bluuebunny/crossref_metadata_2025 huggingface dataset:
Dose Response to Ethanol‐Containing Liquid Diets for Use in a Murine Model for Studies of Biological Effects due to Ethanol Consumption
Authors: Monahan Clifton M. , Padgett Eric L. , Biber Kristen L. , Moscatello Kim M. , Johnston Frances L. , Wolcott R. Michael
Published: May 2006

Dose‐response experiments were performed to establish an optimum concentration of ethanol (EtOH) in liquid diet formulations for use with a murine model (C57BL/6) of potential biological effects attributable to EtOH consumption. An optimum condon was predetermined to be the highest EtOH concentration consumed by mice without resulting in a loss of body weight Feeding trials were performed using EtOH concentrations that ranged from 25 to 36% ethanol‐derived calories (EDC) during 7‐day experiments, or 10 to 30% EDC fed during 21‐day experiments. The parameters studied included body weight changes, diet consumptions, daily g EtOH kg−1 body weight, as well as differences in mononuclear cell numbers from the spleen, thymus, and bone marrow. Diet consumptions by the EtOH groups and pair‐fed (PF) groups were monitored by weight rather than by volume. During either 7‐day or 21‐day trials, diet consumptions were lower by groups receiving diets of higher EtOH concentrations; however, daily EtOH intake was maximal by groups fed diets of 25% EDC in all experiments. These mice also gained weight, whereas mice maintained on 30% EM: did not gain weight, and mice maintained on diets of 33 or 36% EDC lost significant body weight Body weight changes in PF groups were similar to their respective EtOH group. Changes in mononudear cell numbers of the spleen and thymus paralleled the changes seen in body weights. In the 7‐day trials, cell counts declined progressively in groups maintained on diets of high EDC (≥30% EDC) or their PF controls. From the 21‐day trials, cell counts of both the 30% EDC group and their PF controls declined, compared with all other groups. Together, the conclusion drawn from these findings was that nutritional stress was principally responsible for the mononuclear cell depletions. This contradicts previous reports and highlights the need for strict attention to the pair‐feeding paradigm to avoid masking a nutritional component of such studies through overfeeding of the PF controls. Liquid diets of 25% EDC were determined to be optimal for immunological studies using a murine model, because this concentration maximizes EtOH consumption and maintains body weight of the experimental animals.
Moderately High Consumption of Ethanol Suppresses Bone Resorption in Ovariectomized but not in Sexually Intact Adult Female Rats
Authors: Fanti P. , Monier‐Faugere M.‐C. , Geng Z. , Cohen D. , Malluche H.H.
Published: May 2006

Epidemiological studies suggest that moderate consumption of alcoholic beverages may be beneficial for bone in postmenopausal women. To investigate prospectively these uncontrolled obsewations, female rats were divided in four groups of 10 animals each and treated with 1) ovariectomy (OVX) and 2.5% ethanol diet (OVX‐ETOH group), 2) OVX and control diet (OVX‐C group), 3) sham surgery and 25% ethanol diet (SHAM‐ETOH group), or 3) sham surgery and control diet (SHAM‐C group). Three weeks after surgery, bone histomor‐phometfy revealed that the OVX‐C group, as expected, had lower trabecular bone volume and higher parameters of bone formation and resorption than the SHAM‐C group (p < 0.01). Intake of ethanol did not change these parameters in the SHAM rats, but in the OVX rats it was associated with sharp reduction in parameters of bone resorption (p < 0.01) without a concomitant effect on parameters of bone formation. The cytokines are believed to contribute to accelerated bone resorption during the early postmenopausal period. Indeed, the peripheral blood monocybc cells (PBMC) from the OVX‐C rats produced higher amounts of TNF‐α than the PBMC from the SHAM‐C rats (p < 0.05) and administration of ethanol prevented this increase in OVX rats but had no effect in SHAM rats. In summary, short‐tetm intake of moderate doses of ethanol was associated with markedly different eftects in rats with and without ovarian function. Although ethanol had no significant effect on the bone tissue and TNF‐α production of the SHAM rats, it was associated with markedly lower parameters of bone resorption and less TNF‐α production in the OVX animals. This suggests that exposure to low‐dose ethanol may protect from osteopenia following cessation of ovarian function.
Effects of Chronic Ethanol Consumption and Aging on 5‐HT2A Receptors and 5‐HT Reuptake Sites
Authors: Druse Mary J. , Tajuddin Nuzhath F. , Ricken John D.
Published: May 2006

The serotonergic system in brain is adversely affected by both aging and chronic ethanol consumption. The present study examined the combined effects of aging and chronic ethanol consumption on two components of the serotonergic system. Serotonin (5‐HT) reuptake sites and 5‐HT2A receptors were quantitated in brain areas of 5‐, 14‐, and 24‐month‐old male Fischer 344 rats that were pair‐fed a control or 6.6% (v/v) ethanol‐containing liquid diet on a chronic basis. The regions examined include those containing the cell bodies and projections of serotonergic neurons. These experiments demonstrated the sensitivity of the serotonergic system of male Fischer 344 rats to both aging and chronic ethanol consumption. In control rats, aging was associated with a decline in the concentration of 5‐HT2A receptors in the nucleus accumbens and four cortical regions: frontal, parietal, piriform, and cingulate cortex. 5‐HT2A receptors were also reduced in the frontal, parietal, and cingulate cortex of aged ethanol‐fed rats. In contrast, 5‐HT reuptake sites were increased in older rats in the frontal cortex, nucleus accumbens, amygdala, and CA3 region of the hippocampus. If comparable changes in 5‐HT2A receptors and 5‐HT reuptake sites occur in elderly humans, they may contribute to ethanol consumption, and lead to cognitive and other age‐related problems. These changes may also alter the effectiveness of serotonergic drugs used in the treatment of alcoholism and mental disorders. The effects of chronic ethanol consumption were more limited. The only significant ethanol effect was an increase of 5‐HT2A receptors in the nucleus accumbens of 5‐month‐old ethanol‐fed rats.
Therapeutic Motor Training Increases Parallel Fiber Synapse Number Per Purkinje Neuron in Cerebellar Cortex of Rats Given Postnatal Binge Alcohol Exposure: Preliminary Report
Authors: Klintsova Anna Y. , Matthews Jessica T. , Goodlett Charles R. , Napper Ruth M. A. , Greenough William T.
Published: May 2006

