Persistent abnormalities in central nervous system function (long-term tolerance) after brief ethanol administration

Abstract

Listen

Translate article

Almost 15 years ago it was demonstrated that elevated tolerance to a narcotic would persist despite many months of abstinence. Since approximately 100 million Americans ingest ethanol and some 5–10% of these develop ethanol dependence on one or more occasions, evaluation of this frequently addicting sedative for long-term or persistent effects seemed warranted. Preliminary studies in 1973 of rapid eye movement sleep modification in response to ethanol challenge demonstrated that rodents made dependent upon ethanol for a 6-week period responded abnormally to an ethanol challenge 6 months later. In order to confirm the ability of ethanol to produce such persistent changes in the central nervous system response to this drug a simpler paradigm was developed. Sprague-Dawley rats were addicted to ethanol by administration of 6 g ethanol/kg per day in divided dosage every 8 hours by feeding needle for 6 weeks. Control animals were given equicaloric sucrose by the same means and both sets of animals were fed identical quantities of liquid diet. After withdrawal, all animals were fed and housed similarly for a 6-month period. Their control and post-ethanol challenge locomotor activities were the basis for concluding that those rats previously dependent upon ethanol revealed significantly lessened evidence of sedation (greater agitation) in response to the ethanol challenge. In an attempt to elucidate correlates or determinants of this mechanism, brain biogenic amines were measured during ethanol dependency as well as after 2 weeks and after 2 months of abstinence in rats previously fed either ethanol or equicaloric sucrose by feeding needle for 1 week. The dopamine metabolite, 3,4-dihydroxyphenylacetic acid, was significantly depleted from the striatum during ethanol administration, whereas hypothalamic norepinephrine, normal during this period, was depleted 2 weeks later but returned to normal by 2 months. This represents further evidence that dopamine depletion is somehow correlated with ethanol dependence, whereas hypothalamic norepinephrine depletion occurs during the period of tolerance. In any event, the presumption that the effect of ethanol upon brain function is readily reversible can no longer be accepted.