RESUMO
AIM: To investigate pro-inflammatory markers in the blood and associate with cognitive impairment. METHODS: Il-6 and ferritin were assayed in the blood of 27 patients, divided according to Lesch typology, at the commencement and after 21 days of detoxification, together with a battery of cognitive tests. RESULTS: A significantly higher mean level of IL-6 was present in the blood of patients with Lesch typology 1 compared to the other typologies 2 and 3 on admission to the Detoxification Ward which did not alter significantly after detoxification. The mean level of IL-6 was initially elevated in Lesch typology 2 alcohol abusers and declined to the reference range after detoxification. Lesch typology 3 alcohol abusers showed normal levels of IL-6 at both time points. Only in Lesch typology 1 were the levels of ferritin and IL-10 significantly elevated at the start of the detoxification process. Cognitive impairment, as ascertained by Stroop test and Brown-Peterson procedure was greater in Lesch typology 1 than the other 2 patient groups. CONCLUSION: Such data might indicate a greater degree of neuroinflammation in Lesch typology 1 alcoholic patients. SHORT SUMMARY: Dividing a heterogeneous group of alcoholic subjects into homogenous groups according to Lesch typology, identifies a greater pro-inflammatory profile in Lesch typology 1 patients who also showed greater cognitive impairment.
Assuntos
Alcoolismo/diagnóstico , Alcoolismo/psicologia , Disfunção Cognitiva/sangue , Ferritinas/sangue , Mediadores da Inflamação/sangue , Interleucina-10/sangue , Interleucina-6/sangue , Adulto , Alcoolismo/sangue , Alcoolismo/complicações , Biomarcadores/sangue , Disfunção Cognitiva/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes NeuropsicológicosRESUMO
AIMS: The aim of the study was to evaluate rat models of intermittent alcohol abuse (heavy session/'heavy session' drinking) in relation to inflammatory changes in specific brain regions as well as in the periphery. Furthermore, the study was aimed to assess whether there are inflammatory changes in the blood of human intermittent alcohol abusers who might be associated with changes in neuronal circuitry in the brain, as assessed by functional magnetic resonance imaging (fMRI), which cause adverse effects on memory and learning. METHODS: Various regimes of intermittent alcohol administration have been used in rat models, which vary with respect to the dose and duration of ethanol administration as well as the time of abstinence. Immunohistological methods were used to identify activated microglia in specific brain regions. The response of isolated alveolar macrophages to in vitro stimuli was assessed by the assay of nitric oxide and the pro-inflammatory cytokines IL-6 and TNFα. Blood samples were collected from university students who had been heavy session drinkers for 2 years to assess whether there was an inflammatory cytokine profile that correlated with cognitive test scores as well as fMRI findings. RESULTS: The extent of microglia activation appears to depend on the doses and duration of ethanol administration. In addition, there is activation of phagocytic cells in the periphery, e.g. alveolar macrophages, in the rat models of heavy session drinking. Changes in the plasma levels of pro- and anti-inflammatory cytokines were present in heavy session drinking students, although no changes were identified in specific cognitive tests (which may be because of compensatory changes in the prefrontal cortex, as identified by fMRI). CONCLUSION: Changes in the cytokine levels induced by intermittent ethanol abuse may provoke inflammatory pathways in specific brain regions, such as hippocampus and prefrontal cortex (particularly during the stage of active neurogenesis in the adolescent brain), which might induce cognitive impairment in susceptible individuals.
