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Ethanol Levels (ethanol + level)
Selected AbstractsDifferential Dietary Ethanol Intake and Blood Ethanol Levels in Adolescent and Adult Rats: Effects on Anxiety-Like Behavior and Seizure ThresholdsALCOHOLISM, Issue 8 2008Tiffany A. Wills Background:, Adult rats exhibit increased anxiety-like behavior after exposure to repeated cycles of chronic ethanol and withdrawal. While adolescent rats have differential responses to both acute and chronic ethanol treatments, the potential differences in the effects of repeated withdrawals in this population have yet to be determined. Methods:, Male adult and adolescent rats received three 5-day cycles of either a 4.5% or 7% ethanol diet (ED) separated by two 2-day withdrawal periods. Five hours into the final withdrawal, rats were tested for social interaction (SI) deficits (an index of anxiety-like behavior) and then assessed for seizure thresholds (audiogenic and bicuculline-induced). Ethanol intake was monitored throughout, and blood ethanol concentrations (BEC) were obtained from a separate group of rats. Results:, Adolescent rats have reduced SI during the final withdrawal from either ED and exhibit a greater reduction in SI compared to adult rats when exposed to a 7%ED. Audiogenic seizures were not increased during withdrawal from either ED in adult rats, but adolescent rats that received 7%ED displayed increased seizures. The bicuculline seizure thresholds were decreased in both ages exposed to a 7%ED, but only adolescent rats showed this decreased threshold after 4.5%ED. Ethanol intakes and BECs were higher in adolescent rats compared to similarly treated adults. However, ethanol intakes and BECs were comparable between 4.5%ED-treated adolescent and 7%ED-treated adult rats. Conclusions:, Behavioral results from the 7%ED-treated groups suggested that adolescent rats may be more vulnerable to repeated withdrawals from ethanol than adults; however, differences in ethanol intake and BECs may be at least in part responsible. When ethanol intakes and BECs were similar between 4.5%ED-treated adolescent and 7%ED-treated adult rats, behavioral effects were not different. Importantly, these data illustrated that adolescent rats can exhibit anxiety and reduced seizure thresholds following this repeated withdrawal paradigm. [source] In Vivo Time-Course Changes in Ethanol Levels Sampled With Subcutaneous MicrodialysisALCOHOLISM, Issue 3 2008Eric A. Engleman Background:, The objective of this study was to determine time-course changes in in vivo ethanol (EtOH) concentrations using a novel subcutaneous (s.c.) microdialysis sampling technique. The hypothesis to be tested was that EtOH concentrations in the s.c. fluid would reflect blood EtOH concentrations. If this is the case, then s.c. microdialysis could allow a more detailed analysis of changes in in vivo levels of EtOH under different drinking paradigms. Methods:, Adult male and female Wistar rats and male alcohol-preferring (P) rats were used in this study. A loop-style microdialysis probe was designed for s.c. applications. After initial in vitro characterization, probes were implanted under the skin between the shoulder blades. Animals were allowed to recover 4 to 24 hours prior to microdialysis collection (2.0 ,l/min flow rate with isotonic saline). In vivo microdialysis experiments were then conducted to determine (i) the extraction fraction (or clearance) using EtOH no-net-flux (NNF) coupled with the alcohol clamp method, (ii) the dose,response and time-course effects after systemic EtOH administration and to compare with blood EtOH levels, and (iii) the time-course changes in EtOH levels during and after an EtOH drinking episode. Results:, In vivo probe recovery (extraction fraction) obtained using the alcohol clamp method was 69 ± 3%, and was comparable to the in vitro recovery of 73 ± 2%. For the EtOH dose,response experiment, rats injected i.p. with 0.5, 1.0, or 2.0 g/kg EtOH showed a clear dose,response effect in the s.c. dialysate samples. Peak concentrations (70, 123, and 203 mg%, respectively) were reached by 15 minutes after injection. In an experiment comparing levels of EtOH in s.c. dialysis and arterial blood samples in rats administered 1.0 g/kg EtOH, similar time-course changes in in vivo EtOH concentrations were observed with both i.g. and i.p. EtOH administration. In P rats drinking 15% EtOH during a 1-hour scheduled access period, EtOH levels in s.c. microdialysates rose rapidly over the session and peaked at approximately 50 mg% at 60 to 80 minutes. Conclusions:, Overall, these experiments indicate that s.c. EtOH and blood EtOH concentrations follow a similar time course. Moreover, s.c. microdialysis can be useful as an experimental approach for determining detailed time-course changes in in vivo EtOH concentrations associated with alcohol drinking episodes. [source] The Efficacy of Esmolol versus Lidocaine to Attenuate the Hemodynamic Response to Intubation in Isolated Head Trauma PatientsACADEMIC EMERGENCY MEDICINE, Issue 