RESUMO
OBJECTIVE: Neurophysiological and pathological effects of ethanol may be mediated, to an important extent, via the glutamatergic system. Animal studies indicate the acute effects of ethanol disrupt glutamatergic neurotransmission by inhibiting the response of the N-methyl-D-aspartate (NMDA) receptor. Persistent attenuation of glutamatergic neurotransmission by chronic ethanol exposure results in the compensatory up-regulation of NMDA receptors. Whether glutamatergic neurotransmission and oxidative stress are enhanced during ethanol withdrawal in humans is unknown. METHOD: CSF was obtained from 18 matched comparison subjects and from 18 patients with alcohol dependence 1 week and 1 month after cessation of ethanol ingestion. CSF samples were analyzed for excitatory neurotransmitters, gamma-aminobutyric acid (GABA), and markers for oxidative stress. RESULTS: The alcohol-dependent patients' CSF levels of aspartate, glycine, and N-acetylaspartylglutamate were all higher than those of the comparison subjects, and their concentration of GABA was lower. In addition, there were significant correlations between excitatory neurotransmitters and oxidative stress markers, which suggest that the two mechanisms may play an interactive role in neurotoxicity mediated by ethanol withdrawal. CONCLUSIONS: The data suggest that augmentation of excitatory neurotransmission may lead to enhanced oxidative stress, which, in concert with reduced inhibitory neurotransmission, may contribute to the symptoms of ethanol withdrawal and associated neurotoxicity in humans. Whether these abnormalities represent a trait- or state-dependent marker of ethanol dependence remains to be resolved.
Assuntos
Alcoolismo/fisiopatologia , Etanol/efeitos adversos , Glutamatos/fisiologia , Estresse Oxidativo/fisiologia , Síndrome de Abstinência a Substâncias/fisiopatologia , Transmissão Sináptica/fisiologia , Adulto , Alcoolismo/metabolismo , Ácido Aspártico/metabolismo , Ácido Aspártico/fisiologia , Dipeptídeos/metabolismo , Dipeptídeos/fisiologia , Etanol/farmacologia , Aminoácidos Excitatórios/metabolismo , Aminoácidos Excitatórios/fisiologia , Feminino , Glutamatos/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Receptores de Glutamato/metabolismo , Receptores de Glutamato/fisiologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Síndrome de Abstinência a Substâncias/metabolismo , Superóxido Dismutase/líquido cefalorraquidiano , Superóxido Dismutase/metabolismo , Regulação para Cima/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo , Ácido gama-Aminobutírico/fisiologiaRESUMO
Studies from several countries, representing diverse cultures, have reported an association between violent suicide attempts by patients with unipolar depression and personality disorders and low concentrations of the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF). Related investigations have documented a similar inverse correlation between impulsive, externally directed aggressive behavior and CSF 5-HIAA in a subgroup of violent offenders. In these individuals, low CSF 5-HIAA concentrations are also associated with a predisposition to mild hypoglycemia, a history of early-onset alcohol and substance abuse, a family history of type II alcoholism, and disturbances in diurnal activity rhythm. These data are discussed in the context of a proposed model for the pathophysiology of a postulated "low serotonin syndrome."