Because therapeutic approaches to fetal alcohol effects in humans have been rare, this study explored the rehabilitative effect of complex motor training on an animal model of binge drinking in the third trimester of human pregnancy. Neonatal alcohol exposure induces significant and permanent reductions in Purkinje and granule cell number accompanied by impaired motor behavior in rats. The purpose of this study was to determine: (1) whether the motor skill impairment caused by exposure to alcohol in the early postnatal period could be ameliorated by the learning of a set of complex motor tasks that had been demonstrated to cause synaptogenesis in the cerebellar cortex; and (2) the extent to which cerebellar neurons in alcohol‐exposed (AE) rats exhibit synaptic plasticity. The AE group was given 4.5 g/kg/day of ethanol from postnatal days 4 to 9 via an artificial rearing procedure producing a mean peak blood alcohol level of 257 mg/dl. Control groups consisted of a gastrostomy control (GC) group, that received an isocaloric mixture of maltose/dextrin instead of ethanol, and a suckle control (SC) group, that was reared normally by dams. At ˜6 months of age, animals from the three groups were assigned either to a rehabilitation condition (RC; that received 10 days of training on the motor tasks) or to an inactive condition (IC; where rats stayed in isolation in their cages). Although SC rats were significantly faster to complete the course in the first 5 days of training, there were no differences in ability to perform among animals from all three groups—SC, GC, and AE—at the end of the training period. Unbiased stereological techniques were used to obtain estimates of the number of parallel fiber synapses/Purkinje cell within the cerebellar paramedian lobule. Results showed that the RC rats from the SC and AE groups had significantly more synapses/Purkinje cell than corresponding IC animals. These data demonstrate that rehabilitative intervention (complex motor training) can improve motor performance impaired by postnatal alcohol exposure and that surviving Purkinje neurons retain the capacity for synaptic plasticity.
Prepulse Inhibition of the Startle Reflex: Preliminary Study of the Effects of a Low Dose of Alcohol in Humans
Authors: Hutchison Kent E. , Rohsenow Damaris , Monti Peter , Palfai Tibor , Swift Robert
Published: May 2006

The present study was designed to examine the effects of a low dose of alcohol on prepulse inhibition (PPI) of the startle response and self‐report measures of affect. Eighteen subjects participated in a counterbalanced repeated‐measures design in which they received a beverage with alcohol during one session and a nonalcohol beverage during a different experimental session. The startle response was probed in two separate 10‐min blocks immediately after consumption of the alcohol. Although alcohol significantly suppressed the startle response in general, it did not do so to an extent that compromised detection of PPI. The effects of alcohol on PPI were primarily evident in the first block and were dependent on baseline levels of PPI, such that alcohol resulted in a reduction of PPI in subjects who demonstrated low PPI at baseline and an increase in PPI for subjects with high PPI at baseline. Alcohol also significantly increased self‐reported stimulation during the first block and increased negative affect during the second block. These findings suggest that baseline PPI may reflect an important individual difference that is predictive of the direction and magnitude of alcohol‐induced changes in sensorimotor gating.
Disinhibited Personality and Sensitivity to Alcohol Reinforcement: Independent Correlates of Drinking Behavior in Sons of Alcoholics
Authors: Conrad Patricia J. , Petersen Jordan B. , Pihl Robert O.
Published: May 2006

Thirty nonalcoholic young (18 to 30 years) males with extensive multigenerational family histories of male alcoholism and 29 age‐matched, family history‐negative controls completed a variety of trait personality questionnaires, participated in a competitive stress task (while sober and alcohol‐intoxicated), and were assessed for self‐report and laboratory drinking behavior. Low academic achievement, disinhibited personality (as measured by the P Scale of the Eysenck Personality Questionnaire), and sensitivity to alcohol reinforcement were significant and powerful independent predictors of self‐report (approximate R2= 0.40, p < 0.0001) and laboratory (approximate R2= 0.20, p < 0.0001) drinking behavior. There seemed to be some specificity with respect to the facets of drinking behavior accounted for by each independent variable: low academic achievement and sensitivity to alcohol reinforcement were more related to quantity of alcohol consumption and frequency of excessive consumption, whereas psychoticism was more related to self‐reported negative consequences with alcohol. A cluster analysis on three identified correlates of drinking behavior indicated that the two experimental groups could be more accurately subdivided into three homogeneous types. Multigenerational family history males were disproportionately represented in two of these groups: one characterized by enhanced sensitivity to alcohol reinforcement and the other characterized by high psychoticism scores and alcohol‐related problems.
Ethanol Feeding Causes Inactivation of Both State 1 and State 2 Rat Hepatic Asialoglycoprotein Receptors
Authors: Tworek Benita L. , Oka Janet A. , Casey Carol A. , Weigel Paul H.
Published: May 2006