1 2001M. Andrew Levitt DO Abstract. Objective: To assess the effect of esmolol vs lidocaine to attenuate the detrimental rise in heart rate and blood pressure during intubation of patients with isolated head trauma. Methods: This was a prospective, double-blind, randomized study, performed at an urban, county teaching emergency department. Participants were 30 patients with isolated head trauma. Each underwent a standardized intubation protocol including esmolol or lidocaine, both at 2 mg/kg. Results: Esmolol was used in 16 patients and lidocaine in 14. Mechanisms of injury included 12 assaults, 6 motor vehicle collisions, 6 falls, 4 auto-vs-pedestrian crashes, and 2 bicycle incidents. Mean ethanol level was 0.116 ± 0.133 SD (range 0-0.482). Mean Glasgow Coma Scale (GCS) score was 7.9 ± 4.0 SD. Cranial computed tomography (CT) hemorrhagic findings included 9 subdural/epidural hematomas, 6 cortex hemorrhages, and 2 multi-hemorrhages. Eleven patients received surgical intervention: 9 patients received a craniotomy, and 2 a ventricular catheter. The 2-minute time interval around intubation was used to assess each drug's efficacy. The mean difference change between groups for heart rate was 4.0 beats/min (95% CI = -17.7 to 9.7 beats/min), for systolic blood pressure was 1.3 mm Hg (95% CI = -27.8 to 30.4 mm Hg), and for diastolic blood pressure was 2.6 mm Hg (95% CI = -27.1 to 21.9 mm Hg). The power of this study was 90% to detect a 20-beat/min difference in heart rate, a 35-mm Hg difference in systolic blood pressure, and a 20-mm Hg difference in diastolic blood pressure. Conclusions: Esmolol and lidocaine have similar efficacies to attenuate moderate hemodynamic response to intubation of patients with isolated head trauma. [source] Clinical Characteristics as Predictors of Recurrent Alcohol-related SeizuresACADEMIC EMERGENCY MEDICINE, Issue 8 2000Niels K. Rathlev MD Abstract. Objective: To determine whether clinical data available in the emergency department can accurately predict a subset of patients at low risk of developing recurrent seizures following one or more initial alcohol-related seizures in the out-of-hospital arena. Methods: This was a retrospective secondary analysis of data obtained from the placebo arms of two prospective, randomized trials of drug treatments for the prevention of recurrent alcohol-related seizures. Subjects with and without one or more recurrent alcohol-related seizures during the study period were compared according to the following characteristics: 1) age, 2) gender, 3) daily ethanol consumption, 4) years of ethanol abuse, 5) previous alcohol-related seizure, 6) previous seizure of other etiology, 7) temperature, 8) heart rate, 9) systolic blood pressure, 10) diastolic blood pressure, 11) respiratory rate, and 12) ethanol level. Data were analyzed with t-tests and chi-square where appropriate. Results: One hundred five placebo-treated patients were analyzed and 31 (30%) developed recurrent alcohol-related seizures. None of the listed characteristics were statistically different between the two groups except for the initial ethanol level. Subjects with an ethanol level higher than 100 mg/dL were less likely (0%) to develop recurrent seizures than patients with a level equal to or below 100 mg/dL (36%) (p < 0.01). Conclusions: An initial ethanol level higher than 100 mg/dL was significantly associated with a low risk for recurrent alcohol-related seizures during the observation period. No other low-risk clinical characteristics could be identified. [source] Effects of a Novel Cognition-Enhancing Agent on Fetal Ethanol-Induced Learning DeficitsALCOHOLISM, Issue 10 2010Daniel D. Savage Background:, Drinking during pregnancy has been associated with learning disabilities in affected offspring. At present, there are no clinically effective pharmacotherapeutic interventions for these learning deficits. Here, we examined the effects of ABT-239, a histamine H3 receptor antagonist, on fetal ethanol-induced fear conditioning and spatial memory deficits. Methods and Results:, Long-Evans rat dams stably consumed a mean of 2.82 g ethanol/kg during a 4-hour period each day during pregnancy. This voluntary drinking pattern produced a mean peak serum ethanol level of 84 mg/dl. Maternal weight gain, litter size and birth weights were not different between the ethanol-consuming and control groups. Female adult offspring from the control and fetal alcohol-exposed (FAE) groups received saline or 1 mg ABT-239/kg 30 minutes prior to fear conditioning training. Three days later, freezing time to the context was significantly reduced in saline-treated FAE rats compared to control. Freezing time in ABT-239-treated FAE rats was not different than that in controls. In the spatial navigation study, adult male offspring received a single injection of saline or ABT-239 30 minutes prior to 12 training trials on a fixed platform version of the Morris Water Task. All rats reached the same performance asymptote on Trials 9 to 12 on Day 1. However, 4 days later, first-trial