Product Of Ethanol Metabolism Research Articles

Polyphenols from persimmon fruit attenuate acetaldehyde-induced DNA double-strand breaks by scavenging acetaldehyde

Acetaldehyde, a metabolic product of ethanol, induces DNA damage and genome instability. Accumulation of acetaldehyde due to alcohol consumption or aldehyde dehydrogenase (ALDH2) deficiency increases the risks of various types of cancers, including esophageal cancer. Although acetaldehyde chemically induces DNA adducts, the repair process of the lesions remains unclear. To investigate the mechanism of repair of acetaldehyde-induced DNA damage, we determined the repair pathway using siRNA knockdown and immunofluorescence assays of repair factors. Herein, we report that acetaldehyde induces DNA double-strand breaks (DSBs) in human U2OS cells and that both DSB repair pathways, non-homologous end-joining (NHEJ) and homology-directed repair (HDR), are required for the repair of acetaldehyde-induced DNA damage. Our findings suggest that acetaldehyde-induced DNA adducts are converted into DSBs and repaired via NHEJ or HDR in human cells. To reduce the risk of acetaldehyde-associated carcinogenesis, we investigated potential strategies of reducing acetaldehyde-induced DNA damage. We report that polyphenols extracted from persimmon fruits and epigallocatechin, a major component of persimmon polyphenols, attenuate acetaldehyde-induced DNA damage without affecting the repair kinetics. The data suggest that persimmon polyphenols suppress DSB formation by scavenging acetaldehyde. Persimmon polyphenols can potentially inhibit carcinogenesis following alcohol consumption.

Aldehyde dehydrogenase with hepatocellular carcinoma

Acetaldehyde dehydrogenase 2 (ALDH2) is a key enzyme in liver acetaldehyde metabolism (product of ethanol metabolism). Globally, about 8% of the population and about 30% to 40% of the East Asian population carry defective genes that encode no / low activity ALDH2. Recently, many studies have focused on the relationship between ALDH and viral hepatitis, alcoholic liver disease, liver fibrosis and liver cancer. Importantly, ALDH2 expression is closely related to the risk, pathogenesis and prognosis of liver cancer, so it can be used as a potential therapeutic target. This article summarizes and reviews the new progress and new research directions of this field.

Redox Regulation of Hexokinases.

Hexokinases are key enzymes that are responsible for the first reaction of glycolysis, but they also moonlight other cellular processes, including mitochondrial redox signaling regulation. Modulation of hexokinase activity and spatiotemporal location by reactive oxygen and nitrogen species as well as other gasotransmitters serves as the basis for a unique, underexplored method of tight and flexible regulation of these fundamental enzymes. Recent Advances: Redox modifications of thiols serve as a molecular code that enables the precise and complex regulation of hexokinases. Redox regulation of hexokinases is also used by multiple parasites to cause widespread and severe diseases, including malaria, Chagas disease, and sleeping sickness. Redox-active molecules affect each other, and the moonlighting activity of hexokinases provides another feedback loop that affects the cellular redox status and is hijacked in malignantly transformed cells. Several compounds affect the redox status of hexokinases in vivo. These include the dehydroascorbic acid (oxidized form of vitamin C), pyrrolidinium porrolidine-1-carbodithioate (contraceptive), peroxynitrite (product of ethanol metabolism), alloxan (a glucose analog), and isobenzothiazolinone ebselen. However, very limited information is available regarding which amino acid residues in hexokinases are affected by redox signaling. Except in cases of monogenic diabetes, direct evidence is absent for disease phenotypes that are associated with variations within motifs that are susceptible to redox signaling. Further studies should address the propensity of hexokinases and their disease-associated variants to participate in redox regulation. Robust and straightforward proteomic methods are needed to understand the context and consequences of hexokinase-mediated redox regulation in health and disease.