Previous studies have shown that ethanol feeding in rats causes inactivation and redistribution of ˜50% of the total asialoglycoprotein receptors (ASGPRs) in hepatocytes (Tworek et al., J. Biol. Chem. 271:2531, 1996), and that two equal populations of hepatic ASGPRs mediate ligand uptake and processing via two functionally different pathways (Weigel in Glycoconjugates: Composition, Structure and Function, Marcel Dekker, 1992, p. 421). The purpose of this study was to determine if ethanol feeding causes preferential inactivation of only one of these two ASGPR populations, which have been designated state 1 and state 2 ASGPRs. The state 2, but not state 1, ASGPRs are inactivated in isolated hepatocytes by a variety of drugs and inhibitors. State 2 ASGPRs can also be inactivated in permeable cells by ATP treatment and then reactivated by treatment with fatty acyl coenzyme As. In the present study, permeable cell assays for state 2 ASGPR inactivation and reactivation were used to assess whether hepatocytes from ethanol‐fed rats contain inactive state 2 ASGPRs. The results show that preferential inactivation of one ASGPR population does not occur after ethanol feeding. That inactive ASGPRs could not be reactivated by treatment with palmitoyl‐coenzyme A to a greater extent in ethanol‐fed versus control cells indicates there is not a larger pool of inactivated state 2 ASGPRs in treated cells. We conclude that ethanol feeding causes equal inactivation of both state 1 and state 2 ASGPRs. Ethanol feeding may represent the first treatment found to inactivate state 1 ASGPRs.
The Effect of Cold Stress on Lymphocyte Proliferation in Fetal Ethanol‐Exposed Rats
Authors: Giberson Pamela K. , Kim C. Kwon , Hutchinson Shannon , Yu Wayne , Junker Anne , Weinberg Joanne
Published: May 2006

Prenatal ethanol exposure and stress have each been shown to have significant effects on the immune system. This study examined the possible interactive effects of prenatal ethanol exposure and exposure to stress later in life on the immune system. Differential vulnerability to these challenges in female and male offspring was assessed. At 5 to 6 months of age, female and male offspring from prenatal ethanol‐exposed (E), pair‐fed (PF), and ad libitum‐fed control (C) conditions were exposed to 0, 1, or 3 days of cold (4°C). At the end of the cold period, the proliferative response of splenic lymphocytes to the mitogens concanavalin A (Con A) and pokeweed mitogen (PWM) was assessed. The data demonstrate a significant interactive effect between prenatal ethanol exposure and cold stress in female offspring. After 1 day of cold stress, E females had significantly increased PWM‐induced lymphocyte proliferation compared with PF and C females, and significantly increased Con A‐induced lymphocyte proliferation compared with PF females. There were no differences in PWM or Con A‐induced lymphocyte proliferation among E, PF, and C females after 0 or 3 days of cold stress, nor among E, PF, and C males on any test day. Regardless of prenatal treatment, females exposed to 1 or 3 days of cold had significantly greater basal plasma corticosterone levels than females not exposed to cold. In contrast, only E males exposed to 1 or 3 days of cold had significantly increased basal plasma corticosterone levels, compared with E males not exposed to cold; PF and C males showed no significant change in basal corticosterone after cold stress. These data demonstrate that, in response to the challenge of cold stress, changes in lymphocyte proliferation to PWM and Con A may occur selectively in E females. Moreover, the interactive effects of prenatal ethanol and cold stress may result in enhanced rather than suppressed immune responsiveness.
Content of Dynorphins and k‐Opioid Receptors in Distinct Brain Regions of C57BL/6 and DBA/2 Mice
Authors: Jamensky Neil T. , Gianoulakis Christina
Published: May 2006

Differences in the activity of various components of the endogenous opioid system under basal conditions and after ethanol exposure have been reported between strains and lines of animals showing either high or low ethanol consumption. The objective of the present studies was to investigate the presence of differences in (a) the density of k‐opioid binding sites, (b) the content of prodynorphin mRNA, and (c) the content of dynorphin peptides in distinct brain regions between the C57BL/6 (ethanol‐preferring) and the DBA/2 (ethanol‐avoiding) mice. Results indicated that the C57BL/6 mice have a higher content of k‐opioid binding sites and dynorphin A1‐13 in the amygdala, and dynorphin A 1–8 in the ventral tegmental area, whereas the DBA/2 mice presented a significantly higher content of k‐opioid binding sites, prodynorphin mRNA, as well as dynorphin A 1–13 and dynorphin A 1–8 peptides in the nucleus accumbens and septum. In addition, the DBA/2 mice presented a higher content of k‐opioid receptors in the periaqueductal gray and dynorphin A1‐13 and dynorphin A 1–8 in the caudate putamen. Because enhanced stimulation of the k‐opioid receptors at the level of the nucleus accumbens has been associated with decreased dopamine release and aversive states, the higher content of k‐opioid receptors, prodynorphin mRNA, and dynorphin peptides (the endogenous ligand of k‐binding sites) in regions of the limbic system of the DBA/2 mice may play an important role in determining their low alcohol consumption.
Differences in Free‐Choice Ethanol Acceptance between Taste Aversion‐Prone and Taste Aversion‐Resistant Rats
Authors: Orr T. Edward , Walters Paul A. , Elkins Ralph L.
Published: May 2006