retention of platform location was significantly worse in the saline-treated FAE rats compared control offspring. Retention by ABT-239-treated FAE rats was similar to that by controls. ABT-239's effect on spatial memory retention in FAE rats was dose dependent. Conclusions:, These results suggest that ABT-239 administered prior to training can improve retention of acquired information by FAE offspring on more challenging versions of hippocampal-sensitive learning tasks. Further, the differential effects of ABT-239 in FAE offspring compared to controls raises questions about the impact of fetal ethanol exposure on histaminergic neurotransmission in affected offspring. [source] Polymorphisms of Alcohol Dehydrogenase-1B and Aldehyde Dehydrogenase-2 and the Blood and Salivary Ethanol and Acetaldehyde Concentrations of Japanese Alcoholic MenALCOHOLISM, Issue 7 2010Akira Yokoyama Background:, The effects of genetic polymorphism of aldehyde dehydrogenase-2 (ALDH2) on alcohol metabolism are striking in nonalcoholics, and the effects of genetic polymorphism of alcohol dehydrogenase-1B (ADH1B) are modest at most, whereas genetic polymorphisms of both strongly affect the susceptibility to alcoholism and upper aerodigestive tract (UADT) cancer of drinkers. Methods:, We evaluated associations between ADH1B/ADH1C/ALDH2 genotypes and the blood and salivary ethanol and acetaldehyde levels of 168 Japanese alcoholic men who came to our hospital for the first time in the morning and had been drinking until the day before. Results:, The ethanol levels in their blood and saliva were similar, but the acetaldehyde levels in their saliva were much higher than in their blood, probably because of acetaldehyde production by oral bacteria. Blood and salivary ethanol and acetaldehyde levels were both significantly higher in the subjects with the less active ADH1B*1/*1 genotype than in the ADH1B*2 carriers, but none of the levels differed according to ALDH2 genotype. Significant linkage disequilibrium was detected between the ADH1B and ADH1C genotypes, but ADH1C genotype did not affect the blood or salivary ethanol or acetaldehyde levels. High blood acetaldehyde levels were found even in the active ALDH2*1/*1 alcoholics, which were comparable with the levels of the inactive heterozygous ALDH2*1/*2 alcoholics with less active ADH1B*1/*1. The slope of the increase in blood acetaldehyde level as the blood ethanol level increased was significantly steeper in alcoholics with inactive heterozygous ALDH2*1/*2 plus ADH1B*2 allele than with any other genotype combinations, but the slopes of the increase in salivary acetaldehyde level as the salivary ethanol level increased did not differ between the groups of subjects with any combinations of ALDH2 and ADH1B genotypes. Conclusions:, The ADH1B/ALDH2 genotype affected the blood and salivary ethanol and acetaldehyde levels of nonabstinent alcoholics in a different manner from nonalcoholics, and clear effects of ADH1B genotype and less clear effects of ALDH2 were observed in the alcoholics. Alterations in alcohol metabolism as a result of alcoholism may modify the gene effects, and these findings provide some clues in regard to associations between the genotypes and the risks of alcoholism and UADT cancer. [source] A New Mechanism for Ethanol Oxidation Mediated by Cytochrome P450 2E1: Bulk Polarity of the Active Site Makes a DifferenceCHEMBIOCHEM, Issue 3 2007Yong Wang Breaking the habit. A new mechanism, called reversed dual hydrogen abstraction (R-DHA), is presented for ethanol oxidation by cytochrome P450 2E1 (CYP2E1). It is shown that the competition of R-DHA with the consensus mechanism (gem -diol) is modulated by the ethanol population in the enzyme pocket. Thus, as a response to growing blood ethanol level, CYP2E1 adapts its ethanol metabolism by a mechanistic switch from gem -diol to R-DHA. [source] Bradycardia and sinus arrest during percutaneous ethanol injection therapy for hepatocellular carcinomaEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 3 2004A. Ferlitsch Abstract Background, Percutaneous ethanol injection (PEI) is an established method in the treatment of hepatocellular carcinoma (HCC) and considered a safe procedure, with severe complications occurring rarely. Cardiac arrhythmias have not been reported to date. Aim of the study was to investigate the occurrence of dysrhythmias during PEI. Patients and methods, Twenty-six consecutive patients with inoperable HCC were included. During ultrasound-guided PEI with 95% ethanol, electrocardiogram (ECG) monitoring was performed before starting and continuously during PEI. Results, During PEI a significant reduction in mean heart rate (> 20%) was seen in 15 of 26 (58%) patients. In 11 of 26 patients (42%) occurrence of sinuatrial block (SAB) or atrioventricular block (AVB) was observed after a median time of 9 s (range 4,50) from the start of PEI with a median length of 24 s (range 12,480). Clinical symptoms were seen in two patients, including episodes of unconsciousness, seizure-like symptoms in both and a