Wpływ produktów metabolizmu alkoholu etylowego na wątrobę – przegląd literatury

ENWEndNote BIBJabRef, Mendeley RISPapers, Reference Manager, RefWorks, Zotero AMA Kołota A. The effect of the products of ethanol metabolism on the liver – a review. Alcoholism and Drug Addiction/Alkoholizm i Narkomania. 2018;31(3):225-242. doi:10.5114/ain.2018.81664. APA Kołota, A. (2018). The effect of the products of ethanol metabolism on the liver – a review. Alcoholism and Drug Addiction/Alkoholizm i Narkomania, 31(3), 225-242. https://doi.org/10.5114/ain.2018.81664 Chicago Kołota, Aleksandra. 2018. "The effect of the products of ethanol metabolism on the liver – a review". Alcoholism and Drug Addiction/Alkoholizm i Narkomania 31 (3): 225-242. doi:10.5114/ain.2018.81664. Harvard Kołota, A. (2018). The effect of the products of ethanol metabolism on the liver – a review. Alcoholism and Drug Addiction/Alkoholizm i Narkomania, 31(3), pp.225-242. https://doi.org/10.5114/ain.2018.81664 MLA Kołota, Aleksandra. "The effect of the products of ethanol metabolism on the liver – a review." Alcoholism and Drug Addiction/Alkoholizm i Narkomania, vol. 31, no. 3, 2018, pp. 225-242. doi:10.5114/ain.2018.81664. Vancouver Kołota A. The effect of the products of ethanol metabolism on the liver – a review. Alcoholism and Drug Addiction/Alkoholizm i Narkomania. 2018;31(3):225-242. doi:10.5114/ain.2018.81664.

Mechanisms of naturally evolved ethanol resistance in Drosophila melanogaster.

The decaying fruit in which Drosophila melanogaster feed and breed can contain ethanol in concentrations as high as 6-7%. In this cosmopolitan species, populations from temperate regions are consistently more resistant to ethanol poisoning than populations from the tropics, but little is known about the physiological basis of this difference. I show that when exposed to low levels of ethanol vapor, flies from a tropical African population accumulated 2-3 times more internal ethanol than flies from a European population, giving evidence that faster ethanol catabolism by European flies contributes to the resistance difference. Using lines differing only in the origin of their third chromosome, however, I show that faster ethanol elimination cannot fully explain the resistance difference, because relative to African third chromosomes, European third chromosomes confer substantially higher ethanol resistance, while having little effect on internal ethanol concentrations. European third chromosomes also confer higher resistance to acetic acid, a metabolic product of ethanol, than African third chromosomes, suggesting that the higher ethanol resistance conferred by the former might be due to increased resistance to deleterious effects of ethanol-derived acetic acid. In support of this hypothesis, when ethanol catabolism was blocked with an Alcohol dehydrogenase mutant, there was no difference in ethanol resistance between flies with European and African third chromosomes.

Thiamine Metabolism in Neurons and Their Vital Capacity Upon the Action of Ethanol and Acetaldehyde

We studied the sensitivity of a few reactions of thiamine metabolism in nerve cells upon the action of ethanol and acetaldehyde, as well as effects of the above-mentioned agents on vital capacity of cultured cells of different origins. Experiments were carried out on preparations of isolated nerve endings (synaptosomes), preparations of synaptosomal plasma membranes (SPMs), preparations of enzymes, and cell cultures. We estimated the ІС50 for the effects of ethanol and acetaldehyde on reactions that are the components of metabolism of the mobile thiamine pool in the cells. Ethanol in physiological concentrations inhibited the thiamine-binding activity of SPMs (ІС50 = 3.9 mM). At the same time, this agent used in the above concentrations practically did not influence the thiamine phosphate hydrolase activity of SPMs (estimated by the thiamine triphosphatase activity) and thiamine pyrophosphate kinase (TPK) activity. A product of ethanol metabolism, acetaldehyde, inhibited the thiamine triphosphatase activity with K і = 6.2 μM and the TPK activity with K і = 1.2 μM. The survival indices of cultured cells were estimated under conditions of the addition of ethanol and acetaldehyde to the medium. The cells of an astrocytic origin (line strain 1321 N1) and blood cells (line strain U937) practically did not respond to the presence of ethanol or acetaldehyde even in rather high concentrations in the culture medium. Under conditions of primary culture, neuron-like (differentiated) cultured РС-12 cells and also cerebellar granular neurons responded by significant decreases in the index of vital capacity to the addition of the above agents.

