ABSTRACT
Alcohol abuse is a worldwide health problem with high economic costs to health systems. Emerging evidence suggests that modulation of brain nicotinic acetylcholine receptors (nAChRs) may be a therapeutic target for alcohol dependence. In this work, we assess the effectiveness of four doses of erysodine (1.5, 2.0, 4.0 or 8.0â¯mg/kg/day, i.p.), a competitive antagonist of nAChRs, on voluntary ethanol consumption behavior in alcohol-preferring UChB rats, administered during three consecutive days. Results show that erysodine administration produces a dose-dependent reduction in ethanol consumption respect to saline injection (control group). The highest doses of erysodine (4 and 8â¯mg/kg) reduce (45 and 66%, respectively) the ethanol intake during treatment period and first day of post-treatment compared to control group. While, the lowest doses of erysodine (1.5 and 2â¯mg/kg) only reduce ethanol intake during one day of treatment period. These effective reductions in ethanol intake were 23 and 29% for 1.5 and 2â¯mg/kg erysodine, respectively. Locomotor activity induced by a high dose of erysodine (10â¯mg/kg) was similar to those observed with saline injection in control rats, showing that the reduction in ethanol intake was not produced by hypolocomotor effect induced by erysodine. This is the first report showing that erysodine reduces ethanol intake in UChB rats in a dose-dependent manner. Our results highlight the role of nAChRs in the reward effects of ethanol and its modulation as a potentially effective pharmacological alternative for alcohol dependence treatment.
Subject(s)
Alcohol Deterrents/pharmacology , Alcohol Drinking/drug therapy , Dihydro-beta-Erythroidine/analogs & derivatives , Nicotinic Antagonists/pharmacology , Alcohol Drinking/metabolism , Animals , Central Nervous System Depressants/administration & dosage , Dihydro-beta-Erythroidine/pharmacology , Dose-Response Relationship, Drug , Ethanol/administration & dosage , Male , Motor Activity/drug effects , Motor Activity/physiology , Random Allocation , Rats, Sprague-Dawley , Rats, Wistar , Receptors, Nicotinic/metabolism , RewardABSTRACT
Blocking aldehyde dehydrogenase with the drug disulfiram leads to an accumulation of intracellular acetaldehyde, which negatively affects the viability of the yeast Saccharomyces cerevisiae. Mutants of the yeast gene PSO2, which encodes a protein specific for repair of DNA interstrand cross-links, showed higher sensitivity to disulfiram compared to the wild type. This leads us to suggest that accumulated acetaldehyde induces DNA lesions, including highly deleterious interstrand cross-links. Acetaldehyde induced the expression of a PSO2-lacZ reporter construct that is specifically inducible by bi- or poly-functional mutagens, e.g., nitrogen mustard and photo-activated psoralens. Chronic exposure of yeast cells to disulfiram and acute exposure to acetaldehyde induced forward mutagenesis in the yeast CAN1 gene. Disulfiram-induced mutability of a pso2Delta mutant was significantly increased over that of the isogenic wild type; however, this was not found for acetaldehyde-induced mutagenesis. Spontaneous mutability at the CAN1 locus was elevated in pso2Delta, suggesting that growth of glucose-repressed yeast produces DNA lesions that, in the absence of Pso2p-mediated crosslink repair, are partially removed by an error-prone DNA repair mechanism. The use of disulfiram in the control of human alcohol abuse increases cellular acetaldehyde pools, which, based on our observations, enhances the risk of mutagenesis and of other genetic damage.