respiratory arrest during PEI in one patient, requiring mechanical ventilation. In four of 12 patients with repeat interventions, dysrhythmias were reproducible during monthly performed procedures. There was a significant association between the occurrence of SAB or AVB and the amount of instilled alcohol (P = 0·03) and post-PEI serum ethanol levels (P = 0·03). Conclusions, Bradycardia and block formation occur frequently during PEI. These symptoms could be explained by a vasovagal reaction and/or the direct effect of ethanol on the sinus node or the right atrial conduction system. Ethanol dose is an important factor for the occurrence of SAB/AVB. ECG-monitoring seems mandatory during PEI. Prophylactic use of intravenously administered Atropine might be useful. [source] PRECLINICAL STUDY: Effects of concurrent access to multiple ethanol concentrations and repeated deprivations on alcohol intake of high-alcohol-drinking (HAD) ratsADDICTION BIOLOGY, Issue 2 2009Zachary A. Rodd ABSTRACT High-alcohol-drinking rats, given access to 10% ethanol, expressed an alcohol deprivation effect (ADE) only after multiple deprivations. In alcohol-preferring (P) rats, concurrent access to multiple ethanol concentrations combined with repeated cycles of EtOH access and deprivation produced excessive ethanol drinking. The current study was undertaken to examine the effects of repeated alcohol deprivations with concurrent access to multiple concentrations of ethanol on ethanol intake of HAD replicate lines of rats. HAD-1 and HAD-2 rats received access to 10, 20 and 30% (v/v) ethanol for 6 weeks. Rats from each replicate line were assigned to: (1) a non-deprived group; (2) a group initially deprived of ethanol for 2 weeks; or (3) a group initially deprived for 8 weeks. Following the restoration of the ethanol solutions, cycle of 2 weeks of ethanol exposure and 2 weeks of alcohol deprivation was repeated three times for a total of four deprivations. Following the initial ethanol deprivation period, deprived groups significantly increased ethanol intakes during the initial 24-hour re-exposure period. Multiple deprivations increased ethanol intakes, shifted preference to higher ethanol concentrations and prolonged the duration of the elevated ethanol intakes for up to 5 days. In addition, repeated deprivations increased ethanol intake in the first 2-hour re-exposure period as high as 5,7 g/kg (which are equivalent to amounts consumed in 24 hours by HAD rats), and produced blood ethanol levels in excess of 150 mg%. The results indicate that HAD rats exhibit ,loss-of-control' of alcohol drinking with repeated deprivations when multiple ethanol concentrations are available. [source] Alcohol-induced free radicals in mice: Direct toxicants or signaling molecules?HEPATOLOGY, Issue 5 2001Ming Yin Tumor necrosis factor , (TNF-,) and free radicals are produced in early alcohol-induced liver injury. Recently, pathology caused by alcohol was blocked nearly completely in tumor necrosis factor , receptor 1 (TNF-R1) knockout mice. With this model, it is now possible to evaluate whether free radicals are directly toxic or act as redox regulators of TNF-, production. Specifically, if free radicals were directly toxic, a parallel decrease in free radicals and pathology in TNF-R1 knockout mice would be predicted. If they only affect TNF-, production, radicals would be expected to remain high while pathology is diminished. Accordingly, free radical production in TNF-R1 knockout mice was studied here. The enteral alcohol delivery model used mice lacking TNF-R1 (p55) and wild-type control C57Bl/6J mice. Animals received a liquid diet continuously with either ethanol or isocaloric maltose-dextrin as control for 4 weeks. Urine ethanol levels fluctuated from 10 to 500 mg/dL in a cyclic pattern in mice receiving ethanol. Ethanol elevated liver:body weight ratios, serum alanine transaminase (ALT) levels, and pathology scores in wild-type mice. These parameters were blunted nearly completely in TNF-R1 knockout mice. Ethanol treatment increased free radical production in wild-type mice compared with animals fed a high-fat control diet. There were no differences in intensity of free radical signals regardless of the presence or absence of TNF-R1; however, pathology differed markedly between these groups. These findings are consistent with the hypothesis that free radicals act as redox signals for TNF-, production and do not directly damage cells in early alcohol-induced hepatic injury. [source] Direct and correlated responses to selection for larval ethanol tolerance in Drosophila melanogasterJOURNAL OF EVOLUTIONARY BIOLOGY, Issue 2 2001J. D. Fry Ethanol is an important larval resource and toxin for natural Drosophila melanogaster populations, and ethanol tolerance is genetically variable within and among populations. If ethanol-tolerant genotypes have relatively low fitness in the absence of ethanol, as suggested by the results of an earlier study, genetic variation for ethanol tolerance could be maintained by variation in ethanol