Chronic Ethanol Consumption Alters Mammalian Gastrointestinal Content Metabolites

Chronic ethanol consumption is associated with not only the alteration of metabolic profiles in biofluids but also the composition of the gut microbiome. Our understanding of the importance of the intestinal microbiota as well as the disturbances elicited by ethanol intervention is limited by the fact that previous analyses have primarily focused on biofluids and liver tissue metabolome; the metabolic profiles of the gastrointestinal (GI) contents are rarely investigated. In this study, we applied a metabonomics approach using a high performance liquid chromatography-time-of-flight mass spectrometry (HPLC-TOF MS) and gas chromatography-mass spectrometry (GC-MS) to characterize the metabolic alterations of the contents within the GI tract (stomach, duodenum, jejunum, ileum, cecum, colon, and rectum) in male Sprague-Dawley rats following 8 weeks of ethanol exposure. We obtained a snapshot of the distinct changes of the intestinal content metabolite composition in rats with ethanol exposure, which indicated a profound impact of ethanol consumption on the intestinal metabolome. Many metabolic pathways that are critical for host physiology were affected, including markedly altered bile acids, increased fatty acids and steroids, decreased carnitines and metabolites involved in lipid metabolism, a significant decrease of all amino acids and branched chain amino acids, and significantly decreased short chain fatty acids except for acetic acid, which rapidly elevated as a product of ethanol metabolism. These results provide an improved understanding of the systemic alteration of intestinal content metabolites in mammals and the interplay between the host and its complex resident microbiota and may aid in the design of new therapeutic strategies that target these interactions.

Genotoxicity of alcohol is linked to DNA replication-associated damage and homologous recombination repair

Although alcohol consumption is related to increased cancer risk, its molecular mechanism remains unclear. Here, we demonstrate that an intake of 10% alcohol for 4 weeks in rats is genotoxic due to induction of micronuclei. Acetaldehyde (AA), the first product of ethanol metabolism, is believed to be responsible for DNA damage induced by alcohol. Here, we observe that AA effectively blocks DNA replication elongation in mammalian cells, resulting in DNA double-strand breaks associated with replication. AA-induced DNA damage sites colocalize with the homologous recombination (HR) repair protein RAD51. HR measured in the hypoxhantineguaninefosforibosyltransferase (HPRT) gene is effectively induced by AA and recombination defective mammalian cells are hypersensitive to AA, clearly demonstrating that HR is essential in the repair of AA-induced DNA damage. Altogether, our data indicate that alcohol genotoxicity related to AA produces replication lesions on DNA triggering HR repair.

Ethanol stimulates epithelial sodium channels by elevating reactive oxygen species

Alcohol affects total body sodium balance, but the molecular mechanism of its effect remains unclear. We used single-channel methods to examine how ethanol affects epithelial sodium channels (ENaC) in A6 distal nephron cells. The data showed that ethanol significantly increased both ENaC open probability (P(o)) and the number of active ENaC in patches (N). 1-Propanol and 1-butanol also increased ENaC activity, but iso-alcohols did not. The effects of ethanol were mimicked by acetaldehyde, the first metabolic product of ethanol, but not by acetone, the metabolic product of 2-propanol. Besides increasing open probability and apparent density of active channels, confocal microscopy and surface biotinylation showed that ethanol significantly increased α-ENaC protein in the apical membrane. The effects of ethanol on ENaC P(o) and N were abolished by a superoxide scavenger, 4-hydroxy-2,2,6,6-tetramethylpiperidinyloxy (TEMPOL) and blocked by the phosphatidylinositol 3-kinase inhibitor LY294002. Consistent with an effect of ethanol-induced reactive oxygen species (ROS) on ENaC, primary alcohols and acetaldehyde elevated intracellular ROS, but secondary alcohols did not. Taken together with our previous finding that ROS stimulate ENaC, the current results suggest that ethanol stimulates ENaC by elevating intracellular ROS probably via its metabolic product acetaldehyde.

