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BACKGROUND: Phosphatidylethanol (PEth) is a direct marker of alcohol consumption, which has been known for almost 30 years. Each PEth molecule carries 2 fatty acids, which differ in chain length and degree of unsaturation. It is formed by means of phospholipase D in the presence of ethanol. Usually, this marker was used by quantification of the PEth homologue 16:0/18:1. The intention of this work was to get more information about the distribution and the quantity of the different PEth homologues. METHODS: Blood samples from 12 alcohol-dependent subjects were collected and analyzed during withdrawal therapy. For comparison, blood from 78 healthy social drinkers was also analyzed. PEth analysis was performed as follows: after liquid-liquid extraction, the homologues were separated on a Luna Phenyl Hexyl column, injected to an HPLC system (1100 system; Agilent) and identified by ESI-MS/MS (QTrap 2000; AB Sciex) using multiple reaction monitoring. RESULTS: PEth 16:0/18:1 is the major homologue comparing the area ratios of PEth homologues in blood samples from alcoholics. Additional prevalent homologues were PEth 16:0/18:2, 18:0/18:2, and 18:0/18:1. The homologues occurring in blood samples from alcoholics as well as from social drinkers were mostly the same, but differences among their distribution pattern were observed. CONCLUSIONS: In addition to the approach to quantitate the PEth homologue 16:0/18:1, this is a new and alternative proceeding for the differentiation between alcoholics and social drinkers using this alcohol consumption marker.

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Chronic ethanol exposure produces profound disruptions in both brain rhythms and diurnal behaviors. The thalamus has been identified as a neural pacemaker of both normal and abnormal rhythms with low-threshold, transient (T-type) Ca(2+) channels participating in this activity. We therefore examined T-type channel gene expression and physiology in the thalamus of C57Bl/6 mice during a 4-wk schedule of chronic intermittent ethanol exposures in a vapor chamber. We found that chronic ethanol disrupts the normal daily variations of both thalamic T-type channel mRNA levels and alters thalamic T-type channel gating properties. The changes measured in channel expression and function were associated with an increase in low-threshold bursts of action potentials during acute withdrawal periods. Additionally, the observed molecular and physiological alterations in the channel properties in wild-type mice occurred in parallel with a progressive disruption in the normal daily variations in theta (4-9 Hz) power recorded in the cortical electroencephalogram. Theta rhythms remained disrupted during a subsequent week of withdrawal but were restored with the T-type channel blocker ethosuximide. Our results demonstrate that a key ion channel underlying the generation of thalamic rhythms is altered during chronic ethanol exposure and withdrawal and may be a novel target in the management of abnormal network activity due to chronic alcoholism.

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This review summarizes the pioneering steps culminating in the identification of a novel disease, fatal familial insomnia (FFI), a hereditary prion disease. Together with Morvan's chorea and delirium tremens, FFI is characterized by an inability to sleep associated with motor and autonomic overactivation. We named this pattern agrypnia excitata, a syndrome caused by a dysfunction in thalamolimbic circuits. This review highlights the strategic role of the limbic thalamus in the central autonomic network running from the limbic cortex to the lower brainstem and regulating sleep and wakefulness.

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One hundred and fifty-seven men with alcohol withdrawal syndrome, including 127 with delirium of different severity, have been studied. During delirium, sequestration of erythrocytes in the vessels and exudation of the fluid into the cellular space developed. There were marked capillary blood flow disturbances with erythrocyte aggregation, metabolic acidosis, compensated with respiratory alkalosis, total lactate dehydrogenase activity elevation, Na+ and K+ decrease in blood plasma and K+ reduction in erythrocytes in a severe form of alcohol delirium. The authors suggest that the complex of disorders observed is similar to shock process, and hemodynamic disturbances may be involved in the development of consciousness disorders.

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O objetivo deste artigo é o de revisar e descrever as principais alteracões neurofarmacológicas causadas pela exposicão crônica ao álcool, assim como os fenômenos ocorridos durante o período de abstinência. São apresentados dados referentes às alteracões neuroadaptativas e de tolerância ocorridas nos principais sistemas de monoaminas, aminoácidos neurotransmissores e canais de cálcio, o que está relacionado a uma piora no prognóstico de portadores de comorbidades psiquiátricas com o consumo de álcool. São também descritos alguns estudos relevantes que demonstram o envolvimento de outros mecanismos de acão do álcool no sistema nervoso central, como o envolvimento de opióides, entre outras substâncias. O artigo reafirma a importância, para clínicos e pesquisadores, de um sempre maior entendimento do mecanismo de acão central do álcool, pois dele depende a busca por novas opcões farmacológicas, tanto para a reducão dos danos provocados pelo seu uso crônico, como para o tratamento da síndrome de abstinência a esta substância.