Taste aversion (TA)‐prone (TAP) and TA‐resistant (TAR) rats were tested for naive, nonforced acceptance of ethanol. Ethanol acceptance had played no role in line development. Rather, the lines had been developed via bidirectional, nonsibling matings based on susceptibility to develop cyclophosphamide‐induced conditioned TAs to a 0.1% saccharin solution (at cyclophosphamide doses of 12.5 mg/kg for males and 15.0 mg/kg for females, ip). Rats from the 23rd selectively bred generations, with no prior exposure to ethanol, were given 24‐hr access to a two‐bottle choice between plain tap water and a solution of ethanol in water. Rats were initially given access to 1% ethanol in water, and the ethanol concentration was increased by 1% every 3 days to a maximum of 10%. Ethanol consumption (g ethanol consumed/kg body weight) and preference scores (volume ethanol solution consumed/total fluid intake) were determined by daily bottle weighings. At 1% ethanol concentration, there were no differences between the rat lines in terms of ethanol consumption or preference. At concentrations of 2 to 10%, TAP rats consumed less ethanol and showed a decreased preference for the ethanol solutions than TAR rats. Maximum ethanol consumption was reached at the 6% concentration for both lines. The mean (±SE) values of consumption at 6% ethanol were 1.8 (±0.8) and 5.6 (±0.5) g of ethanol/kg body weight for TAP and TAR rats, respectively. Mean (±SE) preference scores at 6% ethanol were 26 (±12) and 76 (±6) for TAP and TAR rats, respectively. These findings indicate that differences in TA conditionability may be associated with the propensity of rats to be high or low consumers of ethanol. Based on these data, it is hypothesized that high susceptibility for TA conditionability may deter many individuals from consuming the high levels of ethanol that usually precede alcohol tolerance and dependence.
Genetics, Ethanol and the Fos Response: A Comparison of the C57BL/6J and DBA/2J Inbred Mouse Strains
Authors: Hitzemann Barbara , Hitzemann Robert
Published: May 2006

The effect of ethanol (0.25 to 4 g/kg) on the number of Fos‐like immunoreactive (Fos‐li) neurons was studied in the C57BL/6J (B6) and DBA/2J (D2) inbred mouse strains. The brain regions emphasized in the analysis were from the basal ganglia and some associated limbic nuclei. The question addressed was whether or not the D2 and B6 strains differed in these regions in a way that could explain the marked psychomotor stimulation of the D2, but not the B6, strain over the dose range of 1 to 2 g/kg of ethanol. Over the dose range of 0.25 to 2 g/kg, ethanol caused a modest increase in the number of Fos‐li neurons within the caudate putamen (dorsolateral and dorsomedial) and the nucleus accumbens (core and shell), but there were no marked strain effects. There was no significant effect in either strain of ethanol treatment (0.25 to 2 g/kg) in the globus pallidus, ventral pallidum, and subthalamic nucleus. However, at 4 g/kg, there was a dramatic (>100%) increase of Fos‐li neurons in the D2 but not B6 strain. A similar effect was noted in the entopeduncular nucleus, the substantia nigra zona reticulata (and compacta), but not the ventral tegmental area. A marked and substantial (>200%) Fos response was seen in the central amygdaloid nucleus (CeA) of the D2 strain over the entire dose range; in contrast, a substantial Fos response in the B6 strain was seen only at the 4 g/kg dose. The paraventricular thalamic nucleus, in general, paralleled data in the CeA; but, the Fos response was more modest, and the results for the D2 strain were significant only at the 2 g/kg dose. Overall, data suggest that ethanol at low to moderate doses induces significant, strain‐dependent Fos responses in some limbic structures, but not in the basal ganglia. The possibility is considered that activation of some neurons in the CeA are permissive for expression of the ethanol‐induced increase in motor activity.
NMDA Receptor Binding in Adult Rat Brain after Several Chronic Ethanol Treatment Protocols
Authors: Rudolph Joseph G. , Walker Don W. , Limuro Yugi , Thurman Ronald G. , Crews Fulton T.
Published: May 2006

The amino acid L‐glutamate is a major excitatory neurotransmitter that is involved in many CNS functions, including learning, memory, long‐term potentiation, and synaptic plasticity. Acute exposures to ethanol (50 to 200 mM) have been shown to inhibit NMDA receptor responses, whereas chronic exposure to ethanol leads to adaptive supersensitivity thought to be involved in ethanol dependence and tolerance. To investigate the effects of chronic ethanol exposure on glutamate receptor density, we examined the binding of both NMDA and non‐NMDA ligands in rat brain after several chronic ethanol treatment protocols using a number of different rat strains. No increases in the binding of [3H]MK‐801, [3H]CGP 39653, or the polyamine specific competitive antagonist, [3H]ifenprodil, were seen after two well‐used chronic ethanol treatments. These included the 2‐week liquid diet developed by Frye et al. (J. Pharmacol. Exp. Ther. 216:306‐314, 1981) and the 4‐day binge treatment developed by Ma‐jchrowicz (Psychopharmacologia 43:245‐254, 1975). However, small increases in the binding of both the NMDA noncompetitive antagonist [3H]MK‐801, as well as the competitive NMDA antagonist [3H]CGP 39653, were seen in select frontal brain regions after 3 weeks of the Walker‐Freund chronic ethanol liquid diet When this chronic liquid diet treatment was extended to a period of 6 weeks, these increases in receptor binding were diminished to nonsignificant levels. The binding of the non‐NMDA ligands [3H]AMPA and [3H]kainate were not significantly affected by either length of Walker‐Freund liquid diet exposure. When rats were treated chronically with ethanol for 30 days using the paradigm developed by Tsukamoto et al. (Hepatology 5:224‐232, 1985), small, but significant, increases in the binding of [3H]MK‐801 were seen in the CA1 and dentate gyrus regions of the hippocampus. These studies indicate that robust increases in NMDA receptor binding do not occur with several chronic ethanol treatment protocols, and suggests that NMDA receptor supersensitivity during the development of tolerance and dependence to ethanol may not simply be due to changes in the density of NMDA receptors, but may involve other mechanisms.
Effects of Prenatal Ethanol Exposure on Phospholipase C‐β1 and Phospholipase A2 in Hippocampus and Medial Frontal Cortex of Adult Rat Offspring
Authors: Allan Andrea M. , Weeber Edwin J. , Savage Daniel D. , Caldwell Kevin K.
Published: May 2006