Pathways of liver injury in alcoholic liver disease

The development of ethanol-induced liver injury including liver cirrhosis and severe alcoholic steatohepatitis (ASH) is a complex process involving various liver cell types and mainly factors released under the control of the innate immune system. Chronic ethanol consumption induces oxidative stress and production of reactive oxygen species (ROS), cytokine release, mitochondrial dysfunction, endoplasmic reticulum stress, and others. ROS initiate lipid peroxidation that directly damages plasma and intracellular membranes and leads to the production of reactive aldehydes with potent pro-inflammatory and pro-fibrotic properties. Oxidative stress and ROS are predominantly generated through the induction of cytochrome P450-2E1 (CYP2E1). A key role for this enzyme in ethanol-induced liver injury has been demonstrated by its inhibition through chlormethiazole and by the finding that CYP2E1 knock-out (KO) mice do not show evidence of ethanol-induced liver disease [1]. Furthermore, transgenic overexpression of human CYP2E1 in a mouse model results in more severe liver disease. Both the hydroxyethyl radical and acetaldehyde, the first products of ethanol metabolism, can bind glutathione (GSH), a tripeptide that acts as a direct free radical scavenger. The transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) protects cells against xenobiotic and oxidative stress. Nrf2 KO mice exhibit a dramatically increased mortality after ethanol feeding, highlighting the important role of oxidative stress in ethanol-induced injury [1] (Fig. 1).

Ethanol Stimulates Epithelial Sodium Channels via Reactive Oxygen Species

Disorders of electrolyte and water metabolism with resultant retention of sodium and water are common in alcoholics. However, the mechanisms responsible are largely unknown. In the present study, we found that ethanol stimulates the epithelial Na+ channel (ENaC) in A6 distal nephron cells. The data from cell-attached patch-clamp experiments showed that ethanol significantly increased both ENaC open probability (Po) and the number of active ENaC in the patch (N). The effects were mimicked by acetaldehyde, the first metabolic product of ethanol, as well as by n-propanol, another primary alcohol which can be oxidized to form an aldehyde, but not by iso-propanol, a secondary alcohol which can also be oxidized, but which forms a ketone rather than an aldehyde. Confocal microscopy combined with biotinylation experiments showed that ethanol significantly increased α-ENaC protein in the apical membrane. Primary alcohols and acetaldehyde elevated intracellular reactive oxygen species (ROS). The effects of ethanol on ENaC Po and N were abolished by a superoxide dismutase mimetic compound, 4-hydroxy-2,2,6,6-tetramethylpiperidinyloxy (TEMPOL). Together with our previous finding that ROS stimulate ENaC, these results suggest that ethanol stimulates ENaC by elevating intracellular ROS probably via its metabolic product acetaldehyde. Supported by 2R01DK067110 to HPM, P01 DK061521, R37 DK037963, and P50 AA013757 to DCE

Developmental Perspective on the Role of Genes in Smoking Risk

Developmental Perspective on the Role of Genes in Smoking Risk

Ethanol and acetaldehyde exposure induces specific epigenetic modifications in the prodynorphin gene promoter in a human neuroblastoma cell line