Assuntos
Transtornos do Sistema Nervoso Induzidos por Álcool/imunologia , Intoxicação Alcoólica/imunologia , Modelos Animais de Doenças , Etanol/toxicidade , Imunidade Inata/efeitos dos fármacos , Adolescente , Animais , Citocinas/imunologia , Humanos , Imuno-Histoquímica , Microglia/efeitos dos fármacos , Fagócitos/efeitos dos fármacos , Ratos , Transdução de Sinais/imunologiaRESUMO
AIMS: The effect of 'binge drinking' coupled or not with chronic nicotine administration on nucleus accumbens (NAc) glutamate, arginine, taurine and hydroxyl radical levels has been investigated in these present studies. METHODS AND RESULTS: Ethanol, 2 or 3 g/kg, has been administered to male or female adult rats in a 'binge-type' regime for 3 weeks, +/- nicotine, and changes in glutamate, arginine and taurine content in the NAc, assayed by microdialysis after a further dose of ethanol. The basal concentration of NAc glutamate increased 8-fold in the female adult rats but did not change significantly after further doses of ethanol. In contrast, the male adult rats showed no changes in basal glutamate content but exhibited a dose-dependent increase in NAc glutamate after further doses of ethanol. NAc arginine basal levels decreased significantly in both male and female adult rats after further doses of ethanol. Co-administration of nicotine modified the toxicity of ethanol as exemplified by diminishment of both the basal NAc glutamate release as well as modifying the release of this excitatory amino acid after further ethanol doses, particularly in female rats. In addition, the marked changes in arginine release after further ethanol doses were less evident. There was no evidence for increased hydroxyl radical production in the NAc after 'binge drinking' +/- nicotine. CONCLUSION: There appeared to be a greater vulnerability to ethanol toxicity in female adult rats after 'binge drinking'. It remains unclear whether the increased release of glutamate during the microdialysis evokes activation of inducible nitric oxide synthase (iNOS), which would utilize arginine in the formation of nitric oxide.
Assuntos
Depressores do Sistema Nervoso Central/efeitos adversos , Etanol/efeitos adversos , Estimulantes Ganglionares/farmacologia , Nicotina/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Consumo de Bebidas Alcoólicas/metabolismo , Animais , Arginina/metabolismo , Catecóis/análise , Catecóis/metabolismo , Depressores do Sistema Nervoso Central/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Etanol/metabolismo , Espaço Extracelular/metabolismo , Feminino , Estimulantes Ganglionares/administração & dosagem , Estimulantes Ganglionares/metabolismo , Ácido Glutâmico/metabolismo , Hidroxibenzoatos , Masculino , Microdiálise , Nicotina/administração & dosagem , Nicotina/metabolismo , Núcleo Accumbens/metabolismo , Ratos , Ratos Wistar , Taurina/análise , Taurina/metabolismo , Fatores de TempoRESUMO
The morbidity and mortality resulting from alcohol-related diseases globally impose a substantive cost to society. To minimize the financial burden on society and improve the quality of life for individuals suffering from the ill effects of alcohol abuse, substantial research in the alcohol field is focused on understanding the mechanisms by which alcohol-related diseases develop and progress. Since ethical concerns and inherent difficulties limit the amount of alcohol abuse research that can be performed in humans, most studies are performed in laboratory animals. This article summarizes the various laboratory models of alcohol abuse that are currently available and are used to study the mechanisms by which alcohol abuse induces organ damage and immune defects. The strengths and weaknesses of each of the models are discussed. Integrated into the review are the presentations that were made in the symposium "Methods of Ethanol Application in Alcohol Model-How Long is Long Enough" at the joint 2008 Research Society on Alcoholism (RSA) and International Society for Biomedical Research on Alcoholism (ISBRA) meeting, Washington, DC, emphasizing the importance not only of selecting the most appropriate laboratory alcohol model to address the specific goals of a project but also of ensuring that the findings can be extrapolated to alcohol-induced diseases in humans.
Assuntos
Alcoolismo/imunologia , Alcoolismo/patologia , Modelos Animais de Doenças , Etanol/farmacologia , Imunidade/efeitos dos fármacos , Intoxicação Alcoólica/imunologia , Animais , Relação Dose-Resposta a Droga , Vias de Administração de Medicamentos , Esquema de Medicação , Etanol/administração & dosagem , HumanosRESUMO
In this short review, neurochemical targets are identified where nicotine, and possibly ethanol, may interact to prevent the occurrence of Parkinson's disease. These are (a) the nicotinic acetycholine receptors present in the nigrostriatal area or on the surface of microglia, (b) monoamine oxidases and (c) inducible nitric oxide synthase. If such induced changes can be verified in clinical studies, this may help in the design of new therapeutic drugs which may be of relevance to diminish the incidence and perhaps the progression of the debilitating condition of Parkinson's disease.
