Acute Ethanol Administration Research Articles

PET imaging in rat brain shows opposite effects of acute and chronic alcohol exposure on phosphodiesterase-4B, an indirect biomarker of cAMP activity.

The cyclic adenosine monophosphate (cAMP) cascade is thought to play an important role in regulating alcohol-dependent behaviors, with potentially opposite effects following acute versus chronic administration. Phosphodiesterase 4 (PDE4) is the primary brain enzyme that metabolizes cAMP, thereby terminating its signal. Radioligand binding to PDE4 serves as an indirect biomarker of cAMP activity, as cAMP-protein kinase A (PKA)-mediated phosphorylation of PDE4 increases its affinity for radioligand binding ~10-fold. Of the four PDE4 subtypes, PDE4B polymorphisms are known to be strongly associated with alcohol and substance use disorders. This study imaged rats with the PDE4B-preferring positron emission tomography (PET) radioligand [18F]PF-06445974 following acute and chronic ethanol administration, aiming to explore the potential of PDE4B PET imaging for future human studies. Compared to the control group treated with saline, acute alcohol administration (i.p. ethanol 0.5 g/kg) significantly increased whole brain uptake of [18F]PF-06445974 as early as 30 minutes post-exposure. This effect persisted at 2 hours, peaked at 4 hours, and diminished at 6 hours and 24 hours post-exposure. In contrast, in a rat model of alcohol dependence, [18F]PF-06445974 brain uptake was significantly reduced at 5 hours post-exposure and was normalized by 3 days. This reduction may reflect long-term adaptation to repeated alcohol-induced activation of cAMP signaling with chronic exposure. Taken together, the results suggest that PET imaging of PDE4B in individuals with alcohol use disorder (AUD) should be considered in conjunction with ongoing trials of PDE4 inhibitors to treat alcohol withdrawal and reduce alcohol consumption.

Suppression of Microglial Activation by Acute Ethanol Administration through HT7 Stimulation

Suppression of Microglial Activation by Acute Ethanol Administration through HT7 Stimulation

Neutral sphingomyelinase controls acute and chronic alcohol effects on brain activity

Alcohol consumption is a widespread phenomenon throughout the world. However, how recreational alcohol use evolves into alcohol use disorder (AUD) remains poorly understood. The Smpd3 gene and its coded protein neutral sphingomyelinase (NSM) are associated with alcohol consumption in humans and alcohol-related behaviors in mice, suggesting a potential role in this transition.Using multiparametric magnetic resonance imaging, we characterized the role of NSM in acute and chronic effects of alcohol on brain anatomy and function in female mice.Chronic voluntary alcohol consumption (16 vol% for at least 6 days) affected brain anatomy in WT mice, reducing regional structure volume predominantly in cortical regions. Attenuated NSM activity prevented these anatomical changes. Functional MRI linked these anatomical adaptations to functional changes: Chronic alcohol consumption in mice significantly modulated resting state functional connectivity (RS FC) in response to an acute ethanol challenge (i.p. bolus of 2 g kg−1) in heterozygous NSM knockout (Fro), but not in WT mice. Acute ethanol administration in alcohol-naïve WT mice significantly decreased RS FC in cortical and brainstem regions, a key finding that was amplified in Fro mice. Regarding direct pharmacological effects, acute ethanol administration increased the regional cerebral blood volume (rCBV) in many brain areas. Here, chronic alcohol consumption otherwise attenuated the acute rCBV response in WT mice but enhanced it in Fro mice. Altogether, these findings suggest a differential role for NSM in acute and chronic functional brain responses to alcohol. Therefore, targeting NSM may be useful in the prevention or treatment of AUD.

Subregion and sex differences in ethanol activation of cholinergic and glutamatergic cells in the mesopontine tegmentum

Ethanol engages cholinergic signaling and elicits endogenous acetylcholine release. Acetylcholine input to the midbrain originates from the mesopontine tegmentum (MPT), which is composed of the laterodorsal tegmentum (LDT) and the pedunculopontine tegmental nucleus (PPN). We investigated the effect of acute and chronic ethanol administration on cholinergic and glutamatergic neuron activation in the PPN and LDT in male and female mice. We show that ethanol activates neurons of the PPN and not the LDT in male mice. Chronic 15 daily injections of 2 g/kg ethanol induced Fos expression in cholinergic and glutamatergic PPN neurons in male mice, whereas ethanol did not increase cholinergic and glutamatergic neuronal activation in the LDT. A single acute 4 g/kg injection, but not a single 2 g/kg injection, induced cholinergic neuron activation in the male PPN but not the LDT. In contrast, acute or chronic ethanol at either dose or duration had no effect on the activation of cholinergic or glutamatergic neurons in the MPT of female mice. Female mice had higher baseline level of activation in cholinergic neurons compared with males. We also found a population of co-labeled cholinergic and glutamatergic neurons in the PPN and LDT which were highly active in the saline- and ethanol-treated groups in both sexes. These findings illustrate the complex differential effects of ethanol across dose, time point, MPT subregion and sex.