levels among breeding sites. I selected for ethanol tolerance in large laboratory populations by maintaining flies on ethanol-supplemented media. After 90 generations, the populations were compared with control populations in egg-to-adult survival and development rate on ethanol-supplemented and unsupplemented food. When compared on ethanol-supplemented food, the ethanol-selected populations had higher survival and faster development than the control populations, but on unsupplemented food, the populations did not differ in either trait. These results give no evidence for a ,trade-off' between the ability to survive and develop rapidly in the presence of ethanol and the ability to do so in its absence. The effect of physiological induction of ethanol tolerance by exposing eggs to ethanol was also investigated; exposing eggs to ethanol strongly increased subsequent larval survival on ethanol-supplemented food, but did not affect survival on regular food, and slowed development on both ethanol-supplemented and regular food, partly by delaying egg hatch. [source] Ghrelin Receptor Antagonism Decreases Alcohol Consumption and Activation of Perioculomotor Urocortin-Containing NeuronsALCOHOLISM, Issue 9 2010Simranjit Kaur Background:, The current therapies for alcohol abuse disorders are not effective in all patients, and continued development of pharmacotherapies is needed. One approach that has generated recent interest is the antagonism of ghrelin receptors. Ghrelin is a gut-derived peptide important in energy homeostasis and regulation of hunger. Recent studies have implicated ghrelin in alcoholism, showing altered plasma ghrelin levels in alcoholic patients as well as reduced intakes of alcohol in ghrelin receptor knockout mice and in mice treated with ghrelin receptor antagonists. The aim of this study was to determine the neuroanatomical locus/loci of the effect of ghrelin receptor antagonism on alcohol consumption using the ghrelin receptor antagonist, D-Lys3-GHRP-6. Methods:, In Experiment 1, male C57BL/6J mice were injected with saline 3 hours into the dark cycle and allowed access to 15% (v/v) ethanol or water for 2 hours in a 2-bottle choice experiment. On test day, the mice were injected with either saline or 400 nmol of the ghrelin receptor antagonist, D-Lys3-GHRP-6, and allowed to drink 15% ethanol or water for 4 hours. The preference for alcohol and alcohol intake were determined. In Experiment 2, the same procedure was followed as in Experiment 1 but mice were only allowed access to a single bottle of 20% ethanol (v/v), and alcohol intake was determined. Blood ethanol levels were analyzed, and immunohistochemistry for c-Fos was carried out to investigate changes in neural activity. To further elucidate the mechanism by which D-Lys3-GHRP-6 affects alcohol intake, in Experiment 3, the effect of D-Lys3-GHRP-6 on the neural activation induced by intraperitoneal ethanol was investigated. For the c-Fos studies, brain regions containing ghrelin receptors were analyzed, i.e. the perioculomotor urocortin population of neurons (pIIIu), the ventral tegmental area (VTA), and the arcuate nucleus (Arc). In Experiment 4, to test if blood ethanol concentrations were affected by D-Lys3-GHRP-6, blood samples were taken at 2 time-points after D-Lys3-GHRP-6 pretreatment and systemic ethanol administration. Results:, In Experiment 1, D-Lys3-GHRP-6 reduced preference to alcohol and in a follow-up experiment (Experiment 2) also dramatically reduced alcohol intake when compared to saline-treated mice. The resulting blood ethanol concentrations were lower in mice treated with the ghrelin receptor antagonist. Immunohistochemistry for c-Fos showed fewer immunopositive cells in the pIIIu of the antagonist-treated mice but no difference was seen in the VTA or Arc. In Experiment 3, D-Lys3-GHRP-6 reduced the induction of c-Fos by intraperitoneal ethanol in the pIIIu but had no effect in the VTA. In the Arc, there was a significant increase in the number of c-Fos immunopositive cells after D-Lys3-GHRP-6 administration, but the antagonist had no effect on ethanol-induced expression of c-Fos. D-Lys3-GHRP-6-pretreatment also did not affect the blood ethanol concentrations observed after a systemic injection of ethanol when compared to saline-pretreated mice (Experiment 4). Conclusions:, These findings indicate that the action of ghrelin on the regulation of alcohol consumption may occur via the pIIIu. [source] Chronic Ethanol Disrupts Circadian Photic Entrainment and Daily Locomotor Activity in the MouseALCOHOLISM, Issue 7 2010Allison J. Brager Background:, Chronic ethanol abuse is associated with disrupted circadian rhythms and sleep. Ethanol administration impairs circadian clock phase-resetting, suggesting a mode for the disruptive effect of alcohol abuse on circadian timing. Here, we extend previous studies to explore the effects of chronic forced ethanol on photic phase-resetting, photic entrainment, and daily locomotor activity patterns in C57BL/6J mice. Methods:, First, microdialysis was used to