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The objective of this paper is to review and describe the main neuropharmacological changes caused by the chronic use of alcohol and those observed during its withdrawal period. The results show international data referring to the involvement of monoamine systems, neurotransmitters and calcium channels in both neuroadaptation and tolerance to alcohol effects and withdrawal. Relevant studies showing the participation of other systems in those mechanisms, as opioids and other substances, are also shown. The article reinforces the importance, for both physicians and researchers, of an always growing understanding of alcohol central mechanisms of action. This understanding is necessary to new pharmacological options to alcohol harm reduction as well as to alcohol withdrawal treatment.

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The author reports his results of parenteral piracetam treatment in 193 patients admitted to the Psychiatric Department of Semmelweis Hospital with alcohol withdrawal delirium. Alcohol withdrawal delirium is a complex metabolic disorder, the disturbance of the highest cerebral integrative functions, which is caused by the impairment of cerebral oxidative metabolism. Piracetam is effective on most neurotransmitter systems, without a specific receptor agonism or antagonism, increases the effectivity of different biogenic amine systems, has also an effect on membrane permeability, increases the concentration of NMDA (methyl-D-aspartate) receptors in the impaired brain and improves cognitive functions. In the patients suffered from alcohol dependence piracetam produces positive morphologic changes, by decreasing lipofuscin accumulation. In early stage it prevents the development of delirium. Despite of the great number (approximately 150) of medication that were tried in the treatment of delirium, the ideal one still has not been found. Among the accessible therapeutic possibilities the author searched for methods which make the treatment more effective. The administration of parental piracetam, therefore was brought into his therapeutical protocol. Parenteral piracetam--similarly to literature data--proved to be effective in the treatment of alcohol withdrawal delirium. Considering the present--insufficient--hospital financing, it is remarkable that though the costs of the new therapy are higher than the traditional meprobamat therapy, through less side effect it is more economical (overall costs lower) and by decreasing the time of delirium it is more humane to the patients.

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Little is known about 5-hydroxyindolacetic acid (5-HIAA) and homovanillic acid (HVA) levels in cerebrospinal fluid of patients with Delirium Tremens revealed at onset by seizures. The aim of the study is to understand the biochemical abnormalities induced by seizures in the cerebrospinal fluid of patients involved by Delirium Tremens. Nine patients 42-62 years of age, who had experienced a Delirium Tremens after alcohol withdrawal, with one or two seizures at onset, were included in this study. The lumbar puncture (and a CT scan) were performed after the last seizure. Nine patients with neither Delirium Tremens nor seizure, needing a lumbar puncture for their medical problem, were matched by sex and by age. For the measures of 5-HIAA and HVA, we systematically took the first cm3. The mean value of 5-HIAA levels were 12.70 ng ml(-1) in the group of nine patients with Delirium Tremens versus 13.45 ng ml(-1) in the control group. The mean value of HVA levels were 19.81 ng ml(-1) in the group of nine patients with Delirium Tremens versus 25.25 ng ml(-1) in the control group. The differences were not statistically significant. During a Delirium Tremens with seizure at onset, there are no statistically significant changes in 5-HIAA and HVA levels in the cerebrospinal fluid. Our work raises the question of the role of Delirium Tremens in the normalization of the levels of neuro-mediators that usually decrease soon after seizures.

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Previous studies have implicated the dopamine and opioid systems in the induction and maintenance of ethanol consumption. This study investigated, in alcohol-preferring Fawn-Hooded (FH) rats, whether chronic free-choice ethanol consumption and subsequent withdrawal cause alterations in central mu-opioid, dopamine D(1), and D(2) receptor density using autoradiography. FH rats were given a free choice between a 5% ethanol solution and tap water (n = 25) and displayed a mean ethanol consumption of 5.6 g/kg/day. A parallel group of FH rats (n = 5) only had access to tap water. Rats were then withdrawn from ethanol for 0, 1, 2, 5, or 10 days and killed by cervical dislocation and decapitation. Increases in mu-opioid receptor density were observed in the nucleus accumbens and ventral tegmental area upon withdrawal compared with the ethanol naive group. In the lateral amygdala, binding in all withdrawal groups was significantly different from the ethanol naive FH rats, and also from the chronic ethanol rats. An increase in dopamine D(1) receptor density was observed in the substantia nigra, pars reticulata in the 5- and 10-day withdrawal groups compared with ethanol naive. Accumbal dopamine D(2) receptor density (+25-30%) increased in the 10-day withdrawal group compared with both naive and chronic ethanol groups. These findings demonstrate that the opioid and dopamine systems are susceptible to modulation by chronic ethanol consumption and withdrawal in the FH rat. Furthermore, although acute ethanol withdrawal results in modulation of mu-opioid receptors, effects on dopamine receptors are delayed and only become evident 5 to 10 days after withdrawal.