Assuntos
Depressores do Sistema Nervoso Central/uso terapêutico , Colinérgicos/uso terapêutico , Etanol/uso terapêutico , Doença de Parkinson/metabolismo , Doença de Parkinson/prevenção & controle , Animais , Química Encefálica/efeitos dos fármacos , Humanos , Doença de Parkinson/tratamento farmacológico , Receptores Nicotínicos/metabolismoRESUMO
The neuropathological and immune changes induced in the brain by 'binge drinking' have been investigated in a rat model. Evidence of neuro-inflammation was identified in the 'binge drinking' rat model of alcohol abuse after 3 weeks of administration of 2 or 3 g/kg ethanol (EtOH), three times per day for two consecutive days, followed by 5 days of abstinence: Firstly, alveolar macrophages, isolated from these animals, showed significant increases in inducible nitric oxide synthase, as assayed by nitrite release, both before and after lipopolysaccaharide stimulation. Secondly, significant numbers of activated microglia were present in the dentate gyrus region of the hippocampus of the 'binge drinking' model, after major histocompatibility complex class II staining, by comparison with the control. Microdialysis studies in the ventral hippocampus identified a significant increase in the basal extracellular concentration of glutamate, in both the 2 and 3 g/kg administered 'binge drinking' rats. In contrast, no changes in the hippocampal extracellular concentrations, of GABA and taurine, or the dopamine and serotonin metabolites were observed under basal conditions. A further dose of EtOH induced a significant decrease in the concentrations of both 3,4-dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid, whereas glutamate, taurine and GABA levels were unaffected. There was no evidence that EtOH preference was initiated by the 'binge drinking' regimen. Our results suggest that the possible toxicity associated with 'binge drinking' maybe directed by the elevated glutamate levels, which in turn, activate phagocytic cells to release their inflammatory cytokines and chemokines, ultimately leading to neuro-inflammation.
Assuntos
Alcoolismo/patologia , Líquido Extracelular/metabolismo , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Aminoácidos/metabolismo , Animais , Monoaminas Biogênicas/metabolismo , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Etanol/administração & dosagem , Etanol/efeitos adversos , Feminino , Hipocampo/efeitos dos fármacos , Antígenos de Histocompatibilidade Classe II/metabolismo , Ácido Hidroxi-Indolacético/metabolismo , Macrófagos Alveolares/enzimologia , Macrófagos Alveolares/patologia , Microdiálise/métodos , Microglia/metabolismo , Microglia/patologia , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos , Ratos WistarRESUMO
The brain damage, which occurs after either chronic alcoholization or binge drinking regimes, shows distinct biochemical and neurotransmitter differences. An excessive amount of glutamate is released into specific brain regions during binge drinking (in excess of 4- to 5-fold of the normal basal concentration) that is not evident during periods of excessive alcohol consumption in chronic alcohol abusers. Increases in glutamate release are only observed during the initial stages of withdrawal from chronic alcoholism ( approximately 2- to 3-fold) due to alterations in the sensitivities of the NMDA receptors. Such changes in either density or sensitivity of these receptors are reported to be unaltered by binge drinking. When such excesses of glutamate are released in these two different models of alcohol abuse, a wide range of biochemical changes occur, mediated in part by increased fluxes of calcium ions and/or activation of various G-protein-associated signalling pathways. Cellular studies of alveolar macrophages isolated from these two animal models of alcohol abuse showed enhanced (binge drinking) or reduced (chronic alcoholization) lipopolysaccharide (LPS)-stimulated NO release. Such studies could suggest that neuroadaptation occurs with the development of tolerance to alcohol's effects in both neurotransmitter function and cellular processes during chronic alcoholization that delay the occurrence of brain damage. In contrast, 'binge drinking' induces immediate and toxic effects and there is no evidence of an increased preference for alcohol as seen after withdrawal from chronic alcoholization.