Previous studies in our laboratory using a rat model of fetal alcohol exposure (FAE) suggest that FAE‐induced behavioral deficits are, in part, linked to neurochemical and electrophysiological deficits in long‐term potentiation (LTP) in the entorhinal cortical perforant path projection to the hippocampal formation. Several findings suggest that signal‐activated phospholipase C (PLC) and phospholipase A2 (PLA2) are critical to the induction and maintenance of LTP. Thus, alterations in phospholipid metabolism may play a significant role in the LTP deficits observed in FAE offspring. To test this hypothesis, we measured PLC‐β1 and PLA2 activities in the hippocampus and medial frontal cortex of adult rats prenatally exposed to ethanol.

PLC‐β1 activities were significantly decreased by 20 to 30% in both the hippocampus and medial frontal cortex of FAE rats, compared with ad libitum and pair‐fed controls. Total Ca2+‐dependent PLA2 activity was 25% lower in the medial frontal cortex of FAE rats, but did not significantly differ from controls in the hippocampal formation. Approximately 30% of the measured activity in both the medial frontal cortex and hippocampal formation of ad libitum and pair‐fed animals was associated with an 85 kDa cytosolic PLA2 form. Cytosolic PLA2 activities were significantly reduced in both the medial frontal cortex and hippocampal formation of FAE rats, compared with controls. These changes in Ca2+‐dependent PLA2 and PLC‐β1 activities, coupled with reports of FAE‐induced deficits in protein kinase C activity, indicate that prenatal exposure to moderate quantities of ethanol causes profound and long‐lasting deficits in the cellular signaling mechanisms associated with activity‐dependent synaptic plasticity and memory formation.
The Impact of Acute Ethanol on Reproductive Hormone Synthesis, Processing, and Secretion in Female Rats at Proestrous
Authors: LaPaglia N. , Steiner J. , Kirsteins L. , Emanuele M. A. , Emanuele N.
Published: May 2006

It is the purpose of this study to investigate the effects of acute ethanol (EtOH) on the female rat hypothalamic‐pituitary‐gonadal (HPG) axis. The molecular and cellular mechanistic details of such effects have been studied intensively in the male rat. However, there has been relatively little in‐depth study of EtOH's effects on the adult, postpubertal female rat. Adult female rats with confirmed 4‐ or 5‐day estrous cycles were given a single injection of EtOH or saline between noon and 1:00 PM on proestrous and were killed at 4:00 PM. EtOH caused a sharp 97% reduction in luteinizing hormone (LH) serum levels (p < 0.001), compared with controls with no concomitant change in LH mRNA. EtOH also significantly reduced hypothalamic LH releasing hormone (LHRH) by 49% (p < 0.01), with no change in content of the precursor pro‐LHRH compared with saline‐injected controls. The ratio of LHRH to pro‐LHRH was also significantly reduced by EtOH (p < 0.05), compared with control. There was no EtOH‐induced change in LHRH mRNA. Compared with saline, EtOH reduced both serum estradiol by 37% (p < 0.02) and progesterone by 47% (p < 0.001). These results show that EtOH has profound disruptive effects on the female HPG axis. Our data suggests that EtOH decreases the releasable LHRH pool either by decreasing conversion of pro‐LHRH to LHRH and/or by increasing local LHRH degradation. This acutely restricts the release of LH and subsequent estradiol and progesterone secretion.
Isradipine and Naltrexone in Combination with Isradipine Interact with a Period of Abstinence to Reduce Rats’Intakes of an Alcoholic Beverage
Authors: Gardell Luis R. , Reid Larry D. , Boedeker Kirsten L. , Liakos Thomas M. , Hubbell Christopher L.
Published: May 2006

Individually housed rats were placed on a daily regimen of only 2 hr a day to drink both water and a sweetened alcoholic beverage. Initially, rats took little ethanol, but after 3 weeks, they took, on average, >2.0 g/kg daily. With achievement of stable intakes, the rats were deprived of opportunity to drink ethanol for 24 days and then the daily regimen was reinstated. With the reinstatement, various injections were given daily for 25 days or more: placebos, doses of isradipine (1.0 or 3.0 mg/kg), naltrexone (3.0 mg/kg), and a combination of isradipine (1.0 mg/kg) and naltrexone (3.0 mg/kg). The combination produced favorable effects with the fewest limiting side‐effects. The period of abstinence decreased daily intakes of ethanol and interacted with the drugs to produce large, sustained decreases in intakes of ethanol.
Opposite Effects of Ro 15‐4513 on Acquisition and Maintenance of Ethanol Drinking Behavior in Male Wistar Rats
Authors: Buczek Y. , Tomkins D. M. , Lê A. D. , Sellers E. M.
Published: May 2006

