the profiles of activity after MK‐801 and chlordiazepoxide were distinct from that of ethanol in the various rat lines. Therefore, the effects of ethanol on locomotor activity cannot be accounted for by reference solely to its antagonist‐like action at NMDA receptors and/or its agonist‐like action at GABA/benzodiazepine receptors.
Acute Effects of Ethanol on Ingestive Behavior in Rats
Authors: Blackburn Ruth E. , Stricker Edward M. , Verbalis Joseph G.
Published: April 2006

The effects of acute ethanol administration on the ingestion of NaCl and food were assessed in adult rats subjected to 1‐hr drinking and feeding tests 30 min after intraperitoneal administration of ethanol. Ethanol pretreatment did not induce spontaneous NaCl ingestion, but significantly potentiated angiotensin II‐stimulated salt appetite, but not water intake, in a dose‐dependent manner. Similarly, ethanol pretreatment significantly potentiated neuropeptide γ‐stimulated food intake in nonfasted rats, but did not, by itself, cause spontaneous food ingestion. Ethanol pretreatment also significantly blunted pituitary secretion of oxytocin in response to multiple excitatory stimuli. Finally, administration of oxytocin intracerebroventricularly prevented the ethanol‐induced potentiation of salt appetite elicited by angiotensin II. In view of our previous findings that central oxytocin secretion inhibits both NaCl and food intake, we propose that ethanol potentiates the ingestion of various solutes in rats, in part, by inhibiting brain‐projecting oxytocinergic pathways concurrently with its well‐known effects to inhibit pituitary oxytocin secretion.
Differential Effects of Ethanol Consumption on Synthesis of Cytoplasmic and Mitochondrial Encoded Subunits of the ATP Synthase
Authors: Coleman William B. , Cahill Alan , Ivester Priscilla , Cunningham Carol C.
Published: April 2006

The relative concentrations of several subunits of the mitochondrial F0.F1‐ATP synthase were determined in mitochondria and submitochondrial particles prepared from the livers of ethanol‐fed and control rats. The polypeptides were separated by sodium dodecylsulfate‐polyacrylamide gel electrophoresis and the stained gels were analyzed by densitometry for the relative concentrations of the ATP synthase subunits. A significant decrease in the relative concentration of the mitochondrial gene product, ATPase subunit 8, was observed in mitochondria and submitochondrial particles from ethanol‐fed animals. The relative concentration of the other mitochondrial encoded ATPase subunit, ATPase 6, was also depressed, as confirmed in submitochondrial particles. In contrast, there were no significant ethanol‐related depressions in subunits α, β, and OSCP of the F0. F1 or the adenine nucleotide carrier in intact mitochondria. These results demonstrate that ethanol consumption causes a decrease in the content of mitochondrial synthesized subunits 6 and 8 whereas no effect is exerted on the concentrations of nuclear gene products of the ATP synthase complex. Likewise, the adenine nucleotide transporter, also a nuclear gene product, is unaffected by ethanol consumption.
Mitochondrial Function Reflected by the Decarboxylation of [13C]Ketoisocaproate Is Impaired in Alcoholics
Authors: Witschi Anne , Mossi Sandro , Meyer Beat , Junker Edith , Lauterburg Bemhard H.
Published: April 2006

Mitochondria of patients with alcoholic liver disease exhibit structural abnormalities, and mitochondria isolated from animals exposed to ethanol are functionally deficient when studied in vitro. To assess possible functional consequences of these ethanol‐associated alterations in vivo, we measured mitochondrial function in alcoholics noninvasively with a breath test.