Salvia officinalis flowers extract ameliorates liver and kidney injuries induced by simultaneous intoxication with ethanol/castor oil.

The current study investigated the possible mechanisms of aqueous extract Salvia officinalis flowers (SF-AE) and its protective effects against hepatorenal toxicities produced by simultaneous acute administration of ethanol (EtOH)/castor oil (CO). Healthy male rats (N = 50) were separated into five equal groups: control, Ethanol (EtOH) + Castor oil (CO), doses of increasing orders of SF-AE (50, 100, and 200 mg/kg, b.w., p.o.) during 15 days. Liver and kidney injuries were induced by EtOH (4 g/kg, b.w., p.o.) combined with CO (5 mL/kg, b.w., p.o.). Compared to the control group, SF-AE pretreatment protected against simultaneous administration of EtOH and CO-caused serious histological alterations in liver and kidney tissues. SF-AE also reversed liver and kidney biochemical parameters and lipid profile alterations. More importantly, SF-AE significantly reduced the malondialdehyde (MDA) level and counteracted the depletion of both enzymatic and non-enzymatic antioxidants. SF-AE also prevents against inflammation induced by EtOH combined with CO, expressed by the rise of inflammation biomarkers (C-reactive protein: CRP and alkaline phosphatase: ALP). Additionally, combined EtOH intoxication and CO poisoning exerted an increase in H2 O2 , free iron and calcium levels. Impressively, SF-AE treatment regulated levels of these studied intracellular mediators in a dose-dependent manner. In conclusion, SF-AE can potentially improve liver and kidney injuries associated with biochemical parameter deregulations, possibly by controlling oxidative stress and inflammation.

Combination of Cysteine and Glutathione Prevents Ethanol-Induced Hangover and Liver Damage by Modulation of Nrf2 Signaling in HepG2 Cells and Mice.

Excessive alcohol consumption increases oxidative stress, leading to alcoholic liver disease. In this study, the protective effects of a mixture of cysteine and glutathione against ethanol-induced hangover and liver damage were evaluated in mice and HepG2 cells. Ethanol (2 mL/kg) was orally administered to the mice 30 min before receiving the test compounds (200 mg/kg), and the behavioral and oxidative stress-related biochemical parameters altered by ethanol were analyzed. Acute ethanol administration increased anxiety behavior and decreased balance coordination in mice (p < 0.001); however, a mixture of cysteine and glutathione (MIX) in a 3:1 ratio improved alcohol-induced behavior more effectively than the individual compounds (p < 0.001). The MIX group showed higher ethanol-metabolizing enzyme activity than the control group (p < 0.001) and significantly suppressed the elevation of serum alcohol (p < 0.01) and acetaldehyde (p < 0.001) levels after 1 h of ethanol administration. In HepG2 cells, 2.5 mM MIX accelerated ethanol metabolism and reduced cytochrome P450 2E1 mRNA expression (p < 0.001). MIX also increased the expression of antioxidant enzymes through the upregulation of nuclear erythroid 2-related factor 2 (Nrf2) signaling and consequently suppressed the overproduction of reactive oxygen species and malondialdehyde (p < 0.001). Collectively, MIX alleviates the hangover symptoms and attenuates the alcohol-induced oxidative stress by regulating the Nrf2 pathway.

Changes in serotonin neurotransmission as assayed by microdialysis after acute, intermittent or chronic ethanol administration and withdrawal.