Assuntos
Alcoolismo/patologia , Química Encefálica/efeitos dos fármacos , Dano Encefálico Crônico/induzido quimicamente , Neurotransmissores/metabolismo , Doença Aguda , Aminoácidos/fisiologia , Animais , Dano Encefálico Crônico/patologia , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , FosforilaçãoRESUMO
AIMS: The possible interaction between nicotine and 'binge drinking' in eliciting changes in behavioural patterns of 'binge drinking' rats as well as nucleus accumbens (NAc) glutamate levels has been investigated in these present studies. METHODS: Adult or adolescent male and female rats received ethanol, 2 g/kg or 3 g/kg, by gavage in a 'binge drinking' regimen (3 times/day over a 6 h period, for 2 days followed by 5 days of abstinence) combined with or without nicotine, 0.3 g/kg, for either a 5-week (adult) or a 4-week (adolescent) period. Motor activity was then assessed for a period of 60 min after three further doses of ethanol or water. In addition, the NAc glutamate level was assayed in each group for 1 h after the first gavage regimen with ethanol, 2 g/kg or 3 g/kg, or water. RESULTS: Adult female rats showed greater sensitivity to each ethanol dose (2 g/kg and 3 g/kg) than the adult male rats, their motor activity decreasing during the first and third 'binge'. In contrast, in male adult rats, the sedative effects of ethanol were reduced, particularly after the third binge when no significant changes in the locomotor activity were apparent between the ethanol-administered male rats and controls. Adolescent rats did differ in their response to ethanol in comparison with adult rats. It was noteworthy that in young female adolescent rats, given 2 g/kg ethanol, motor activity was enhanced, thereby indicating that adolescent female rats are less sensitive to the sedative effects of ethanol at specific doses. In addition, male and female adolescent rats showed little change in locomotor activity in comparison with controls during the third 'binge administration' possibly indicating that tolerance to such alcohol doses was occurring. Nicotine administration did prevent the decrease in locomotor activity after ethanol administration during the first binge regimen in both male and female adolescents as well as adult female rats. However, after the third binge, such alcohol-induced changes in motor activity were not so well defined in the female adult rats that now showed significant decreases in motor activity. In contrast, adolescent male and female rats still showed similar motor activity to that of the controls. No clear association between the NAc glutamate extracellular content and locomotor activity was discernible in either adult or adolescent rats in these present studies. However, chronic nicotine administration markedly reduced the elevated basal glutamate content in the 'binge drinking female' adult rats. CONCLUSIONS: These studies have shown clear and distinct differences, with respect to both sensitivity and tolerance, in adult and adolescent male and female rats, which could be modified by supplementation with nicotine.
Assuntos
Etanol/toxicidade , Atividade Motora/fisiologia , Nicotina/toxicidade , Núcleo Accumbens/química , Caracteres Sexuais , Animais , Esquema de Medicação , Feminino , Ácido Glutâmico/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Ratos , Ratos Wistar , AutoadministraçãoRESUMO
AIM: The aim of the present study is to examine the distribution of plasma excitatory and inhibitory amino acids, according to the age and current breath alcohol levels (BrAl+/-), of alcohol-dependent patients. PARTICIPANTS AND METHODS: 78 alcohol-dependent patients (mean age=46.2+/-11 years, men/women=54/24) were clinically tested, including the determination of the major excitatory as well as inhibitory amino acids. The independent variables were gender, age and current alcohol consumption measured with the breath alcohol level (BrAl+/-status). RESULTS: In comparison to BrAl negatives, BrAl positives had higher plasma levels of glutamic acid (P=0.01) and proline (P=0.026), and lower levels of aminobutyric acid (P=0.002), serine (P=0.031) and urea (P=0.01). In the BrAl positives, no age effect was found related to the plasma amino acids. In contrast, the BrAl negatives displayed age-related differences. The older (>or=50 years) BrAl negative patients had higher plasma levels of cystine, tyrosine, citrulline and urea, and lower histidine levels, compared to the younger group (<50 years). In general, differences in plasma levels of certain amino acids were dependent on gender, BrAl status, age and biochemical markers (GGT, MCV) of alcohol abuse. CONCLUSIONS: Abstaining patients (BrAl-/) display age-related differences in AAs' distribution, while active drinking (BrAl+/) seems to even out those differences, underpinning the hypothesis that drinking mimics changes seen with advanced age.
Assuntos
Alcoolismo/sangue , Aminoácidos/sangue , Etanol/sangue , Adulto , Fatores Etários , Idoso , Testes Respiratórios/métodos , Etanol/análise , Jejum/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Although TauA shares few common characteristics with other known periplasmic binding protein, TauA is a putative periplasmic binding protein, part of tauABCD gene cluster involved in sulfonate transport in sulphate starvation condition. This protein was expressed in E. coli BL 21 and purified before to assess its binding functionalities. Measurement of K (d) value (mean 11.3 nM) by binding/dialysis studies revealed high affinity and specificity with taurine and also indicated that TauA possessed a unique binding site for its ligand. Comparisons with other periplasmic binding proteins suggests TauA plays a major role in ABC transport system and could be ideal candidate to serve as taurine catcher in biological fluids.