Acute treatment with Ro 15‐4513, a benzodiazepine receptor inverse agonist, has been consistently shown to suppress ethanol self administration behavior by rats. The aim of the present study was to examine the effect of Ro 15‐4513 on the acquisition and maintenance of ethanol drinking behavior in male Wistar rats. In rats maintained on a limited access procedure with a choice of 12% w/v ethanol solution and water, acute treatment with Ro 15‐4513 (0.1 to 3.0 mg/kg) suppressed ethanol intake in a selective and dose‐related manner (p < 0.01). However, by the fourth day of chronic Ro 15‐4513 treatment, ethanol intake had returned to baseline levels. In contrast, chronic administration of Ro 15‐4513 during the acquisition phase increased ethanol drinking behavior, compared with vehicle (p < 0.05). To assess whether the effects of Ro 15‐4513 on ethanol intake were due to an alteration in ethanol kinetics or on behavior, blood ethanol levels and rat social interaction behavior were also assessed. Neither acute nor chronic Ro 15‐4513 treatment significantly altered ethanol kinetics after oral administration of ethanol (1.0 g/kg), but did suppress locomotor activity and time spent engaged in active social interaction at the 1.0 and 3.0 mg/kg doses. These results show that Ro 15‐4513 has opposite effects on ethanol consumption during the acquisition and maintenance phases of ethanol drinking behavior, suggesting that different mechanisms regulate Ro 15‐4513's effects on acquisition and maintenance of ethanol intake. Ro 15‐4513's reported anxiogenic or memory enhancing properties may be responsible for its effects on acquisition.
I: The Effects of Recombinant Human Insulin‐Like Growth Factor‐1 on Nutritional Recovery in the Malnourished Alcoholic Rat
Authors: Mendenhall Charles L. , Roselle Gary A. , Grossman Charles J. , Gartside Peter
Published: May 2006

Background/aims: Alcoholics with severe liver disease (ALD) typically demonstrate the findings of protein calorie malnutrition. Such an occurrence might be anticipated with insulin‐like growth factor‐1 (IGF‐1) deficiency. Furthermore, serum levels of IGF‐1 are frequently very low in patients with alcoholic liver disease. The present study was undertaken to evaluate in an in vivo rat model of alcoholism and malnutrition, the possibility of a therapeutic application for IGF‐1. Methods: Controlled injury was induced by 14 days of calorie restriction and alcohol feeding (phase 1), which induced a 9% loss of body mass. Changes were compared with pair‐fed, calorie‐restricted controls that lost 7.8% of body mass and to unrestricted control rats that gained 28% above their pretreatment body mass during the same period. Recovery was evaluated after 28 days of treatment using various combinations of: (1) high calorie intake, (2) cessation from alcohol feeding, and (3) IGF‐1. Results: Liver injury was minimal, but protein calorie malnutrition was moderately severe after phase 1 treatments. During recovery (phase 2), continuous consumption of alcohol—even in the presence of high calories and IGF‐1 treatment—produced an incomplete nutritional recovery and, compared with normal rats, was associated with lower serum IGF‐1 levels. The group treated with all three modalities (high calories, IGF‐1, and abstinence from ethanol) had the most rapid and complete restoration of body weight Conclusions: Recovery of nutritional status in the malnourished rat correlates significantly with serum IGF‐1 levels. In the absence of ethanol and with sufficient caloric intake, IGF‐1 treatment increased serum IGF‐1 concentrations and accelerated nutritional recovery. Even with adequate calories, ethanol negated this recovery and was associated with lower serum IGF‐1 concentrations. Further studies, both basic and clinical, are needed to better understand the mechanisms involved and to establish whether in patients with severe Liver disease IGF‐1 treatment would produce an accelerated improvement in nutritional status and improve both morbity and mortality. These animal studies suggest that this is the case.
Transferrin Isoform Distribution: Gender and Alcohol Consumption
Authors: Mårtensson Ola , Härlin Annika , Brandt Ragnhild , Seppä Kaija , Sillanaukee Pekka
Published: May 2006

Transferrin (Tf) has different isoforms based on the degree of sialylation of its two N‐linked oligosaccharide chains. The least sialylated isoforms of Tf; with 0 (asialo Tf), 1 (monosialo Tf), and 2 (disialo Tf) sialic acids are referred to as carbohydrate‐deficient transferrin (COT). CDT has been reported to be a specific and sensitive marker for the detection and monitoring of alcohol abuse. However, the possible differences between the three CDT isoforms in males and females relative to alcohol consumption has not been known. The present study included 82 males (M) and 43 females (F) with well documented drinking habits. The Tf isoforms were separated by FPLC and measured by RIA in the collected fractions, as well as by a commercially available method (CDTect RIA). The results were expressed as relative values and absolute values. Female low consumers compared to male low consumers had higher levels of asialo Tf (p < 0.01) and monosialo Tf (p < 0.01), but not of disialo Tf or sum of asialo, monosialo, and disialo Tf. Male high consumers and chronic consumers compared to male low consumers had 53% and 219% higher levels of asialo Tf, 4% and 28% higher monosialo Tf, 57% and 148% higher disialo Tf, and 48% and 134% higher sum of CDT isoforms, respectively. The corresponding increases in females were for asialo Tf 68% and 249%, for monosialo Tf 36% and 58%, for disialo Tf 54% and 225%, and for sum of CDT isoforms 52% and 192%, respectively. For both genders, total Tf, trisialo Tf, and the levels of more sialylated transferrin isoforms were constant when comparing the consumption groups. Results expressed as relative values and absolute values were in good agreement In conclusion, the present study indicates that alcohol consumption strongly increases the levels of asialo Tf and disialo Tf and slightly increases the level of monosialo Tf. However, women had higher asialo Tf and monosialo Tf levels than men. Alcohol consumption does not increase trisialo or more sialyated Tf subfractions. Expressing the CDT results as absolute or relative values made no obvious difference in diagnostic efficiency.
Neurocircuitry Targets in Ethanol Reward and Dependence
Authors: Koob George F. , Roberts Amanda J. , Schulteis Gery , Parsons Loren H. , Heyser Charles J. , Hyytiä Petri , Merlo‐Pich Emilio , Weiss Friedbert
Published: May 2006