The serotonergic neurotransmitter system is involved in many ethanol-induced changes, including many behavioural alterations, as well as contributing to alcohol dependence and its withdrawal. This review has evaluated microdialysis studies where alterations in the serotonin system, that is, serotonin, 5-HT, or its metabolite 5-hydroxyindoleacetic acid, 5-HIAA, have been reported during different ethanol intoxication states, as well as in animals showing alcohol preference or not. Changes in 5-HT receptors and the 5-HT transporter are briefly reviewed to comprehend the significance of changes in microdialysate 5-HT concentrations. Changes in 5-HT content following acute, chronic and during ethanol withdrawal states are evaluated. In addition, the serotoninergic system was assessed in animals that have been genetically selected for alcohol preference to ascertain whether changes in this monoamine microdialysate content may contribute to alcohol preference. Changes occurred in 5-HT signalling in the limbic brain regions, increasing after acute ethanol administration in specific brain regions, particularly at higher doses, while chronic alcohol exposure essentially decreased serotonergic transmission. Such changes may play a pivotal role in emotion-driven craving and relapse. Depending on the dosage, mode of administration and consumption rate, ethanol affects specific brain regions in different ways, enhancing or reducing 5-HT microdialysate content, thereby inducing behavioural and cognitive functions and enhancing ethanol consumption. Microdialysis studies demonstrated that ethanol induces several alterations in 5-HT content as well as its metabolites, 5-HIAA and 5-HTOL, not only in its release from a specific brain region but also in the modifications of its different receptor subtypes and its transporter.

Features of hemodynamic parameters during chronic and acute episodic introduction of ethanol to animals in model experiments

Diseases of the cardiovascular system continue to occupy the first place in the world among all causes of death in the population. One of the leading medical and social factors in the growth of the number of cardiovascular pathologies is alcohol consumption.The purpose of this work: to study the effect of chronic and acute episodic administration of ethanol on the features of hemodynamic parameters in rats.Materials and methods. The study was carried out on non-linear mature male rats. The group that underwent acute administration of ethanol every five days (days 1,6, 11, 16, 21) was intraperitoneally injected with a 20 % ethanol solution (5 g/kg).The group subjected to chronic alcoholization was offered 10 % ethanol solution as the only source of liquid for 21 days. Every five days in both groups, hemodynamic parameters such as systolic (SBP) and diastolic (DBP) blood pressure, heart rate (HR) were recorded.Results. With acute use of ethanol, already 30 minutes after administration, changes in hemodynamic parameters were found in the form of a decrease in SBP and DBP by an average of 43 %.60 minutes after the administration of ethanol, there was an increase in SBP and DBP by an average of 11 % relative to the initial data, which at the initial stage of alcohol consumption may be associated with a compensatory reaction of the cardiosystem in response to alcohol poisoning. Under conditions of chronic ethanol use, there was a decrease in the level of SBP, DBP and heart rate by an average of 16 % on the first day of the study, followed by their recovery to the initial values on the 21 st day of the study, which may be a sign of the development of a compensatory reaction of the body and indicate the beginning of the formation of alcoholic dependencies.Conclusions. Acute and chronic administration of ethanol has a significant, but at the same time multidirectional effect on hemodynamic parameters, which can serve as a trigger for the development of various cardiopathologies.

The role of C1473G polymorphism in triptophanhydroxylase-2 gene in the acute ethanol effects on &lt;i&gt;c-fos&lt;/i&gt; gene expression and metabolism of biogenic amines in brain of mice

Tryptophan hydroxylase-2 is a key enzyme in the synthesis of the neurotransmitter serotonin, which plays an important role in the mechanisms of regulation of a wide range of physiological functions and behaviors. In this work, we studied the effect of acute ethanol administration on the expression of the c-fos early response gene and the metabolism of serotonin and catecholamines in the brain structures of B6-1473C and B6-1473G congenic mice, which differ in the C1473G single-nucleotide substitution in the Tph2 gene and enzyme activity. Acute alcoholization led to a significant increase in c-fos gene expression in the frontal cortex and striatum of B6-1473G mice and the hippocampus of B6-1473C mice. The introduction of ethanol caused a decrease in the index of serotonin metabolism in the nucleus accumbens in B6-1473C mice, as well as in the hippocampus and striatum of B6-1473G mice. Also, ethanol led to a decrease in the level of norepinephrine in the hypothalamus in B6-1473C mice. Thus, the C1473G polymorphism in the Tph2 gene has a significant effect on changes in the c-fos gene expression pattern and metabolism of biogenic amines in the brain induced by acute ethanol administration.