characterize the circadian patterns of ethanol uptake in the suprachiasmatic (SCN) circadian clock and correlate this with systemic ethanol levels and episodic drinking of 10 or 15% ethanol. Second, the effects of chronic forced ethanol drinking and withdrawal on photic phase-delays of the circadian activity rhythm were assessed. Third, the effects of chronic ethanol drinking on entrainment to a weak photic zeitgeber (1 minute of 25 lux intensity light per day) were assessed. This method was used to minimize any masking actions of light that could mask ethanol effects on clock entrainment. Results:, Peak ethanol levels in the SCN and periphery occurred during the dark phase and coincided with the time when light normally induces phase-delays in mice. These delays were dose-dependently inhibited by chronic ethanol and its withdrawal. Chronic ethanol did not impede re-entrainment to a shifted light cycle but affected entrainment under the weak photic zeitgeber and disrupted the daily pattern of locomotor activity. Conclusions:, These results confirm that chronic ethanol consumption and withdrawal markedly impair circadian clock photic phase-resetting. Ethanol also disturbs the temporal structure of nighttime locomotor activity and photic entrainment. Collectively, these results suggest a direct action of ethanol on the SCN clock. [source] Differential Central NOS-NO Signaling Underlies Clonidine Exacerbation of Ethanol-Evoked Behavioral ImpairmentALCOHOLISM, Issue 3 2010Tara S. Bender Background:, The molecular mechanisms that underlie clonidine exacerbation of behavioral impairment caused by ethanol are not fully known. We tested the hypothesis that nitric oxide synthase (NOS)-derived nitric oxide (NO) signaling in the locus coeruleus (LC) is implicated in this phenomenon. Methods:, Male Sprague,Dawley rats with intracisternal (i.c.) and jugular vein cannulae implanted 6 days earlier were tested for drug-induced behavioral impairment. The latter was assessed as the duration of loss of righting reflex (LORR) and rotorod performance every 15 minutes until the rat recovered to the baseline walk criterion (180 seconds). In a separate cohort, we measured p-neuronal NOS (nNOS), p-endothelial NOS (eNOS), and p-ERK1/2 in the LC following drug treatment, vehicle, or NOS inhibitor. Results:, Rats that received clonidine [60 Ig/kg, i.v. (intravenous)] followed by ethanol (1 or 1.5 g/kg, i.v.) exhibited synergistic impairment of rotorod performance. Intracisternal pretreatment with nonselective NOS inhibitor N, -nitro- l -arginine methyl ester (l -NAME, 0.5 mg) or selective nNOS inhibitor N -propyl- l -arginine (1 ,g) exacerbated the impairment of rotorod performance caused by clonidine,ethanol combination. Exacerbation of behavioral impairment was caused by l -NAME enhancement of the effect of ethanol, not clonidine. l -NAME did not influence blood ethanol levels; thus, the interaction was pharmacodynamic. LORR caused by clonidine (60 ,g/kg, i.v.),ethanol (1 g/kg, i.v.) combination was abolished by selective inhibition of central eNOS (l -NIO, 10 ,g i.c.) but not by nNOS inhibition under the same conditions. Western blot analyses complemented the pharmacological evidence by demonstrating that clonidine,ethanol combination inhibits phosphorylation (activation) of nNOS (p-nNOS) and increases the level of phosphorylated eNOS (p-eNOS) in the LC; the change in p-nNOS was paralleled by similar change in LC p-ERK1/2. NOS inhibitors alone did not affect the level of nitrate/nitrite, p-nNOS, p-eNOS, or p-ERK1/2 in the LC. Conclusions:, Alterations in NOS-derived NO in the LC underlie clonidine,ethanol induced behavioral impairment. A decrease in nNOS activity, due at least partly to a reduction in nNOS phosphorylation, mediates rotorod impairment, while enhanced eNOS activity contributes to LORR, elicited by clonidine,ethanol combination. [source] Facilitation of Myocardial PI3K/Akt/nNOS Signaling Contributes to Ethanol-Evoked Hypotension in Female RatsALCOHOLISM, Issue 7 2009Mahmoud M. El-Mas Background:, The mechanism by which ethanol reduces cardiac output (CO) and blood pressure (BP) in female rats remains unclear. We tested the hypothesis that enhancement of myocardial phosphatidylinositol 3-kinase (PI3K)/Akt signaling and related neuronal nitric oxide synthase (nNOS) and/or endothelial nitric oxide synthase (eNOS) activity constitutes a cellular mechanism for the hemodynamic effects of ethanol. Methods:, We measured the level of phosphorylated eNOS (p-eNOS) and p-nNOS in the myocardium of ethanol (1 g/kg intragastric, i.g.) treated female rats along with hemodynamic responses [BP, CO, stroke volume, (SV), total peripheral resistance, (TPR)], and myocardial nitrate/nitrite levels (NOx) levels. Further, we investigated the effect of selective pharmacological inhibition of nNOS with N, -propyl- l -arginine (NPLA) or eNOS with N5 -(1-iminoethyl)- l -ornithine (l -NIO) on cellular, hemodynamic, and biochemical effects of ethanol. The effects of PI3K inhibition by wortmannin on the cardiovascular actions