Assuntos
Transportadores de Cassetes de Ligação de ATP/química , Proteínas de Escherichia coli/química , Escherichia coli/metabolismo , Transportadores de Cassetes de Ligação de ATP/fisiologia , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Proteínas de Escherichia coli/fisiologia , Regulação Bacteriana da Expressão Gênica , Cinética , Ligantes , Proteínas de Membrana Transportadoras/química , Proteínas Periplásmicas de Ligação/metabolismo , Plasmídeos/metabolismo , Ligação Proteica , Desnaturação Proteica , Dobramento de Proteína , Taurina/químicaRESUMO
The effects of nicotine, when administered either acutely or chronically, at doses of 0.15, 0.3 or 0.6 mg/kg, on the release of glutamate and arginine in the rat nucleus accumbens have been studied in microdialysis experiments. Glutamate release significantly increased after acute nicotine injection, 0.3 mg/kg, which was accentuated if there was a priming regime of saline for the previous 27 days. This is possibly related to the rewarding effects of nicotine. Five hours after cessation of chronic oral nicotine administration, there were significant increases in glutamate content, which was possibly reflective of a withdrawal process. Significant decreases in nucleus accumbens arginine release were evident, between 1 and 2 h, after chronic nicotine administration. When nicotine was co-administered to rats during chronic ethanol intoxication, at either 0.15 mg/kg or 0.3 mg/kg doses, glutamate release did not increase during the first 12 h of withdrawal. However, a decrease in arginine microdialysate content was still observed with all nicotine doses. The nicotine-induced changes in glutamate and arginine release in nucleus accumbens highlights the complex neuropharmacological interactions evoked by this compound and also identified its possible modulating effect on glutamate release during the initial stages of chronic ethanol withdrawal.
Assuntos
Transtornos do Sistema Nervoso Induzidos por Álcool/metabolismo , Arginina/metabolismo , Ácido Glutâmico/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Síndrome de Abstinência a Substâncias/metabolismo , Tabagismo/metabolismo , Transtornos do Sistema Nervoso Induzidos por Álcool/fisiopatologia , Animais , Química Encefálica/efeitos dos fármacos , Química Encefálica/fisiologia , Depressores do Sistema Nervoso Central/efeitos adversos , Doença Crônica , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interações Medicamentosas/fisiologia , Tolerância a Medicamentos/fisiologia , Etanol/efeitos adversos , Líquido Extracelular/efeitos dos fármacos , Líquido Extracelular/metabolismo , Masculino , Microdiálise , Nicotina/efeitos adversos , Agonistas Nicotínicos/efeitos adversos , Óxido Nítrico/biossíntese , Núcleo Accumbens/metabolismo , Núcleo Accumbens/fisiopatologia , Ratos , Ratos Wistar , Síndrome de Abstinência a Substâncias/fisiopatologia , Tabagismo/fisiopatologiaRESUMO
This study investigated the effect of the new CB1 cannabinoid receptor antagonist, SR147778, on ethanol preference in chronically alcoholized Wistar rats. In study 1, SR147778, at doses of 0.3, 1, or 10 mg/kg/day (mg/kg/d) intraperitonealy (ip), was administered during chronic pulmonary ethanol intoxication for 30 days. The rats were then exposed to a two-bottle choice (ethanol 10% v/v vs. water) for at least 30 days. Neither 0.3 nor 1 mg/kg/d had any effect on ethanol preference. In contrast, the high dose induced a significant transient increase in ethanol intake between days 6 and 10. In study 2, SR147778, at doses of 0.3, 1, or 10 mg/kg/d ip, was administered during the free-choice period after chronic alcoholization. Both ethanol preference and intake were significantly reduced only for 1 and 10 mg/kg/d. These results reinforce the hypothesis that the cannabinoid CB1 receptor is part of the neural substrate mediating alcohol intake and the motivational properties of alcohol. When these results are compared with those obtained with SR141716 (Rimonabant) on ethanol preference, we observed that (1) coadministration of 10 mg/kg/d SR147778 during chronic alcoholization induced a shorter transient increase of ethanol intake than Rimonabant and (2) SR147778 treatment during the free-choice period at doses of 1 and 10 mg/kg/d decreased ethanol intake more dramatically than SR141716 which, furthermore, continued for the duration of the free choice.