The Role of C1473G Polymorphism in Mouse Triptophan Hydroxylase 2 Gene in the Acute Effects of Ethanol on the c-fos Gene Expression and Metabolism of Biogenic Amines in the Brain

Tryptophan hydroxylase 2 is a key enzyme in the synthesis of the neurotransmitter serotonin, which plays an important role in the regulation of behavior and various physiological functions. We studied the effect of acute ethanol administration on the expression of the early response c-fos gene and metabolism of serotonin and catecholamines in the brain structures of B6-1473C and B6-1473G congenic mouse strains differing in the single-nucleotide substitution C1473G in the Tph2 gene and activity of the encoded enzyme. Acute alcoholization led to a significant upregulation of the c-fos gene expression in the frontal cortex and striatum of B6-1473G mice and in the hippocampus of B6-1473C mice and caused a decrease in the index of serotonin metabolism in the nucleus accumbens in B6-1473C mice and in the hippocampus and striatum of B6-1473G mice, as well as to the decrease in the norepinephrine level in the hypothalamus of B6-1473C mice. Therefore, the C1473G polymorphism in the Tph2 gene has a significant effect of acute ethanol administration on the c-fos expression pattern and metabolism of biogenic amines in the mouse brain.

Stability of Analyticity and Holism Indicators During Acute Ethanol Administration

The results of the study of assessing the contribution of the acute alcohol administration factor to the indicators of analyticity–holism on the AHS scale are presented. The study was conducted on a sample of the Russian-speaking culture subjects (N = 59). Analyticity–holism is considered as an indicator reflecting the mentality type. Given that there is data on selective suppression of the neuronal activity of the most differentiated systems by ethanol in animals and humans, the alcohol administration factor is considered by us as a temporary dedifferentiation of the individual experience actualized in behavior. As a result, it was shown that there were no significant changes in the indicators of analyticity–holism during acute alcohol administration. Also, correlation analysis showed that the distribution of individuals on analyticity–holism is reproduced under experimental conditions compared to control ones. The conclusion is made that analyticity and holism are basic psychological characteristics related to an individual&amp;apos;s experience as a whole, rather than its individual components.

Receptor protein tyrosine phosphatase β/ζ regulates loss of neurogenesis in the mouse hippocampus following adolescent acute ethanol exposure

Adolescence is a critical period for brain maturation in which this organ is more vulnerable to the damaging effects of ethanol. Administration of ethanol in mice induces a rapid cerebral upregulation of pleiotrophin (PTN), a cytokine that regulates the neuroinflammatory processes induced by different insults and the behavioral effects of ethanol. PTN binds Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ and inhibits its phosphatase activity, suggesting that RPTPβ/ζ may be involved in the regulation of ethanol effects. To test this hypothesis, we have treated adolescent mice with the RPTPβ/ζ inhibitor MY10 (60 mg/kg) before an acute ethanol (6 g/kg) administration. Treatment with MY10 completely prevented the ethanol-induced neurogenic loss in the hippocampus of both male and female mice. In flow cytometry studies, ethanol tended to increase the number of NeuN+/activated Caspase-3+ cells particularly in female mice, but no significant effects were found. Ethanol increased Iba1+ cell area and the total marked area in the hippocampus of female mice, suggesting sex differences in ethanol-induced microgliosis. In addition, ethanol reduced the circulating levels of IL-6 and IL-10 in both sexes, although this reduction was only found significant in males and not affected by MY10 treatment. Interestingly, MY10 alone increased the total marked area and the number of Iba1+ cells only in the female hippocampus, but tended to reduce the circulating levels of TNF-α only in male mice. In summary, the data identify a novel modulatory role of RPTPβ/ζ on ethanol-induced loss of hippocampal neurogenesis, which seems unrelated to glial and inflammatory responses. The data also suggest sex differences in RPTPβ/ζ function that may be relevant to immune responses and ethanol-induced microglial responses.

Acute Administration of Ethanol and of a D1-Receptor Antagonist Affects the Behavior and Neurochemistry of Adult Zebrafish.