of ethanol and myocardial Akt phosphorylation were also investigated. Results:, The hemodynamic effects of ethanol (reductions in BP, CO, and SV) were associated with significant increases in myocardial NOx and myocardial p-nNOS and p-Akt expressions while myocardial p-eNOS remained unchanged. Prior nNOS inhibition by NPLA (2.5 or 12.5 ,g/kg) attenuated hemodynamic effects of ethanol and abrogated associated increases in myocardial NOx and cardiac p-nNOS contents. The hemodynamic effects of ethanol and increases in myocardial p-Akt phosphorylation were reduced by wortmannin (15 ,g/kg). On the other hand, although eNOS inhibition by l -NIO (4 or 20 mg/kg) in a dose-dependent manner attenuated ethanol-evoked hypotension, the concomitant reductions in CO and SV remained unaltered. Also, selective eNOS inhibition uncovered dramatic increases in TPR in response to ethanol, which appeared to have offset the reduction in CO. Neither NPLA nor l -NIO altered plasma ethanol levels. Conclusions:, These findings implicate the myocardial PI3K/Akt/nNOS signaling in the reductions in BP and CO produced by ethanol in female rats. [source] Chronic Intermittent Injections of High-Dose Ethanol During Adolescence Produce Metabolic, Hypnotic, and Cognitive Tolerance in RatsALCOHOLISM, Issue 10 2003Janelle M. Silvers Background: Many humans are first exposed to ethanol during adolescence, the time at which they are most likely to binge drink ethanol. Chronic intermittent ethanol (CIE) exposure produces ethanol tolerance in adolescent rodents. Recent studies suggested that adolescent animals administered CIE experienced increased cognitive impairment following an ethanol challenge. These studies further explore development of ethanol tolerance caused by CIE in adolescence, and whether CIE during adolescence leads to altered ethanol response in adulthood. Methods: Beginning postnatal day (P) 30, adolescent rats were administered 5.0 g/kg ethanol or saline every 48 hours for 20 days. In experiment I, animals were tested for differential weight gain. In experiment II, loss of righting reflex (LORR) was observed after each injection, then at completion of pretreatment all animals were tested with 5.0 g/kg ethanol and LORR was observed. In experiment III, blood ethanol levels were observed and elimination rates calculated after the first and fifth pretreatments. All animals were tested with 5.0 g/kg at completion of pretreatment and elimination rates were recalculated. In experiment IV, animals were trained on the spatial version of the Morris Water Maze Task (MWMT) on non-treatment days. Following completion of pretreatment and training, animals were tested after receiving an ethanol (1.0, 1.5, or 2.0 g/kg), or saline. Tests for experiments II, III, and IV were repeated in the same animals following 12 ethanol-free days. Results: Chronic intermittent ethanol exposure during adolescence caused differential weight gain (experiment I). Adolescent rats developed tolerance to ethanol-induced LORR (experiment II) and metabolic tolerance to ethanol (experiment III). This tolerance was seen after 12 ethanol-free days. CIE also attenuated ethanol-induced spatial memory deficits in the MWMT (experiment IV). This effect was not long-lasting. Conclusions: Following CIE pretreatment during adolescence, tolerance developed to the hypnotic and cognitive impairing effects of ethanol, along with increased metabolic rate and decreased weight gain. These results further emphasize the ability of CIE to produce a variety of effects during adolescence, some having long-lasting consequences. [source] Operant Self-Administration of Ethanol in Sardinian Alcohol-Preferring RatsALCOHOLISM, Issue 11 2002Giovanni Vacca Background "Work" for ethanol, that is, the ability of a laboratory animal to press a lever to gain access to ethanol, has been proposed as (a) a requirement for definition of an animal model of alcoholism and (b) a measure of ethanol-reinforcing properties. The present study evaluated oral self-administration of ethanol under an operant (lever pressing) procedure in selectively bred Sardinian alcohol-preferring (sP) and alcohol-nonpreferring (sNP) rats. Methods Rats from both lines were initiated to self-administer 10% ethanol, on a fixed ratio 1 schedule and in daily 30 min sessions, by using the Samson sucrose fading procedure. Subsequently, rats were exposed to increasing concentrations of ethanol up to 30% on a fixed ratio 4 schedule. Finally, the extinction responding for ethanol, defined as the maximal number of lever responses reached by each rat in the absence of ethanol reinforcement, was determined. Results The results indicated that sP rats acquired and maintained lever pressing for ethanol, self-administering mean amounts of ethanol in the range of 0.6 to 1.1 g/kg/session, which gave rise to mean blood ethanol levels in the 30 to 45 mg% range. Extinction responding for ethanol in sP rats averaged 73. In contrast, once sucrose was faded out, sNP rats displayed minimal levels of responding for ethanol, and