Assuntos
Alcoolismo/tratamento farmacológico , Piperidinas/farmacologia , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Preferências Alimentares/efeitos dos fármacos , Masculino , Piperidinas/uso terapêutico , Pirazóis/uso terapêutico , Ratos , Ratos Wistar , Rimonabanto , SacaroseRESUMO
Acamprosate is an abstinence-promoting drug widely used in the treatment of alcohol dependence but which has a mechanism of action that has remained obscure for many years. Recently, evidence has emerged that this drug may interact with excitatory glutamatergic neurotransmission in general and as an antagonist of the metabotropic glutamate receptor subtype 5 (mGluR5) in particular. These findings provide, for the first time, a satisfactory, unifying hypothesis that can bring together and explain the diverse neurochemical effects of acamprosate. Glutamic acid is involved in several aspects of alcohol dependence and withdrawal, many of which can be modified by acamprosate. For example, during chronic exposure to alcohol, the glutamatergic system becomes upregulated, leaving the brain exposed to excessive glutamatergic activity when alcohol is abruptly withdrawn. The surge in glutamic acid release that occurs following alcohol withdrawal can be attenuated by acamprosate. The elevated extracellular levels of glutamic acid observed in withdrawal, together with supersensitivity of NMDA receptors, may expose vulnerable neurons to excitotoxicity, possibly contributing to the neuronal loss sometimes observed in chronic alcohol dependence. In vitro studies suggest that the excitotoxicity produced by ethanol can effectively be blocked by acamprosate. Moreover, glutamatergic neurotransmission plays an important role in the acquisition of cue-elicited drinking behaviours, which again can be modulated by acamprosate. In conclusion, the glutamatergic hypothesis of the mechanism of action of acamprosate helps explain many of its effects in human alcohol dependence and points the way to potential new activities, such as neuroprotection, that merit exploration in the clinic.
Assuntos
Alcoolismo/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Taurina/análogos & derivados , Taurina/uso terapêutico , Acamprosato , Animais , Interações Medicamentosas , Etanol/efeitos adversos , Etanol/farmacologia , Aminoácidos Excitatórios/farmacologia , Humanos , Modelos Biológicos , Fármacos Neuroprotetores/farmacologia , Receptores de Glutamato/fisiologia , Taurina/farmacologiaRESUMO
The salicylate trap method, combined with microdialysis, has been used to validate whether reactive oxygen species, particularly hydroxyl radicals, ((*)OH), are generated in the hippocampus of male Wistar rats after acute intraperitoneal administration of either ethanol, 2 and 3 g/kg, or acetaldehyde, 200 mg, or during the initial stages of ethanol withdrawal after chronic ethanol intoxication. Salicylate (5 mM) was infused into the hippocampus via the microdialysis probe and the products of its metabolism by hydroxyl radical, particularly 2,3-dihydroxybenzoic acid (2,3-DHBA) as well as 2,5-dihydroxybenzoic acid (2,5-DHBA) assayed by HPLC (High Pressure Liquid Chromatography). Acetaldehyde, 200 mg/kg, and the higher acute dose of ethanol, 3 g/kg, induced transitory increases in 2,3-DHBA and 2,5-DHBA microdialysate content. At the cessation of four weeks of chronic ethanol intoxication, (by the vapour inhalation method), the mean blood alcohol level was 1.90 g/l. Significant increases of microdialysate 2,3-DHBA and 2,5-DHBA levels were assayed 3 h after alcohol withdrawal which were sustained for a further 5 and 1 h 40 min respectively. Oral administration of Acamprosate, 400 mg/kg/day, during the chronic ethanol intoxication procedure prevented the increased formation of 2,3- and 2,5-DHBA by comparison to rats chronically ethanol intoxicated alone.