Alcohol abuse represents major societal problems, an unmet medical need resulting from our incomplete understanding of the mechanisms underlying alcohol's actions in the brain. To uncover these mechanisms, animal models have been proposed. Here, we explore the effects of acute alcohol administration in zebrafish, a promising animal model in alcohol research. One mechanism via which alcohol may influence behavior is the dopaminergic neurotransmitter system. As a proof-of-concept analysis, we study how D1 dopamine-receptor antagonism may alter the effects of acute alcohol on the behavior of adult zebrafish and on whole brain levels of neurochemicals. We conduct these analyses using a quasi-inbred strain, AB, and a genetically heterogeneous population SFWT. Our results uncover significant alcohol x D1-R antagonist interaction and main effects of these factors in shoaling, but only additive effects of these factors in measures of exploratory behavior. We also find interacting and main effects of alcohol and the D1-R antagonist on dopamine and DOPAC levels, but only alcohol effects on serotonin. We also uncover several strain dependent effects. These results demonstrate that acute alcohol may act through dopaminergic mechanisms for some but not all behavioral phenotypes, a novel discovery, and also suggest that strain differences may, in the future, help us identify molecular mechanisms underlying acute alcohol effects.

Protective effect of Eucommia ulmoides Oliver male flowers on ethanol-induced DNA damage in mouse cerebellum and cerebral cortex.

Ethanol is a principal ingredient of alcoholic beverages with potential neurotoxicity and genotoxicity, and the ethanol‐associated oxidative DNA damage in the central nervous system is well documented. Natural product may offer new options to protect the brain against ethanol‐induced neurotoxicity. The male flower of Eucommia ulmoides (EUF) Oliver has been extensively utilized as the tea, the healthy hot drink on the market. In this study, 19 constituents in the effective fraction of EUF were identified by ultra‐performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS). In the single‐cell gel electrophoresis assay, EUF was observed to ameliorate DNA damage in mouse cerebellum and cerebral cortex caused by acute ethanol administration, which was further confirmed by the morphological observation. The protective effects of EUF were associated with increasing total superoxide dismutase (T‐SOD) and glutathione peroxidase (GSH‐PX) activities, and a decrease in nitric oxide (NO), malondialdehyde (MDA), 8‐hydroxy‐2′‐deoxyguanosine (8‐OHdG), and kelch‐like ECH‐associated protein‐1 (Keap1) levels. Molecular docking results demonstrated that compounds 4, 7, 9, and 16 from EUF have a strong affinity to the Keap1 Kelch domain to hinder the interaction of nuclear factor‐erythroid 2‐related factor 2 (Nrf2) with Keap1. These findings suggest that EUF is a potent inhibitor of ethanol‐induced brain injury possibly via the inhibition of oxidative stress.

Mitochondrial depolarization after acute ethanol treatment drives mitophagy in living mice

ABSTRACT Ethanol increases hepatic mitophagy driven by unknown mechanisms. Type 1 mitophagy sequesters polarized mitochondria for nutrient recovery and cytoplasmic remodeling. In Type 2, mitochondrial depolarization (mtDepo) initiates mitophagy to remove the damaged organelles. Previously, we showed that acute ethanol administration produces reversible hepatic mtDepo. Here, we tested the hypothesis that ethanol-induced mtDepo initiates Type 2 mitophagy. GFP-LC3 transgenic mice were gavaged with ethanol (2–6 g/kg) with and without pre-treatment with agents that decrease or increase mtDepo–Alda-1, tacrolimus, or disulfiram. Without ethanol, virtually all hepatocytes contained polarized mitochondria with infrequent autophagic GFP-LC3 puncta visualized by intravital microscopy. At ~4 h after ethanol treatment, mtDepo occurred in an all-or-none fashion within individual hepatocytes, which increased dose dependently. GFP-LC3 puncta increased in parallel, predominantly in hepatocytes with mtDepo. Mitochondrial PINK1 and PRKN/parkin also increased. After covalent labeling of mitochondria with MitoTracker Red (MTR), GFP-LC3 puncta encircled MTR-labeled mitochondria after ethanol treatment, directly demonstrating mitophagy. GFP-LC3 puncta did not associate with fat droplets visualized with BODIPY558/568, indicating that increased autophagy was not due to lipophagy. Before ethanol administration, rhodamine-dextran (RhDex)-labeled lysosomes showed little association with GFP-LC3. After ethanol treatment, TFEB (transcription factor EB) translocated to nuclei, and lysosomal mass increased. Many GFP-LC3 puncta merged with RhDex-labeled lysosomes, showing autophagosomal processing into lysosomes. After ethanol treatment, disulfiram increased, whereas Alda-1 and tacrolimus decreased mtDepo, and mitophagy changed proportionately. In conclusion, mtDepo after acute ethanol treatment induces mitophagic sequestration and subsequent lysosomal processing. Abbreviations : AcAld, acetaldehyde; ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase; ALD, alcoholic liver disease; Alda-1, N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GFP, green fluorescent protein; LAMP1, lysosomal-associated membrane protein 1; LMNB1, lamin B1; MAA, malondialdehyde-acetaldehyde adducts; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; MPT, mitochondrial permeability transition; mtDAMPS, mitochondrial damage-associated molecular patterns; mtDepo, mitochondrial depolarization; mtDNA, mitochondrial DNA; MTR, MitoTracker Red; PI, propidium iodide; PINK1, PTEN induced putative kinase 1; PRKN, parkin; RhDex, rhodamine dextran; TFEB, transcription factor EB; Tg, transgenic; TMRM, tetramethylrhodamine methylester; TOMM20, translocase of outer mitochondrial membrane 20; VDAC, voltage-dependent anion channel