Alcoholism is a complex behavioral disorder characterized by excessive consumption of ethanol, a narrowing of the behavioral repertoire toward excessive consumption, the development of tolerance and dependence, and impairment in social and occupational functioning. Animal models of the complete syndrome of alcoholism are difficult if not impossible to achieve, but validated animal models exist for many of the different components of the syndrome. Recent work has begun to define the neurocircuits responsible for the two major sources of reinforcement key to animal models of excessive ethanol intake: positive and negative reinforcement. Ethanol appears to interact with ethanol‐sensitive elements within neuronal membranes that convey the specificity of neurochemical action. Ethanol reinforcement appears to be mediated by an activation of GABA‐A receptors, release of opioid peptides, release of dopamine, inhibition of glutamate receptors, and interaction with serotonin systems. These neurocircuits may be altered by chronic ethanol administration as reflected by opposite effects during acute ethanol withdrawal and by the recruitment of other neurotransmitter systems such as the stress neuropeptide corticotropin‐releasing factor. Future challenges will include a focus on understanding how these neuroadaptive changes convey vulnerability to relapse in animals with a history of ethanol dependence.
Cognitive Correlates of Single Neuron Activity in Task‐Performing Animals: Application to Ethanol Research
Authors: Givens Bennet , Williams Joseph , Gill T. Michael
Published: May 2006

The deleterious effects of ethanol on cognitive processes result from an interaction between ethanol and the neural structures that are critical for executing those cognitive functions. Results from studies that employ contemporary behavioral neuroscience techniques are beginning to elucidate the neural circuits that underlie specific cognitive processes, and the stage is set for rigorous investigations into the neural basis for ethanol‐induced cognitive impairments. In this article, the application of single neuron recording techniques to the study of the memory and attentional deficits produced by acute exposure to low levels of ethanol are described, with an emphasis on the advantages of combining physiological techniques with operant behavioral procedures in rats. After reviewing background information on the basic neurophysiological and behavioral techniques, empirical results from this laboratory will be used to illustrate how single‐unit analysis can be applied to the study of ethanol‐induced cognitive impairments.
Application of the Combined Single‐Cell Recording/Intracerebral Microdialysis Method to Alcohol Research in Freely Behaving Animals
Authors: Ludvig Nandor , Fox Steven E. , Kubie John L. , Altura Burton M. , Altura Bella T.
Published: May 2006

Intercellular communication in brain is coded in neuronal firing patterns, determined by the interplay of intra‐ and extracellular molecular systems. It is not clear how ethanol perturbs this molecular interplay in the motivational, emotional, and cognitive neural networks in brain to induce those specific, aberrant, cell‐firing patterns that lead to craving for alcohol, excessive alcohol consumption, and impaired cognition. However, resolution of this problem is essential to an understanding of the basic mechanisms of alcohol‐related disorders and to develop effective therapies for their treatment. It is difficult to obtain information on the molecular background of cell‐firing regulation in brain during behavioral events. We have recently developed a new in vivo method, combined single‐cell recording/ intracerebral microdialysis in freely behaving animals, which has the ability to extract such information from brain. The principal feature of the technique is that it records the firing of single neurons in discrete brain sites and deliver drugs, alone or in combinations, via microdialysis, into the extracellular environment of the recorded cells, while the experimental animal is behaving freely. Accordingly, the method allows the determination of drug actions on cellular firing within distinct neural circuits during normal and abnormal behaviors. Thus, it can provide insights into the physiological or pathophysiological molecular machinery of the examined cells. The present paper describes this method, demonstrates how administration of ethanol via intrahippocampal microdialysis affects the firing of hippocampal place cells, and discusses the potential of the technique in future alcohol research.
Effects of Monensin on Ethanol‐Induced Alterations in Function of Hepatocellular Asialoglycoprotein Receptor Subpopulations
Authors: Tworek Benita L , Wiegert Robert L , Tuma Dean J. , Casey Carol A.
Published: May 2006