Ethanol alters neural activity through interaction with multiple neurotransmitters and neuromodulators. The endogenous opioid system seems to play a key role, since the opioid receptor antagonist naltrexone (ReVia®) attenuates craving for alcohol. We recently reported that ethanol and acetaldehyde, the first product of ethanol metabolism, affect transcription of opioid system genes in human SH-SY5Y neuroblastoma cells. In the current study, potential epigenetic mechanisms were investigated to clarify these effects on prodynorphin gene expression. DNA methylation was analyzed by bisulfite pyrosequencing, and chromatin immunoprecipitation was used to assess putative specific histone modifications at the prodynorphin gene promoter. The results demonstrated a temporal relationship between selective chromatin modifications induced by ethanol and acetaldehyde and changes in prodynorphin gene expression quantitated by real-time qPCR. DNA methylation was not altered in any of the experimental conditions used. The epigenetic changes may precede gene transcription, and histone modifications might keep the prodynorphin gene in a poised state for later reactivation. A link has been observed between gene expression alterations and selective epigenetic modulation in the prodynorphin promoter region, demonstrating a specificity of the changes induced by ethanol and acetaldehyde. The latter may be mediating ethanol effects at the genomic level.

TP53 mutation profile of esophageal squamous cell carcinomas of patients from Southeastern Brazil

Esophageal cancer (EC) is among the 10 most common and fatal malignacies in the world, presenting a marked geographic variation in incidence rates between and within different countries. The TP53 tumor suppressor gene is highly mutated in esophageal tumors and its mutation pattern can offer clues to the etiopathology of the tumor. As Brazil presents one of the highest incidence areas in the West, a deeper knowledge of the molecular mechanisms related to EC development in the Brazilian population is needed. We analyzed the mutation profile of 110 esophageal squamous cell carcinomas (ESCC) of patients from Southeastern Brazil (Rio de Janeiro and São Paulo) and collected data regarding alcohol intake and tobacco smoking. We detected 41 mutations in tumor samples from 38 patients. There was no association between mutation frequency and tobacco smoking or alcohol drinking. The most frequently mutated codons were 179, 214, 220 and 248. Codons 179, 220 and 248 are hot-spots for ESCC, but codon 214 presents only 0.7% of the mutations registered in the IARC database. The mutation profile revealed a high percentage of mutations at A:T base pairs (34.1%) followed by deletions (17.1%). We concluded that the mutation profile detected in this study is different from that of patients from Southern Brazil but very similar to that previously seen in French patients, being characterized by a high frequency of mutations at A:T base pairs, which may be associated with acetaldehyde, the metabolic product of ethanol.

Interaction of Biogenic Amine Hormones with Acetaldehyde

Dopamine (DA), epinephrine (EP), serotonin (5-HT), norepinephrine (NE), and histamine (H) are each hormones derived from aromatic or basic amino acids. Each contains primary or secondary amines, and all, except H, contain hydroxyl groups. These functional groups are capable of reacting with acetaldehyde (AcH), the primary product of ethanol metabolism. In this study, it is shown that 5-min preincubations of the amines with AcH affect a reduction in the prolongation of activated partial thromboplastin time (aPTT) which is caused by AcH. The data suggest that these hormones may form Schiff bases, hemiacetals, and acetals, thereby detoxifying the AcH. It is also suggested that physiological effects of these hormones may be lowered as a consequence of interaction with acetaldehyde in alcoholics. In the absence of AcH, 0.91 mM DA, 5-HT, and EP each exhibited a small statistically significant procoagulant effect on the aPTT assay with values of 30.8 +/- 0.3 s (P = 0.03), 28.5 +/- 1.0 s (P = 0.006), and 31.3 +/- 0.2 s (P = 0.001), respectively, relative to the controls of 32.6 +/- 0.6 s, 32.9 +/- 0.6 s, and 33.0 +/- 0.3 s. Values for 0.91 mM NE and 9.1 mM H were 33.5 +/- 0.8 s (P = 0.14) and 36.0 +/- 0.8 s (P = 0.14), respectively, relative to the controls (32.4 +/- 0.2 s and 34.2 +/- 0.4 s), and exerted a nonsignificant effect upon aPTT.