A mitochondrial function, the decarboxylation of ketoisocaproate (KICA), was assessed by measuring the exhalation of 13CO2 following the administration of 1 mg/kg 2‐keto[1‐13C]isocaproic acid, the decarboxylation of which occurs in mitochondria. The results of the KICA breath test in 12 alcoholic subjects were compared with the results in healthy controls and patients with nonalcoholic liver disease. The peak exhalation of 13CO2 and the fraction of the administered dose decarboxylated in 120 min were both significantly lower in alcoholics than in healthy controls and patients with nonalcoholic liver disease. In alcoholics, KICA decarboxylation was impaired in the presence of normal quantitative liver function tests such as the aminopyrine breath test and galactose elimination capacity, indicating that KICA decarboxylation does not simply reflect a decreased functional hepatic mass. The enrichment of circulating KICA with [13C]KICA was similar in alcoholics and controls, indicating that a decreased bioavailability or an increased dilution of labeled KICA cannot account for the decreased exhalation of 13CO2

It is concluded that mitochondrial function as reflected by KICA decarboxylation is impaired in chronic alcoholics. The functional impairment is specific for ethanol abuse and not a reflection of decreased global hepatic function. KICA decarboxylation could thus be useful as a marker for excessive ethanol consumption.
Effects of Nitric Oxide‐Related Agents on Alcohol Narcosis
Authors: Adams Michael L. , Meyer Edward R. , Sewing Bryan N. , Cicero Theodore J.
Published: April 2006

To examine whether nitric oxide (NO) affects alcohol (ethanol) narcosis, adult male rats were pretreated with a NO synthase (NOS) inhibitor, NG‐nitro‐i‐arginine methyl ester (NAME); a NOS substrate, I‐arginine methyl ester (AME); or a NO donor, isosorbide dinitrate (ISDN); then treated with anesthetic doses (3–5 g/kg, ip) of alcohol. Pretreatment with NAME (30–100 mg/kg, sc) 40 min before alcohol treatment delayed the onset of alcohol‐induced loss of the righting reflex (LORR) and increased the duration of the LORR. NAME (100 mg/kg) pretreatment combined with high doses of alcohol (4–5 g/kg) exerted significant lethal effects, even though treatment with either agent alone or NAME combined with lower doses of alcohol (3–3.5 g/kg) was not lethal. Simultaneous treatment with the NOS substrate AME (100 mg/kg, subcutaneous) blocked the effects of NAME on LORR duration times, but did not alter LORR onset times. The NO donor ISDN (30 mg/kg) given by oral gavage 2 hr before alcohol decreased LORR duration times without affecting the onset of LORR. In addition, ISDN dose‐dependently inhibited NAME‐induced LORR duration increases during alcohol narcosis without significantly altering LORR onset times. Neither ISDN nor NAME significantly altered blood alcohol concentrations. These results suggest that NOS inhibition and subsequent decreases in NO production enhance alcohol‐induced narcosis and that increases in NO concentrations inhibit alcohol narcosis, supporting the hypothesis that inhibition of arginine‐NOS‐NO systems mediates part of the sedative‐hypnotic effect of alcohol.
Low and Moderate Doses of Ethanol Produce Distinct Patterns of Cerebral Metabolic Changes in Rats
Authors: Williams‐Hemby Lisa , Porrino Linda J.
Published: April 2006