Chronic ethanol consumption is associated with multiple impairments in receptor‐mediated endocytosis (RME) in hepatocytes. RME mediated by the asialoglycoprotein receptor seems to be especially impaired by ethanol. In the present study, we determined susceptibility of RME to alterations in ethanol‐fed and pair‐fed control animals by the addition of a carboxylic ionophore, monensin. Monensin inhibits acidification of prelysosomal vesicular compartments, which results in a decrease in the rate of receptor‐ligand dissociation within the cell. Low levels (25 μM) of monensin have been shown to preferentially affect receptor‐ligand dissociation of one subset (state 2) of asialoglycoprotein receptor, whereas dissociation in a second subset (state 1 receptors) seems to be relatively unaffected. We examined whether ethanol treatment preferentially affected one or another of these receptor subpopulations. Male Wistar rats were fed a standard ethanol‐containing (36% of calories) or control diet for 10 to 14 weeks, and hepatocytes were prepared from the animals. Similar to previous results from our laboratory, surface and total ligand and antibody binding were decreased by 30 to 45% (p < 0.01) in ethanol animals, compared with controls. An ethanol‐induced impairment of receptor‐ligand dissociation was also apparent in these cells, as shown by increased ratios of bound‐to‐free ligand during continuous endocytosis. After monensin treatment, surface receptors on both ethanol and control cells showed a similar pattern of redistribution to the cell interior and intracellular inactivation. When kinetics of intracellular receptor‐ligand dissociation were examined upon addition of monensin, the bound‐to‐free ligand ratios in both control and ethanol cells increased dramatically and to an equal extent. These results indicate that, in the ethanol animals, the pattern of sensitivity to monensin is unchanged relative to controls. Thus, the relative proportion of state 1 and state 2 receptor populations do not seem to be affected after long‐term feeding, and ethanol may be a perturbant that affects both state 1 and state 2 receptor function.
The Significance of Family History Status in Relation to Neuropsychological Test Performance and Cerebral Glucose Metabolism Studied with Positron Emission Tomography in Older Alcoholic Patients
Authors: Adams Kenneth M. , Gilman Sid , Johnson‐Greene Doug , Koeppe Robert A. , Junck Larry , Kluin Karen J. , Martorello Susan , Johnson Michael J. , Heumann Mary , Hill Elizabeth
Published: May 2006

Patients with severe chronic alcoholism have decreased rates of glucose metabolism in the medial frontal lobe and correlated abnormalities of neuropsychological functioning. The potential influence of family history of alcoholism has not been examined in these patients. In a retrospective study, we used neuropsychological tests and neuroimaging employing [18F]fluorodeoxyglucose with positron emission tomography to study 48 older subjects who had histories of severe, chronic alcohol dependence. These patients were divided into two groups: 27 with a first‐degree relative with chronic alcoholism and 21 patients without first‐degree relative with chronic alcoholism. No differences were found between groups on either neuropsychological or neuroimaging tests. These results suggest that a family history of alcoholism does not moderate the damaging effects of severe chronic alcoholism on the functioning of the medial frontal lobe.
Alcohol Consumption and Sexually Transmitted Disease Risk Behavior: Partner Mix among Male Korean University Students
Authors: Kim Joohyung , Celentano David D. , Crum Rosa M.
Published: May 2006

Background:This study examined alcohol consumption and sexually transmitted disease risk behavior as related to prostitute visits and sex partner mix among male Korean university students in 1993 to 1994.Methods:Questionnaires were completed by a representative sample of 1103 university students in Seoul. Lifetime sexually transmitted disease risk behavior was categorized as none, only one, and multiple sexual experiences with prostitutes, whereas risk according to partner mix was classified as no sexual experience with prostitutes, sexual experience with prostitutes only, and with both prostitutes and girlfriends. The proportional odds model was applied to the data.Results:A total of 25.8% of the university students had visited prostitutes–17.6% visited twice or more, and 12.9% had sexual experiences with both prostitutes and girlfriends. Heavier alcohol consumption was significantly related to multiple visits to prostitutes (odds ratio = 1.71) and to sexual experiences with both prostitutes and girlfriends (odds ratio = 2.30).Conclusions:In this first systematic study of the association between alcohol consumption and sexual experiences among Korean male university students, alcohol use was associated with risky sexual behaviors, and with first and most recent sexual experience with prostitutes, supporting our hypotheses.
Increased Circulating Products of Lipid Peroxidation in Patients with Alcoholic Liver Disease
Authors: Aleynik Semyon I. , Leo Maria Anna , Aleynik Maria K. , Lieber Charles S.
Published: May 2006

F2‐isoprostanes (F2‐IP) and 4‐hydroxynonenal (4‐HNE), peroxidation products of polyunsaturated fatty acids (PUFA), are considered the most reliable indicators of endogenous lipid peroxidation in vivo. To determine to what extent these are also altered in patients with alcoholic liver disease, plasma free and esterified F2‐IP as well as 4‐HNE were measured by GC/MS in 49 fasting subjects who underwent diagnostic percutaneous needle biopsies of the liver. Compared to patients with mild steatosis and no fibrosis, free F2‐IP and 4‐HNE were strikingly increased in individuals with alcoholic hepatitis. There was also a significant but lesser rise of 4‐HNE in patients with perivenular fibrosis. An increase of F2‐IP was also found in subjects with transition to, or complete, alcoholic cirrhosis, with a comparable trend for 4‐HNE. By contrast, in patients who were drinking heavily up to 48 hr before admission, F2‐IP were not abnormal, but they increased later (p < 0.005). Contrasting with plasma free F2‐IP, esterified F2‐IP were not significantly changed with fibrosis. Thus, whereas circulating esterified F2‐IP were unchanged in patients with alcoholic liver disease, there was an increase in free F2‐IP as well as 4‐HNE during recovery from intoxication. The increase was not a result of accompanying hepatitis C but a function of the stage of alcoholic liver injury, possibly reflecting enhanced lipid peroxidation as well as interference with biliary excretion and/or hepatic esterification.

Alcohol, Liver Disease, 4‐Hydroxynonenal, F2‐lsoprostanes, Lipid Peroxidation.