The Activity of Class I, II, III, and IV Alcohol Dehydrogenase (ADH) Isoenzymes and Aldehyde Dehydrogenase (ALDH) in Esophageal Cancer

Ethanol consumption is associated with an increased risk of esophageal cancer. The carcinogenic compound is acetaldehyde, the product of ethanol metabolism. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are the main enzymes involved in ethanol metabolism, which leads to generation of acetaldehyde. In this study the activity of ADH isoenzymes and ALDH in esophageal cancer were compared with the activity in normal tissue. For measurement of the activity of class I and II ADH isoenzymes and ALDH activity fluorimetric methods were employed. Total ADH activity and activity of class III and IV isoenzymes was measured by the photometric method. Samples were taken from 59 esophageal cancer patients (27 adenocarcinoma, 32 squamous cell cancer). The total activity of ADH and activity of class IV ADH were significantly higher in cancer cells than in healthy tissues. The other tested classes of ADH showed a tendency toward higher activity in cancer than in normal cells. Differences between the activity of enzymes of drinkers and non-drinkers in both cancer and healthy tissue were not significant. Increased ADH IV activity may be a factor intensifying carcinogenesis, because of the increased ability to form acetaldehyde from ethanol.

Acute ethanol exposure disrupts VEGF receptor cell signaling in endothelial cells

Physiological angiogenesis is regulated by various factors, including signaling through vascular endothelial growth factor (VEGF) receptors. We previously reported that a single dose of ethanol (1.4 g/kg), yielding a blood alcohol concentration of 100 mg/dl, significantly impairs angiogenesis in murine wounds, despite adequate levels of VEGF, suggesting direct effects of ethanol on endothelial cell signaling (40). To examine the mechanism by which ethanol influences angiogenesis in wounds, we employed two different in vitro angiogenesis assays to determine whether acute ethanol exposure (100 mg/dl) would have long-lasting effects on VEGF-induced capillary network formation. Ethanol exposure resulted in reduced VEGF-induced cord formation on collagen and reduced capillary network structure on Matrigel in vitro. In addition, ethanol exposure decreased expression of endothelial VEGF receptor-2, as well as VEGF receptor-2 phosphorylation in vitro. Inhibition of ethanol metabolism by 4-methylpyrazole partially abrogated the effect of ethanol on endothelial cell cord formation. However, mice treated with t-butanol, an alcohol not metabolized by alcohol dehydrogenase, exhibited no change in wound vascularity. These results suggest that products of ethanol metabolism are important factors in the development of ethanol-induced changes in endothelial cell responsiveness to VEGF. In vivo, ethanol exposure caused both decreased angiogenesis and increased hypoxia in wounds. Moreover, in vitro experiments demonstrated a direct effect of ethanol on the response to hypoxia in endothelial cells, as ethanol diminished nuclear hypoxia-inducible factor-1alpha protein levels. Together, the data establish that acute ethanol exposure significantly impairs angiogenesis and suggest that this effect is mediated by changes in endothelial cell responsiveness to both VEGF and hypoxia.

Effects of cyanamide and acetaldehyde accumulation on the locomotor stimulant and sedative effects of ethanol in mice