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- Up-regulation of the glutamatergic neurotransmission from chronic ethanol intoxication may cause a hyperexcitable state during alcohol withdrawal that may lead to seizures and delirium tremens. The aim of our study was to evaluate the association between a history of alcohol withdrawal-induced seizures and delirium tremens and a mGlurR7 (Tyr433Phe); and a mGlurR8 (C2756T) metabotropic glutamate receptor polymorphism in alcoholics compared to controls. A total of 182 patients meeting DSM-IV alcohol dependence criteria and 117 controls, both groups being of German descent, were investigated. mGluR7 and mGluR8 polymorphisms were determined using polymerase chain reaction of lymphocyte DNA. History of alcohol withdrawal-induced delirium tremens and seizures were obtained using the Semi-Structured Assessment of Genetics in Alcoholism (SSAGA). Data were cross-checked with inpatients' clinical files. No significant associations were obtained between both receptor polymorphisms and alcohol withdrawal-induced seizures and delirium tremens. The negative results in this study question the role of these polymorphisms in the pathogenesis of alcohol withdrawal-induced seizures and delirium tremens.

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Alcohol-related temporary depressive symptoms are hypothesized to be related to dopaminergic dysfunction. The aim of this study was to investigate whether or not depressive symptoms correlate with reduced dopamine transporter (DAT) availability. We studied the DAT availability in 28 alcoholic subjects with beta-CIT ([123-iodium]-2-betacarbomethoxy-3-beta-(4-iodophenyl)-tropa ne) single photon emission tomography (SPET) and found a reduction in DAT availability during withdrawal that subsequently showed a significant increase during sobriety. The relationship between DAT availability and Montgomery-Asberg Depression Rating scale scores, both during withdrawal and after sobriety, was assessed. The main finding was a statistically significant correlation between DAT variances and depressive symptom scores during both states. The findings indicate a possible dopaminergic etiology for depressive symptoms in alcohol withdrawal, which suggests that dopaminergic antidepressants might be beneficial in the treatment of alcohol withdrawal.

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Use of sodium hypochlorite in combined therapy of patients with alcoholic delirium complicating acute poisoning with psychotropic drugs, caustic poisons, alcohol and its surrogates resulted in an appreciable decrease in the duration of alcoholic delirium.

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The pharmacological properties of gamma-aminobutyric acidA (GABA(A)) receptors are altered by prolonged exposure to ethanol both in vivo and in vitro. We have shown previously that prolonged ethanol exposure elicits selective alterations in various GABA(A) receptor subunit mRNA levels in rat cerebral cortex. Some of these effects are rapidly reversed during ethanol withdrawal. The present study was conducted to determine the effects of prolonged ethanol exposure (dependence) and ethanol withdrawal on cerebral cortical peptide expression for several subunits. GABA(A) receptor alpha1 subunit peptide levels were decreased by nearly 40%, whereas alpha4 subunit peptide levels were increased by 27% in both ethanol-dependent and withdrawn rats. These changes correlate well with observed alterations in mRNA levels following prolonged ethanol exposure in dependent rats, but do not match the effects on mRNA levels during ethanol withdrawal. Beta2/3 subunit peptide levels increased by approximately 32% in both ethanol-dependent rats and rats undergoing ethanol withdrawal. We observed a 30-60% increase in gamma1 subunit peptide levels in both dependent rats and those undergoing withdrawal, also correlating with the previous report on ethanol-induced alterations in mRNA levels. Peptide levels for gamma2 subunits did not differ from control values in either condition. These findings show that specific alterations in GABA(A) receptor subunit peptide levels are associated with ethanol dependence in rats. GABA(A) receptor subunit peptide expression is more stable than mRNA expression, and mRNA levels are not representative of peptide expression during ethanol withdrawal. These findings are consistent with the suggestion that alterations in GABA(A) receptor gene expression underlie the functional properties of GABA(A) receptors in ethanol-dependent rats and those undergoing ethanol withdrawal.

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The DNA-binding activities of AP-1 and Egr proteins were investigated in nuclear extracts of rat brain regions during ethanol withdrawal. Both DNA-binding activities were transiently elevated in the hippocampus and cerebellum 16 h after withdrawal. In the cerebral cortex, AP-1 and Egr DNA-binding activities increased at 16 h and persisted until 32 and 72 h, respectively. The AP-1 DNA-binding activities in all regions at all times after withdrawal were composed of FosB, c-Jun, JunB, and JunD. c-Fos was detected at all times in the cerebral cortex, at 16 h only in the hippocampus, and from 16 to 72 h in the cerebellum. Withdrawal severity did not affect the composition of the AP-1 DNA-binding activities. Two Egr DNA-binding activities were present in the cortex and hippocampus. The faster-migrating complex predominated in hippocampus, and only the slower-migrating complex (identified as Egr-1) was present in the cerebellum. The increase in DNA-binding activity of immediate early gene-encoded transcription factors supports their proposed role in initiating a cascade of altered gene expression underlying the long-term neuronal response to ethanol withdrawal.