Subject(s)
Acetaldehyde/metabolism , Alcohol Deterrents/pharmacology , Aldehyde Oxidoreductases/antagonists & inhibitors , DNA Repair , DNA-Binding Proteins/metabolism , Disulfiram/pharmacology , Nuclear Proteins/metabolism , Saccharomyces cerevisiae Proteins/metabolism , Saccharomyces cerevisiae/drug effects , Acetaldehyde/pharmacology , Amino Acid Transport Systems, Basic/genetics , DNA Damage , DNA, Fungal/genetics , DNA-Binding Proteins/genetics , Endodeoxyribonucleases , Humans , Mutagenesis , Mutation , Nuclear Proteins/genetics , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , Saccharomyces cerevisiae Proteins/geneticsABSTRACT
BACKGROUND: Although disulfiram has been used in the treatment of alcoholism due to the unpleasant sensations its concomitant ingestion with ethanol provokes, some patients reported stimulant effects after its ingestion. This issue has not been addressed in studies with animals. In mice, the stimulant effect of ethanol has been associated with increased locomotor activity and behavioural sensitization. This study sought to analyze the influence of disulfiram on the development of behavioural sensitization to the stimulant effect of ethanol. METHODS: Male Swiss mice pre-treated with vehicle or disulfiram (15 mg/kg) received saline or ethanol (2.0 g/kg) every other day, for 5 days. Forty-eight hours afterwards mice were challenged with Saline, and 48 h later they received Disulfiram, or Disulfiram+Ethanol or Ethanol. RESULTS: The co-administration of disulfiram (15 mg/kg) blocked the development of behavioural sensitization induced by ethanol (2.0 g/kg). Although the acute administration of disulfiram did not alter the locomotor activity, its acute administration-induced higher levels of locomotor activity in mice previously sensitized to ethanol than in controls which received saline. CONCLUSIONS: Our data suggest that besides the known psychological effects (fear of aversive effects) disulfiram efficacy on alcohol dependency treatment could also be due to its pharmacological interference in the brain neurotransmission.
Subject(s)
Alcohol Deterrents/pharmacology , Central Nervous System Depressants/pharmacology , Disulfiram/pharmacology , Ethanol/pharmacology , Motor Activity/drug effects , Alcohol Deterrents/administration & dosage , Analysis of Variance , Animals , Behavior, Animal/drug effects , Central Nervous System Depressants/administration & dosage , Disulfiram/administration & dosage , Dose-Response Relationship, Drug , Ethanol/administration & dosage , Male , Mice , Time FactorsABSTRACT
BACKGROUND: Disulfiram, an inhibitor of aldehyde dehydrogenase used in the treatment of alcoholism, is an effective medication when its intake is supervised by a third person. However, its therapeutic efficacy varies widely, in part due to the fact that disulfiram is a pro-drug that requires its transformation into an active form and because it shows a wide range of secondary effects which often prevent the use of doses that ensure full therapeutic effectiveness. In this preclinical study in rats we report the development of tolerance to disulfiram induced by the chronic ingestion of ethanol, an additional source of variation for the actions of disulfiram with possible therapeutic significance, We also addresses the likely mechanism of this effect. METHODS: Wistar-derived rats bred for generations as high ethanol drinkers (UChB) were trained for either 3 days (Group A) or 30 days (Group B) to choose between ethanol (10% v/v) or water, which were freely available from 2 bottles on a 24-hour basis. Subsequently, animals in both groups were administered disulfiram or cyanamide (another inhibitor of aldehyde dehydrogenase) and ethanol intake in this free choice paradigm was determined. Animals were also administered a standard dose of 1 g ethanol/kg (i.p) and arterial blood acetaldehyde was measured. RESULTS: Disulfiram (12.5 and 25 mg/kg) and cyanamide (10 mg/kg) markedly inhibited ethanol intake (up to 60 to 70%) in animals that had ethanol access for only 3 days (Group A). However both drugs were inactive in inhibiting ethanol intake in animals that had consumed ethanol for 30 days (Group B). Following the injection of 1 g ethanol/kg, arterial blood acetaldehyde levels reached levels of 150 and 300 microM for disulfiram and cyanamide respectively, values which were virtually identical regardless of the length of prior ethanol intake of the animals. CONCLUSIONS: Chronic ethanol intake in high-drinker rats leads to marked tolerance to the aversive effects of disulfiram and cyanamide on ethanol intake despite the presence of consistently high levels of blood acetaldehyde. These findings may have implications for the use of disulfiram for the treatment of alcoholism in humans.