Assuntos
Acetaldeído/administração & dosagem , Dissuasores de Álcool/farmacologia , Alcoolismo/metabolismo , Etanol/administração & dosagem , Hipocampo/metabolismo , Radical Hidroxila/metabolismo , Síndrome de Abstinência a Substâncias/metabolismo , Taurina/análogos & derivados , Acamprosato , Dissuasores de Álcool/administração & dosagem , Alcoolismo/sangue , Animais , Modelos Animais de Doenças , Etanol/sangue , Gentisatos/análise , Hipocampo/efeitos dos fármacos , Hidroxibenzoatos/análise , Masculino , Microdiálise , Ratos , Ratos Wistar , Ácido Salicílico , Taurina/administração & dosagem , Taurina/farmacologia , Fatores de TempoRESUMO
The action of nicotine on the nicotinic receptor-mediated release of inhibitory and excitatory acids in the nucleus accumbens, NAC, of freely moving rats was studied in order to clarify their effects' on reinforcing behavior as estimated by conditioned place preference (CPP). Using the technique of microdialysis, intraperitoneal (i.p.) injections of nicotine (0.15-0.3-0.6 mg/kg), significantly increased aspartate, glutamate, arginine, taurine, and alanine microdialysate content in the nucleus accumbens. The same doses of nicotine were able to elicit a reinforcing effect in a CPP paradigm which was probably associated with the increased brain levels of excitatory acids triggering additional dopamine release in the mesolimbic system.
Assuntos
Aminoácidos/metabolismo , Química Encefálica/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Animais , Relação Dose-Resposta a Droga , Injeções Intraperitoneais , Sistema Límbico/efeitos dos fármacos , Sistema Límbico/metabolismo , Masculino , Microdiálise , Ratos , Ratos Wistar , Olfato/efeitos dos fármacos , Estimulação Química , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/metabolismoRESUMO
RATIONALE: Previous studies have indicated that the conditioned effects of environmental stimuli contribute to ethanol tolerance and abuse. Acamprosate was recently suggested to reduce the effects of environmental stimuli previously associated with ethanol administrations. This action is believed to contribute to the clinical benefits of acamprosate treatment in alcoholics. OBJECTIVES: In the present experiment, a classical drug-conditioning paradigm was used to test whether acamprosate modulates the effects of ethanol-paired environmental stimuli on spontaneous motor activity. METHODS: Wistar rats were divided into three groups: cued, uncued and control. The cued group daily received ethanol injections (2.0 g/kg, IP) in a specific testing environment. The uncued group daily received ethanol injections (2.0 g/kg, IP) in their home cage but never experienced ethanol in the testing environment. The control group was injected with saline and never experienced ethanol. After 8 conditioning days, the rats were IP injected with various ethanol doses (saline, 1.0, 1.5 or 2.0 g/kg) and their spontaneous motor activity in the testing environment was recorded to investigate their respective tolerance to ethanol inhibitory effects. In the second part of the study, the same procedure was repeated with chronically acamprosate-treated rats. The chronic acamprosate treatment (400 mg/kg per day) started 2 weeks before the conditioning procedure by diluting acamprosate in the drinking bottles and was maintained throughout the whole experiment. RESULTS: The cued rats showed a significant environment-dependent tolerance to ethanol inhibitory effects relative to the uncued and control rats. This higher ethanol tolerance of the cued rats was mainly due to a faster recovery from ethanol's inhibitory effects on spontaneous activity. Furthermore, the cued rats showed a higher level of activity in the testing environment after the saline injection. However, it is not clear whether this hyperactivity is a conditioned compensatory response or an increased exploratory behavior. Acamprosate totally abolished the environment-dependent tolerance to ethanol, whereas it did not alter the hyperactivity of the cued rats in the testing environment. CONCLUSIONS: The results of the present study suggest that acamprosate reduces ethanol-conditioned effects. Such an action may be of importance to explain the anti-relapse effects of acamprosate.
Assuntos
Sinais (Psicologia) , Etanol/farmacologia , Atividade Motora/efeitos dos fármacos , Taurina/análogos & derivados , Taurina/farmacologia , Acamprosato , Animais , Relação Dose-Resposta a Droga , Etanol/sangue , Masculino , Atividade Motora/fisiologia , Ratos , Ratos WistarRESUMO
RATIONALE: In spite of many recent studies on the effects of acetaldehyde, it is still unclear whether acetaldehyde mediates the reinforcing and/or aversive effects of ethanol. OBJECTIVES: The present study reexamined the role of acetaldehyde in ethanol-induced conditioned taste aversion (CTA). A first experiment compared ethanol- and acetaldehyde-induced CTA. In a second experiment, cyanamide, an aldehyde dehydrogenase inhibitor, was administered before conditioning with either ethanol or acetaldehyde to investigate the effects of acetaldehyde accumulation. METHODS: A classic CTA protocol was used to associate the taste of a saccharin solution with either ethanol or acetaldehyde injections. In experiment 1, saccharin consumption was followed by injections of either ethanol (0, 0.5, 1.0, 1.5 or 2.0 g/kg) or acetaldehyde (0, 100, 170 or 300 mg/kg). In experiment 2, the rats were pretreated with either saline or cyanamide (25 mg/kg) before conditioning with either ethanol or acetaldehyde. RESULTS: Both ethanol and acetaldehyde induced significant CTA. However, ethanol produced a very strong CTA relative to acetaldehyde that induced only a weak CTA even at toxic doses. Cyanamide pretreatments significantly potentiated ethanol- but not acetaldehyde-induced CTA. CONCLUSIONS: The present results indicate that ethanol-induced CTA does not result from brain acetaldehyde effects. In contrast, it is suggested that the reinforcing effects of brain acetaldehyde might actually reduce ethanol-induced CTA. Our results also suggest that the inhibition of brain catalase activity may contribute to the potentiating effects of cyanamide on ethanol-induced CTA.