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Hereditary factors confer susceptibility to alcohol dependence. Alcohol mediates its reinforcing effects by enhancing dopamine activity in the mesolimbic dopamine system. The role of the dopamine transporter in terminating dopaminergic activity in synaptic neurotransmission suggests that variants of the dopamine transporter gene (DAT1) might contribute to individual differences in vulnerability to addictive behavior. Our population-based association study investigated whether variants of DAT1 confer susceptibility to alcohol dependence in 293 alcoholics and clinically more homogeneous subgroups formed by: positive family history, early age-at-onset, delirium, withdrawal seizures, antisocial tendencies, type 1 and 2 alcoholics. Analyzing a VNTR polymorphism in the 3' untranslated region of DAT1, we found a significantly increased prevalence of the nine-repeat allele in 93 alcoholics displaying withdrawal seizures or delirium, compared with 93 ethnically matched nonalcoholic controls (p = 0.003; OR = 2.44; 95% confidence interval: 1.35-4.43). Our data provide evidence that a major genetic determinant of DAT1 influences vulnerability to severe alcohol withdrawal symptoms.

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OBJECTIVE: The role of a deficiency of vitamin B1 in the development of alcoholic complaints is confined to the case of the Wernicke-Korsakov syndrome. Findings concerning a deficiency of thiamine in alcoholics in comparison with normal persons are contradictory and there are no differentiated tests in the case of delirium tremens. In this study the vitamin B1 absorption in patients with delirium tremens was of interest in connection with the presence or absence of hallucinations and autonomic symptoms. METHOD: Male patients (N = 70) with delirium tremens were compared with a group of 13 controls. The controls and patients were hospitalized in order to ensure abstinence from alcohol. The examination of the delirium patients was carried out with their consent after termination of the delirium tremens and again on discontinuance of drug therapy. In the case of 33 delirium patients the absorption of thiamine was tested again 4 weeks after the first examination. RESULTS: The absorption of vitamin B1 was in general only minimally lower in the case of the delirium patients in comparison with the nonalcoholics. The results showed, however, a considerably greater range of scattering of vitamin B1 absorption in the delirium patients. The absorption conditions showed marked improvement in the 4 weeks after delirium. The extent of absorption of vitamin B1 showed no influence on the duration of delirium. The patients with visual hallucinations, however, showed lower thiamine absorption than patients without such symptoms, whereas no dependence of autonomic symptoms on vitamin B1 absorption was seen. CONCLUSIONS: The disturbed absorption conditions in the delirium patients were obvious at the time of the examination as demonstrated by the wide range of absorption values. Improvement or near normal conditions were registered 4 weeks after the delirium. The absorption conditions had possibly already improved during the few days of alcohol abstinence in the course of the delirium treatment. The reduced vitamin B1 absorption of patients suffering from visual hallucination corresponds to observations of alcoholic hallucinosis.

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Activity of the mesolimbic dopaminergic system was investigated in rats withdrawn from chronic ethanol administration by single-cell extracellular recordings from dopaminergic neurons of the ventrotegmental area, coupled with antidromic identification from the nucleus accumbens, and by microdialysis-technique experiments in the nucleus accumbens. Spontaneous firing rates, spikes per burst, and absolute burst firing but not the number of spontaneously active neurons were found drastically reduced; whereas absolute and relative refractory periods increased in rats withdrawn from chronic ethanol treatment as compared with chronic saline-treated controls. Consistently, dopamine outflow in the nucleus accumbens and its acid metabolites were reduced after abruptly stopping chronic ethanol administration. All these changes, as well as ethanol-withdrawal behavioral signs, were reversed by ethanol administration. This reversal suggests that the abrupt cessation of chronic ethanol administration plays a causal role in the reduction of mesolimbic dopaminergic activity seen in the ethanol-withdrawal syndrome. Results indicate that during the ethanol-withdrawal syndrome the mesolimbic dopaminergic system is tonically reduced in activity, as indexed by electrophysiological and biochemical criteria. Considering the role of the mesolimbic dopaminergic system in the reinforcing properties of ethanol, the depressed activity of this system during the ethanol-withdrawal syndrome may be relevant to the dysphoric state associated with ethanol withdrawal in humans.

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