extinction responding averaged 6. Conclusions The results of the present study extend to the sP/sNP rat lines the finding that ethanol can be established as a reinforcer in selectively bred alcohol-preferring rats, whereas it has modest, if any, reinforcing properties in alcohol-nonpreferring rats. [source] Different Sensitivity to Ethanol in Alcohol-Preferring sP and -Nonpreferring sNP RatsALCOHOLISM, Issue 11 2000Giancarlo Colombo Background and Objectives Clinical research has proposed that initial sensitivity to ethanol may be negatively correlated with levels of subsequent ethanol intake; consistently, alcohol-preferring P rats were found to be less sensitive to the ataxic and sedative/hypnotic effects of ethanol than -nonpreferring NP rats. The present study investigated the initial sensitivity to the ataxic and sedative/hypnotic effects of ethanol and to the sedative/hypnotic effects of pentobarbital and diazepam in selectively bred Sardinian alcohol-preferring sP and -nonpreferring sNP rats. Methods: In experiment 1, time to lose (onset) and regain (sleep time) the righting reflex after the acute intraperitoneal (ip) administration of 3.0 and 3.5 g/kg ethanol were measured in sP and sNP rats. In experiment 2, sP and sNP rats were required to perform a motor coordination task on a Rota-Rod after the acute intragastric administration of 2.0, 2.5, and 3.0 g/kg ethanol. Experiment 3 assessed onset and sleep time in sP and sNP rats after the acute injection of pentobarbital (40 mg/kg; ip) and diazepam (15 and 20 mg/kg; ip). Results: In experiment 1, sP rats took shorter times to lose the righting reflex and regained this reflex over longer periods of time and at lower blood ethanol levels than sNP rats. In experiment 2, ethanol affected motor coordination to a greater extent in sP than sNP rats. In contrast, results from experiment 3 showed that sP and sNP rats were not differentially sensitive to the sedative/hypnotic effects of pentobarbital and diazepam. Conclusions: The results of experiments 1 and 2 suggest that sP rats possess a genetically determined, greater sensitivity to the motor impairing and sedative/hypnotic effects of ethanol than sNP rats. Although caution should be adopted before hypothesizing any comparison to humans, these results may feature sP rats as an experimental model of those subsets of human alcoholics with initial high sensitivity to ethanol challenges. Finally, the results of experiment 3 suggest a minimal involvement of the benzodiazepine and barbiturate recognition sites in the differential sensitivity to ethanol of sP and sNP rats. [source] Genetic Control of Acute Ethanol-Induced Behaviors in DrosophilaALCOHOLISM, Issue 8 2000Carol M. Singh Background: In most organisms in which acute ethanol exposure has been studied, it leads to similar changes in behavior. Generally, low ethanol doses activate the central nervous system, whereas high doses are sedative. Sensitivity to the acute intoxicating effects of ethanol is in part under genetic control in rodents and humans, and reduced sensitivity in humans predicts the development of alcoholism (Crabbe et al., 1994; Schuckit, 1994). We have established Drosophila melanogaster as a model organism to study the mechanisms that regulate acute sensitivity to ethanol. Methods: We measured the effects of ethanol vapor on Drosophila locomotor behaviors by using three different assays. Horizontal locomotion was quantified in a locomotor chamber, turning behavior was assayed in narrow tubes, and ethanol-induced loss of postural control was measured in an inebriometer. Mutants with altered sensitivity to the acute effects of ethanol were generated by treatment with ethyl methane sulfonate and isolated by selection in the inebriometer. We ascertained the effects of these mutations on ethanol pharmacokinetics by measuring ethanol levels in extracts of flies at various times during and after ethanol exposure. Results: Among nearly 30,000 potentially mutant flies tested, we isolated 19 mutant strains with reduced and 4 strains with increased sensitivity to the acute effects of ethanol as measured in the inebriometer. Of these mutants, four showed changes in ethanol absorption. Two mutants, named barfly and tipsy to reflect their reduced and increased ethanol sensitivity in the inebriometer, respectively, were analyzed for locomotor behaviors. Both mutants exhibited ethanol-induced hyperactivity that was indistinguishable from wild type. However, barfly and tipsy displayed reduced and increased sensitivity to the sedative effects of ethanol, respectively. Finally, both mutants showed an increased rate of ethanol-induced turning behavior. Conclusions: The effects of acute ethanol exposure on Drosophila locomotor behaviors are remarkably similar to those described for mammals. The analysis of mutants with altered sensitivity to ethanol revealed that the genetic pathways which regulate these responses are complex and that single genes can affect hyperactivity, turning, and sedation independently. [source] | |||||||||||||