Assuntos
Acetaldeído/farmacologia , Consumo de Bebidas Alcoólicas/metabolismo , Condicionamento Psicológico/efeitos dos fármacos , Etanol/farmacologia , Acetaldeído/administração & dosagem , Acetaldeído/metabolismo , Dissuasores de Álcool/administração & dosagem , Dissuasores de Álcool/farmacologia , Consumo de Bebidas Alcoólicas/psicologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento de Escolha/efeitos dos fármacos , Cianamida/administração & dosagem , Cianamida/farmacologia , Relação Dose-Resposta a Droga , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Etanol/administração & dosagem , Etanol/metabolismo , Masculino , Ratos , Ratos Wistar , Sacarina/administração & dosagem , Cloreto de Sódio/administração & dosagem , Água/administração & dosagemRESUMO
Changes in amino acid levels in the hippocampus during repeated ethanol withdrawal were studied. Wistar rats were made ethanol-dependent by 4-week vapour inhalation. After this first cycle of chronic ethanol treatment, rats underwent repeated and alternate cycles of 24 h of withdrawal followed by 1 week of chronic ethanol treatment. The microdialysis technique was used together with high-performance liquid chromatography and electrochemical detection to separate and quantify different amino acids such as aspartate, glutamate, arginine, taurine, alanine and gamma-aminobutyric acid. During the first cycle of ethanol withdrawal, increases in glutamate, taurine and alanine levels were observed. During the third withdrawal period, further increases were detected in aspartate, glutamate, taurine and alanine in the comparison with levels in the control group. However, the arginine level during the third withdrawal period decreased when compared to that after the first withdrawal period. The results of this study demonstrate that excitatory amino acid levels increased with subsequent withdrawal periods.
Assuntos
Etanol/administração & dosagem , Aminoácidos Excitatórios/metabolismo , Hipocampo/metabolismo , Microdiálise/métodos , Síndrome de Abstinência a Substâncias/metabolismo , Animais , Hipocampo/efeitos dos fármacos , Masculino , Ratos , Ratos WistarRESUMO
Several microdialysis studies have investigated the effects of acute ethanol on extracellular amino acids in various rat brain regions. However, these studies led to conflicting results, suggesting that individual differences between rat strains and lines may play an important role. In the present study, high-alcohol sensitive (HAS) and low-alcohol sensitive (LAS) rats were used to investigate the possible relationship between ethanol sensitivity and the concentrations of extracellular amino acids in the nucleus accumbens. Several groups of HAS and LAS rats were injected with either saline or ethanol (1.0, 2.0 or 3.0 g/kg, i.p.) and the concentrations of amino acids in the nucleus accumbens microdialysates were assayed by electrochemical detection. Acute ethanol induced a dose-dependent increase in extracellular taurine concentrations. However, this increase was significantly reduced at 2.0 and 3.0 g/kg ethanol in HAS rats relative to LAS rats. Since the biological functions of taurine suggest its implication in the reduction of ethanol adverse effects, a higher increase in taurine concentrations may contribute to the lower ethanol sensitivity of LAS rats. Although 2.0 and 3.0 g/kg ethanol did not affect extracellular glutamate concentrations, a significant increase in glutamate was observed after 1.0 g/kg ethanol to HAS rats but not to LAS rats. Such an effect remains unexplained but suggests that discrepancies between the results of previous microdialysate studies may be related to differences in the ethanol sensitivities of various rat strains.