The quantitative autoradiographic 2‐[14C]deoxyglucose method was used to measure the effects of the acute administration of ethanol on local rates of glucose utilization in male Sprague‐Dawley rats. Rates of glucose utilization were measured 10 min after the intraperitoneal administration of 0.00, 0.25, 0.50, and 1.00 g/kg ethanol. The acute administration of the lowest dose of ethanol (0.25 g/kg) significantly increased rates of cerebral metabolism, as compared with vehicle‐treated controls, in structures of the mesocorticolimbic and nigrostriatal dopaminergic systems. Among the affected regions were the nucleus accumbens, medial prefrontal cortex, olfactory tubercle, caudate, ventral tegmental area, and substantia nigra. Acute administration of 0.50 g/kg ethanol resulted in similar trends in increased functional activity; however, significant increases were limited to the somatosensory cortex, posterior nucleus accumbens, and the CA3 region of the hippocampus. In contrast, the administration of 1.00 g/kg ethanol produced widespread decreases in rates of glucose utilization in brain regions involved in processing of sensory and motor information, as well as in portions of the limbic system. These data indicate that the effects of acute ethanol administration on functional activity as reflected by rates of glucose utilization are dose‐dependent. These cerebral metabolic effects parallel the dose‐dependent effects of ethanol on motor behavior, with stimulatory effects generally observed at lower doses and depressive effects at higher doses. Moreover, each of the doses studied produced alterations in functional activity in a unique subset of structures. This suggests that different neuroanatomical circuits mediate the effects of each dose.
Effect of Postnatal Exposure of Female Rats to An Alcohol Diet: Influence of Age and Circulating Sex Steroids
Authors: Lee Soon , Rivier Catherine
Published: April 2006

We have previously reported that when compared with animals fed ad libitum, adult ovariectomized (OVX) female rats fed an alcohol diet, but not its isocaloric equivalent control, showed a blunted ACTH response to the intravenous injection of interleukin‐1β (IL‐1β). The present work was undertaken to determine whether this finding could be extended to intact rats, and whether the stage of sexual maturation and/or circulating sex steroids of ovarian origin modulated the inhibitory influence of alcohol. Intact female rats were exposed to alcohol or pair‐fed between postnatal days 25–35 (group 1), 35–45 (group II), or 45–55 (group III). Animals of comparable age and fed ad libitum served as controls. All alcohol‐exposed animals had similar blood alcohol levels measured during the eighth night of treatment. Group I lost the most weight following exposure to alcohol, but did not show measurable changes in ACTH released in response to 20 or 100 ng IL‐1β/kg. Both alcohol and pair‐feeding caused a modest decrease in IL‐1‐stimulated ACTH in rats of group II, but only alcohol significantly blunted corticotrophs' activity in group III. Group III, when fed alcohol, also showed lower CRF content in the median eminence compared with absolute controls or the isocaloric diet. No measurable changes, however, were observed in steady‐state CRF mRNA levels in the hypothalamus of animals fed any of the diets. When intact and OVX rats were compared at 55 days of age, alcohol feeding caused a decrease in IL‐1‐induced ACTH secretion which was slightly, though not significantly, larger in intact animals. We conclude that in female rats, circulating sex steroids of ovarian origin may modulate the ability of an alcohol diet to blunt the response of the corticotrophs to peripherally administered IL‐1β. As blood‐born cytokines are believed to stimulate ACTH secretion by acting at the level of peptide terminals in the median eminence, the finding of alcohol‐induced decreases in CRF content in this region suggests that the drug alters peptide release from nerve terminals. Whether sex steroids interact with alcohol at that level or through other mechanisms remains to be determined.
Diethyldithiocarbamate Methyl Ester Sulfoxide, an Inhibitor of Rat Liver Mitochondrial Low Km Aldehyde Dehydrogenase and Putative Metabolite of Disulfiram
Authors: Madan Ajay , Faiman Morris D.
Published: April 2006