Role of Acetaldehyde in Ethanol Reversal of Tolerance to Morphine-Induced Respiratory Depression in Mice.

BackgroundOpioid users regularly consume other drugs such as alcohol (ethanol). Acute administration of ethanol rapidly reverses tolerance to morphine-induced respiratory depression. However, recent research has suggested that the primary metabolite of ethanol, acetaldehyde, may play a key role in mediating the CNS effects seen after ethanol consumption. This research investigated the role of acetaldehyde in ethanol reversal of tolerance to morphine-induced respiratory depression.MethodsTolerance was induced in mice by 6-days implantation of a 75 mg morphine pellet with control mice implanted with a placebo pellet. Tolerance was assessed by acute morphine administration on day 6 and respiration measured by plethysmography. Levels of acetaldehyde were inhibited or enhanced by pre-treatments with the acetaldehyde chelator D-penicillamine and the inhibitor of acetaldehyde dehydrogenase disulfiram respectively.ResultsMorphine pellet implanted mice displayed tolerance to an acute dose of morphine compared to placebo pellet implanted controls. Acute acetaldehyde administration dose-dependently reversed tolerance to morphine respiratory depression. As previously demonstrated, ethanol reversed morphine tolerance, and this was inhibited by D-penicillamine pre-treatment. An acute, low dose of ethanol that did not significantly reverse morphine tolerance was able to do so following disulfiram pre-treatment.ConclusionThese data suggest that acetaldehyde, the primary metabolite of ethanol, is responsible for the reversal of morphine tolerance observed following ethanol administration.

Acute and chronic ethanol administration: A potential model of behavioral sensitization using wheel-running in male CD1 mice

RationaleWe define behavioral sensitization as an augmented response to subsequent dosing after chronic intermittent administration of a drug. However, the biphasic effects of ethanol (EtOH), first stimulatory followed by depressive, make animal models of behavioral sensitization rare. ObjectivesThis study aimed to determine a dose of EtOH that did not depress wheel-running (WR) in CD1 mice and then to develop a model of EtOH-induced behavioral sensitization. MethodsFor the first part of this study, male CD1 mice (n = 24, 6/group) were administered either phosphate buffer saline (PBS), 0.5 g/kg, 1 g/kg, or 2 g/kg EtOH at a volume of 3 ml/kg, intraperitoneally (IP). Mice were divided into equal groups and received the weight-based dose once daily on Days 1, 2, 3, 4, and 5. All mice received a challenge dose of 0.5 g/kg on Day 10. In both parts of the study, mice were habituated to the running wheel for 5 min prior to dosing and wheel running was measured for 10 min after each dose. ResultsThe acute dose-response of EtOH effects on wheel running determined a significant difference between doses in wheel running (p < 0.05), with a post-hoc analysis establishing that 0.5 g/kg EtOH resulted in significantly more WR compared to 2 g/kg EtOH (p < 0.05). The chronic study demonstrated a significant main effect of Day (1 vs. 5 vs. Challenge, p < 0.001) and an interaction between Day and Treatment, with post-hoc analysis determining the effect to be between PBS and EtOH WR on Day 5 (p < 0.05). In addition, Bonferroni post-hoc analysis determined no differences between Days in the PBS condition, but a significant difference in the EtOH condition between Day 1 and Day 5 (p < 0.001) and that difference from Day 1 persisted when comparing to the Challenge Day (p < 0.01). ConclusionAfter chronic, intermittent, low dose administration of EtOH, male mice showed an increase in activity as measured by wheel running. Therefore, we laid the groundwork for a potentially useful rodent model for EtOH-induced behavioral sensitization.