Subject(s)
Alcohol Deterrents/pharmacology , Alcohol Drinking/drug therapy , Disulfiram/pharmacology , Drug Tolerance , Ethanol/administration & dosage , Acetaldehyde/blood , Alcohol Dehydrogenase/antagonists & inhibitors , Alcoholism/drug therapy , Animals , Cyanamide/pharmacology , Cyanamide/therapeutic use , Disulfiram/therapeutic use , Enzyme Inhibitors/pharmacology , Female , Rats , Rats, WistarABSTRACT
OBJECTIVE: This study examined the efficacy of a 28-day gabapentin treatment in reducing alcohol consumption and craving. METHOD: A randomized, double-blind, placebo-controlled trial was performed in a Brazilian public outpatient drug treatment center, with 60 male alcohol-dependent subjects with a mean age of 44 years and an average of 27 years of alcohol use, who consumed 17 drinks per day (165-170 g/day) over the past 90 days before baseline and had no other significant medical or psychiatric condition. Subjects were recruited between July 8, 2004, and February 24, 2005. Following screening, 60 subjects were selected and received diazepam and vitamins as treatment for acute withdrawal for at least 7 days. After the detoxification treatment, 30 subjects were randomly assigned to receive gabapentin (300 mg twice daily) for 4 weeks, and 30 subjects, with similar baseline characteristics, were randomly assigned to receive matching placebo tablets for the same period. RESULTS: After 28 days of treatment, the gabapentin group showed a significant reduction in both number of drinks per day and mean percentage of heavy drinking days (p = .02 for both), and an increase in the percentage of days of abstinence (p = .008), compared to the placebo group. Additionally, some improvement in obsessive-compulsive symptoms was noted in both groups after the treatment, but it resulted in a more pronounced decrease in automaticity of drinking and aspects of craving in the gabapentin group than in the placebo group. CONCLUSION: Gabapentin reduces alcohol consumption and craving, which may help patients to maintain abstinence. These results, together with the virtual absence of side effects and a favorable safety profile, support gabapentin as a potential drug for the treatment of alcohol withdrawal and dependence.
Subject(s)
Alcohol Deterrents/therapeutic use , Alcoholism/drug therapy , Alcoholism/epidemiology , Amines/therapeutic use , Cyclohexanecarboxylic Acids/therapeutic use , Ethanol/adverse effects , Substance Withdrawal Syndrome/diagnosis , Substance Withdrawal Syndrome/etiology , gamma-Aminobutyric Acid/therapeutic use , Adolescent , Adult , Aged , Alcohol Deterrents/administration & dosage , Alcohol Deterrents/pharmacology , Ambulatory Care , Amines/administration & dosage , Amines/pharmacology , Blood-Brain Barrier/drug effects , Brazil/epidemiology , Cyclohexanecarboxylic Acids/administration & dosage , Cyclohexanecarboxylic Acids/pharmacology , Double-Blind Method , Drug Administration Schedule , Female , Gabapentin , Humans , Incidence , Male , Middle Aged , Obsessive-Compulsive Disorder/drug therapy , Obsessive-Compulsive Disorder/epidemiology , Obsessive-Compulsive Disorder/psychology , Prevalence , Severity of Illness Index , Substance Withdrawal Syndrome/epidemiology , Temperance , gamma-Aminobutyric Acid/administration & dosage , gamma-Aminobutyric Acid/pharmacologyABSTRACT
Acute tolerance that develops in minutes of an ethanol exposure appears to influence voluntary ethanol consumption in our two selected bred lines, UChA (low ethanol drinker) and UChB (high ethanol drinker)rats. We have reported previously that an acute intraperitoneal (ip.) dose of ethanol (2.3 g/kg) induces both an increase in acute tolerance and a long-lasting increase in voluntary ethanol consumption in UChB rats. In the present paper we investigated the involvement of acetaldehyde produced centrally during ethanol oxidation by brain catalase and its oxidation by mitochondrial aldehyde dehydrogenase, on acute tolerance development and on voluntary ethanol consumption by rats. Acute tolerance developed to motor impairment induced by a dose of ethanol of 2.3 g/kg administered ip. was evaluated by the tilting plane test. Voluntary ethanol consumption by the rat with free access to a 10% v/v ethanol was measured daily. Both parameters were evaluated in controls,saline-pretreated and ethanol-injected rats. One group of rats that received the ethanol injection was pretreated with 3-amino-1,2,4-triazole (AT), a catalase inhibitor, and another group was pretreated with disulfiram, an aldehyde dehydrogenase inhibitor. Brain catalase and aldehyde dehydrogenase activities were measured in both groups of rats. Results show that acute tolerance to motor impairment, as well as ethanol consumption induced by ethanol, appears to be the consequence of acetaldehyde formed centrally during ethanol oxidation via the catalase system, because pretreatment of rats with the catalase inhibitor attenuated the increase in acute tolerance development and the increase in voluntary ethanol consumption in UChB rats that received the acute i.p. dose of ethanol. Moreover, the acetaldehyde metabolizing enzyme also appears to be an important factor in the modulation of acute tolerance development and voluntary ethanol consumption in UChA and UChB rats. The results lead us to propose that the possible mechanism by which the ip. injection of ethanol to UChB rats induces an increase in ethanol consumption is the development of acute tolerance, where acetaldehyde formed during brain ethanol metabolism via catalase and its subsequent oxidation via aldehyde dehydrogenase have an important role.