S‐methyl N,N‐diethylthiolcarbamate sulfoxide (DETC‐MeSO) is a potent inhibitor of rat liver mitochondrial low Km aldehyde dehydrogenase (ALDH2) both in vivo and in vitro, and has been proposed to be the metabolite responsible for ALDH2 inhibition by disulfiram. Diethyldithiocarbamate methyl ester (DDTC‐Me), a key intermediate in the metabolism of disulfiram, has been shown to be bioactivated by microsomal monooxygenases to diethyldithiocarbamate methyl ester sulfoxide (DDTC‐Me sulfoxide). Studies were conducted to determine if DDTC‐Me sulfoxide was also an active metabolite of disulfiram and inhibitor of ALDH2. DDTC‐Me sulfoxide inhibited ALDH2 in vitro with an IC50 of 10 μm, and in vivo with an ID50 of 31 mg/kg (170 μmol/kg). Maximal ALDH2 inhibition in vivo was observed 8 hr after the administration of 45.2 mg/kg DDTC‐Me sulfoxide, with ALDH2 activity returning to control levels after 48 hr. Although DDTC‐Me sulfoxide inhibited ALDH2 in vivo, DDTC‐Me sulfoxide was not detected in plasma from rats treated with either disulfiram (75 mg/kg), DDTC‐Me (122.25 mg/kg), or DDTC‐Me sulfoxide (45.2 mg/kg). However, DDTC‐Me and S‐methyl N,N‐diethylthiolcarbamate (DETC‐Me) were detected in plasma from rats treated with DDTC‐Me sulfoxide. In rats treated with DDTC‐Me sulfoxide and challenged with ethanol, a small increase of ∼9 μm in blood acetaldehyde and an inconsistent drop in blood pressure was observed. In conclusion, DDTC‐Me sulfoxide inhibited ALDH2 in vitro and in vivo, was less potent than DETC‐ MeSO, and was not detected after disulfiram administration.
Increased Endothelium‐Dependent Vascular Relaxation in Ethanol‐Fed Rats
Authors: Hatake Katsuhiko , Wakabayashi Ichiro , Taniguchi Tadaaki , Hishida Shigeru
Published: April 2006

We investigated the mechanism underlying increased relaxation of aortic strips to acetylcholine in rats chronically treated with ethanol. Rats were divided into three groups and maintained on liquid diets containing ethanol (35% of total calories) as the ethanol‐fed group or an equicaloric volume of sucrose instead of ethanol as the sucrose‐fed group for 10 weeks. The control group was also maintained on modified American Institute of Nutrition diet for the same period. Vascular strips of isolated rat aortas were mounted in organ chambers to record isometric tension. The endothelium‐dependent relaxation responses to acetylcholine and calcium ionophore A23187 were greater in ethanol‐fed rats than in control and sucrose‐fed rats. However, the relaxation response to sodium nitroprusside or nifedipine did not differ among the three groups. Acetylcholine, calcium ionophore A23187, and sodium nitroprusside caused an increase in the cGMP contents of rat aortic strips that was similar among the three groups. These results suggest that a cGMP‐independent relaxation mechanism is involved in the increased relaxation response to acetylcholine after chronic treatment with ethanol.
Dopamine D2 Receptor Gene Expression in Rat Lines Selected for Differences in Voluntary Alcohol Consumption
Authors: Syvälahti E. K. G. , Pohjalainen T. , Korpi E. R. , Pälvimäki E.‐P. , Ovaska T. , Kuoppamäki M. , Hietala J.
Published: April 2006

A selective breeding program has led to the establishment of the alcohol‐preferring AA (Alko, Alcohol) and alcohol‐avoiding ANA (Alko, Nonalcohol) rat lines. To reveal putative baseline differences in dopamine receptor gene expression and dopamine receptor binding profile in the AA and ANA rat lines, we assessed striatal D2 mRNA levels in these two rat lines. Autoradiographical studies on dopamine D1 and D2 receptors in the striatum and nucleus accumbens were also performed with [3H]SCH 23390 and [125I]iodosulpiride/[3H]spiperone, respectively. The baseline differences in D1 or D2 receptor binding and D2 receptor gene expression between AA and ANA rat lines are marginal, and are not likely to play a role in the genetic background of the differential alcohol drinking behavior of these rat lines.
Effects of Ethanol on NMDA Receptors in Brain: Possibilities for Mg2+ ‐Ethanol Interactions
Authors: Michaelis Mary L. , Michaelis Elias K.
Published: April 2006