Ethanol enhanced MDPV- and cocaine-induced aggressive behavior in mice: Forensic implications

BackgroundReports concerning the causal link between aggressive behavior and use and abuse of different substances (i.e., alcohol, MDPV) can be found in the literature. Nonetheless, the topic concerning the effects of acute ethanol administration on MDPV and cocaine induced aggressive behavior has yet to be thoroughly investigated. The aim of this study was to investigate such synergistic effects. Materials and methodsA total of 360 male mice were employed in the study. Ethanol was diluted with saline solution and administered 10 min before MDPV or cocaine injection via oral gavage needles. Similarly, MDPV and cocaine were dissolved in saline solution and administered by intraperitoneal injection. Different associations of specific drug doses were then tested. To investigate the acute effects of MDPV and cocaine and their interaction with ethanol on aggression in mice, a resident–intruder test was used. ResultsEthanol alone was ineffective at dosages of 0.05 g/kg and 0.25 g/kg but increased the aggressiveness of the mice at 0.125 g/kg. Similarly, the injection of both cocaine alone and MDPV alone did not significantly increase the aggressiveness of the mice; conversely, the combination of ethanol and cocaine and ethanol and MDPV enhanced aggression at specific ethanol dosages (0.05 g/kg and 0.125 g/kg). ConclusionThis study demonstrated that acute ethanol administration enhances MDPV- and cocaine-induced aggressive behavior in mice. This aggressive response is particularly enhanced when MDVP and cocaine are coupled with specific ethanol dosages, proving that psychostimulant drugs may act synergistically under certain conditions.

Changes in Brain Dopamine Extracellular Concentration after Ethanol Administration; Rat Microdialysis Studies.

The purpose of this review is to evaluate microdialysis studies where alterations in the dopaminergic system have been evaluated after different intoxication states, in animals showing preference or not for alcohol, as well as during alcohol withdrawal. Ethanol administration induces varying alterations in dopamine microdialysate concentrations, thereby modulating the functional output of the dopaminergic system. Administration of low doses of ethanol, intraperitoneally, intravenously, orally or directly into the nucleus accumbens, NAc, increases mesolimbic dopamine, transmission, as shown by increases in dopamine content. Chronic alcohol administration to rats, which show alcohol-dependent behaviour, induced little change in basal dopamine microdialysis content. In contrast, reduced basal dopamine content occurred after ethanol withdrawal, which might be the stimulus to induce alcohol cravings and consumption. Intermittent alcohol consumption did not identify any consistent changes in dopamine transmission. Animals which have been selectively or genetically bred for alcohol preference did not show consistent changes in basal dopamine content although, exhibited a significant ethanol-evoked dopamine response by comparison to non-preference animals. Microdialysis has provided valuable information about ethanol-evoked dopamine release in the different animal models of alcohol abuse. Acute ethanol administration increases dopamine transmission in the rat NAc whereas chronic ethanol consumption shows variable results which might reflect whether the rat is prior to or experiencing ethanol withdrawal. Ethanol withdrawal significantly decreases the extracellular dopamine content. Such changes in dopamine surges will contribute to both drug dependence, e.g. susceptibility to drug withdrawal, and addiction, by compromising the ability to react to normal dopamine fluctuations.

Lactococcus lactis Administration Modulates IgE and IL-4 Production and Promotes Enterobacteria Growth in the Gut from Ethanol-Intake Mice.

It is well known that alcohol can trigger inflammatory effects in the gastrointestinal tract (GIT), interfering with mucosal homeostasis. This study evaluated the effectiveness of Lactococcus lactis treatment in controlling the increase in molecular biomarkers related to allergic inflammation and the effect on the diversity and abundance of the Enterobacteriaceae family in the GIT after high-dose acute administration of ethanol. Mice received ethanol or saline solution by gavage for four consecutive days, and 24 h after the last administration, the animals were given L. lactis or M17 broth orally ad libitum for two consecutive days. The animals were subsequently sacrificed and dissected. L. lactis treatment was able to restore basal levels of secretory immunoglobulin A in the gastric mucosa, serum total immunoglobulin E, interleukin (IL)-4 production in gastric and intestinal tissues, and IL-10 levels in gastric tissue. L. lactis treatment encouraged the diversification of the Enterobacteriaceae population, particularly the commensal species, in the GIT. This research opens a field of studies regarding the modulatory effect of L. lactis on immunological and microbial changes induced after alcohol intake.