Subject(s)
Alcohol Drinking/metabolism , Brain/drug effects , Brain/metabolism , Ethanol/metabolism , Ethanol/pharmacology , Alcohol Deterrents/administration & dosage , Alcohol Deterrents/pharmacology , Aldehyde Dehydrogenase/metabolism , Animals , Brain/enzymology , Catalase/metabolism , Disulfiram/administration & dosage , Disulfiram/pharmacology , Drug Tolerance , Ethanol/administration & dosage , Female , Male , RatsABSTRACT
Metadoxine (pyridoxine-pyrrolidone carboxylate) has been reported to improve liver function tests in alcoholic patients. In the present work we have investigated the effect of metadoxine on some parameters of cellular damage in hepatocytes and hepatic stellate cells in culture treated with ethanol and acetaldehyde. HepG2 and CFSC-2G cells were treated with 50 mM ethanol or 175 microM acetaldehyde as initial concentration in the presence or absence of 10 microg ml(-1) of metadoxine. Twenty-four hours later reduced and oxidized glutathione content, lipid peroxidation damage, collagen secretion and IL-6, IL-8 and TNF- alpha secretion were determined. Our results suggest that metadoxine prevents glutathione depletion and the increase in lipid peroxidation damage caused by ethanol and acetaldehyde in HepG2 cells. In hepatic stellate cells, metadoxine prevents the increase in collagen and attenuated TNF- alpha secretion caused by acetaldehyde. Thus, metadoxine could be useful in preventing the damage produced in early stages of alcoholic liver disease as it prevents the redox imbalance of the hepatocytes and prevents TNF- alpha induction, one of the earliest events in hepatic damage.
Subject(s)
Acetaldehyde/pharmacology , Alcohol Deterrents/pharmacology , Central Nervous System Depressants/pharmacology , Ethanol/pharmacology , Hepatocytes/drug effects , Liver/drug effects , Pyridoxine/pharmacology , Pyrrolidonecarboxylic Acid/pharmacology , Animals , Cell Survival/drug effects , Cells, Cultured , Collagen/metabolism , Drug Combinations , Glutathione/metabolism , Glutathione Disulfide/metabolism , Hepatocytes/metabolism , Hepatocytes/pathology , Humans , Interleukin-6/metabolism , Interleukin-8/metabolism , Liver/metabolism , Liver/pathology , Rats , Tumor Necrosis Factor-alpha/metabolismABSTRACT
The influence of acute ethanol administration on the oxidative stress status of rat brain and liver was assessed by in situ spontaneous organ chemiluminescence (CL). Brain and liver CL was significantly increased after acute ethanol administration to fed rats, a response that is time-dependent and evidenced at doses higher than 1 g/kg. Ethanol-induced CL development is faster in liver compared with brain probably due to the greater ethanol metabolic capacity of the liver, whereas the net enhancement in brain light emission at 3 h after ethanol treatment is higher than that of the liver, which could reflect the greater susceptibility of brain to oxidative stress. The effect of ethanol on brain and liver CL seems to be mediated by acetaldehyde, due to its abolishment by the alcohol dehydrogenase inhibitor 4-methylpyrazole and exacerbation by the aldehyde dehydrogenase inhibitor disulfiram. In brain, these findings were observed in the absence of changes in the activity of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glucose-6-phosphate dehydrogenase. However, the content of brain glutathione was significantly decreased by 31%, by ethanol, thus establishing an enhanced oxidative stress in this tissue.