The major excitatory neurotransmitter in the CNS is L‐glutamate, and one of the subtypes of L‐glutamate receptors, the N‐methyl‐D‐aspartate (NMDA) subtype, has been found to be quite sensitive to inhibition by low concentrations of ethanol (5–50 mm). The NMDA receptor‐ion channels are unique in that they exhibit a voltage‐dependent blockade by physiological concentrations of Mg2+, a blockade that is relieved as the cell membrane is depolarized. Several lines of evidence also suggest that the activity of this receptor‐channel complex may be regulated through a high‐affinity Mg2+ site, which is distinct from the channel‐blocking site and could even be located on the extracellular domain of the protein. This high‐affinity Mg2+ site has been shown to increase the binding of N‐[1‐(2‐thienyl) cyclohexyl]piperidine within the ion channel, as well as the binding of competitive antagonist such as 3‐(±)‐carboxypiperazine‐4‐yl)‐[1,2]‐propyl‐1‐phosphonic acid and the receptor coactivator glycine. The relationship between the acute effects of ethanol on receptor activation and the regulatory properties of Mg2+ is not yet known, although the hypomagnesemia that occurs in chronic alcoholism could certainly have implications for receptor function. A significant amount of molecular characterization of the multiple isoforms of the NMDA receptor‐ion channel will be required before the role of Mg2+ can be clarified and any relationship between Mg2+ regulation and ethanol inhibition established.
Platelet Monoamine Oxidase Activity in Alcoholics, Alcoholics with Drug Dependence, and Cocaine Addicts
Authors: Faraj Bahjat A. , Davis Donald C. , Camp Vernon M. , Mooney Al J. , Holloway Ted , Barika Gibson
Published: April 2006

The main objective of this investigation was to study the influence of drug dependence on platelet monoamine oxidase (MAO) activity in the presence and absence of alcoholism. One hundred and thirteen admissions to alcohol and drug treatment facilities participated in the study. Twenty‐six met the criteria for alcoholism (group I), seventy‐eight subjects were alcohol‐/cocaine‐ and cannabis‐dependent (group II), and the remaining nine were patients with DSM‐III‐R diagnosis of cocaine addiction (group III). MAO activity was assayed radiochemically with [14C]tyramine as a substrate (221 μM). The results of this study showed that platelet MAO activity [nmol of product formed x (mg protein)−1 x hr−1] (mean ± SE) was significantly (p < 0.01) lower in all of these subjects (group 1, 5.50 ± 0.80; group II, 3.90 ± 0.50; group III, 4.3 ± 1.60) as compared with controls (14.85 ± 1.13). Measurements of platelet MAO activity may provide us with a reliable biochemical marker for alcoholism and perhaps addiction to other substances of abuse (i.e., cocaine).
Examination of the Tridimensional Personality Hypothesis of Alcoholism Using Empirically Multivariate Typology
Authors: Yoshino Aihide , Kato Motoichiro , Takeuchi Mika , Ono Yutaka , Kitamura Toshinori
Published: April 2006

Cloninger (1987) has hypothesized a tridimensional personality theory for two types of alcoholism, type 1 and type 2, that exhibit oppodng clinical characteristics and personality traits. The Tridimensional Personality Questionnaire (TPQ) is designed to test this hypothesis on three independent dimensions—novelty seeking (NS), harm avoidance (HA), and reward dependence (RD)—to evaluate the personality trait. We examined the tridimensional personality hypothesis by comparing TPQ scores between two empirically derived multivariate types of alcoholism.

The present study included 191 male subjects with alcoholism. A cluster analysis was conducted using clinical characteristics, and two empirical types, type A and type B, were identified. Type A similar to Cloninger's type 1 and type B is similar to type 2. The TPQ scores given to these two empirical types were compared. Scores on the NS and RD scales were in good agreement with the hypothesis, whereas the HA score was discordant with the hypothesis. HA is highly correlated with the depression scale score that is elevated in type B. We discussed the possibility that type B, which may be called a familial early‐onset alcoholism, is related to character spectrum disorder.