Ethanol administration induces both locomotor stimulant and sedative effects depending upon blood ethanol concentrations. Recent studies in rats and mice suggest that acetaldehyde, the first product of ethanol metabolism, might be involved in the expression of both the stimulant and the sedative effects of ethanol. A number of studies have used the drug cyanamide in an attempt to clarify the role of acetaldehyde in the behavioral effects of ethanol. The results of such studies are, however, difficult to interpret because cyanamide is an inhibitor of the enzymes catalase and aldehyde dehydrogenase, two enzymes with opposite effects on brain acetaldehyde concentrations. This study was aimed at clarifying the effects of cyanamide on ethanol-induced locomotor stimulant and sedative effects in Swiss mice. The locomotor stimulant effects of ethanol were measured in standard activity boxes, whereas the sedative effects of ethanol were quantified using the loss of righting reflex procedure. Cyanamide prevented the locomotor stimulant effects of 2 g/kg ethanol, although this was mainly due to a potentiation of the inhibitory effects of ethanol as evidenced by a prolongation of ethanol-induced loss of righting reflex. Additionally, 4-methylpyrazole, an inhibitor of the enzyme alcohol dehydrogenase, prevented these effects of cyanamide. It is concluded that in vivo the effects of cyanamide are predominantly due to the inhibition of the enzyme aldehyde dehydrogenase, rather than to its effects on catalase.

Captopril and Lisinopril Decrease Acetaldehyde Effects upon the Prothrombin Time

Captopril, a thiol-containing antihypertensive drug, and lisinopril, an amino-containing antihypertensive drug, will both prolong the prothrombin time (PT) of Level I plasma. Acetaldehyde, a product of ethanol metabolism, also prolongs PT. In a study to examine the interrelationship between hypertension, hemostasis, and alcoholism, an examination of the impact of acetaldehyde on the effects of captopril and lisinopril upon PT was undertaken. It was observed that the pre-mixing of 7.7 x 10(-3) M captopril with 40.6 mM acetaldehyde for 30 min at R.T. prior to the addition to plasma results in a prolongation of PT which is less than that caused by acetaldehyde alone. Successive additions of captopril and acetaldehyde to plasma also yield a PT which is less than that of acetaldehyde alone. These data suggest that captopril may partially inactivate and detoxify the acetaldehyde effect on hemostasis upon interaction to form a thiohemiacetal. Captopril may prolong PT by the reduction of the S-S bridges in the coagulation factors. Lisinopril behaves similarly to captopril, prolonging PT. Successive additions of lisinopril and acetaldehyde, or pre-mixtures thereof, to plasma result in a lesser prolongation of clotting time relative to acetaldehyde alone. Since primary amines similar to that of lisinopril readily form Schiff bases with acetaldehyde, these data suggest that both captopril and lisinopril may act to detoxify the acetaldehyde effect upon plasma, albeit by different mechanisms.

Locomotor effects of ethanol and acetaldehyde after peripheral and intraventricular injections in Swiss and C57BL/6J mice

Several studies have suggested that acetaldehyde, the first product of ethanol metabolism, is involved in the locomotor stimulant effects of ethanol in mice, although it has never been formally tested whether acetaldehyde injected directly into the brain of mice has stimulant properties. Recently, it was also shown in rats that both ethanol and acetaldehyde can induce opposite locomotor effects according to the route of administration. Whereas peripheral administrations of ethanol and acetaldehyde induced locomotor depressant effects, their infusions directly into the brain produced locomotor stimulation. The aim of the present study was to characterize in mice the locomotor effects of ethanol and acetaldehyde injected either peripherally by the intraperitoneal route or centrally into the brain ventricles. Additionally, the effects of ethanol and acetaldehyde were compared in two strains of mice known for their differential sensitivity to the locomotor effects of ethanol, namely Swiss and C57BL/6J mice. Ethanol induced a biphasic effect on locomotor activity in Swiss mice, with stimulant effects at low to moderate doses and depressant effects at higher doses. Such a profile of effects was observed whatever the route of administration, peripheral or central. In C57BL/6J mice, ethanol only induced monophasic depressant effects. In this mouse strain, no evidence of the stimulant effects of ethanol was found after either an i.p. or an i.c.v. administration of ethanol. In contrast to ethanol, acetaldehyde yielded only depressant effects in both strains of mice after both peripheral and central administrations. These results indicate that the route of administration does not alter the locomotor effects of ethanol and acetaldehyde in mice. Additionally, the present study shows that the stimulant properties of acetaldehyde, even after direct infusion into the brain, are not as obvious as previously speculated.