PubMed · 11505256
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A Schreiber. 2001. Alcoholism.. https://doi.org/10.1067/moe.2001.116504
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Alcohol is known to affect glutamate transmission. However, how chronic alcohol affects the synaptic structure mediating glutamate transmission is unknown. Repeated alcohol exposure in a subject with familial alcoholic history often leads to alcohol addiction. The current study adopts alcohol-preferring rats, which are known to develop high drinking. Two-photon microscopy analysis indicates that chronic alcohol of 14 weeks either, under continuous alcohol (C-Alc) or with repeated deprivation (RD-Alc), causes dysmorphology--thickened, beaded, and disoriented dendrites that are reminiscent of reactive astrocytes--in a subpopulation of medium spiny neurons. The density of dendritic spines was found differentially lower in the nucleus accumbens of RD-Alc and C-Alc groups as compared with those of Water groups. Large-sized spines and multiple-headed spines were increased in the RD-Alc group. The NMDA receptor subunit NR1 proteins, as analyzed with Western blot, were upregulated in C-Alc, but not in RD-Alc. The upregulated NMDA receptor subunits of NR1 however, are predominantly a splice variant isoform with truncated exon 21, which is required for membrane-bound trafficking or anchoring into a spine synaptic site. These maladaptations may contribute to the transformation of spines. The changes, in density and head-size of spines and the corresponding NMDA receptors, demonstrated an alteration of microcircuitry for glutamate reception. The current study demonstrates for the first time that chronic alcohol exposure causes structural alteration of dendrites and their spines in the key reward brain region in animals that have a genetic background leading to alcohol addiction.
Endocannabinoid signaling plays the important role in regulation of ethanol intake. Fatty acid amide hydrolase (FAAH) is a key membrane protein for metabolism of endocannabinoids, including anandamide, and blockade of FAAH increases the level of anandamide in the brain. To determine if FAAH regulates ethanol consumption, we studied mutant mice with deletion of the FAAH gene. Null mutant mice showed higher preference for alcohol and voluntarily consumed more alcohol than wild-type littermates. There was no significant difference in consumption of sweet or bitter solutions. To determine the specificity of FAAH for ethanol intake, we studied additional ethanol-related behaviors. There were no differences between null mutant and wild-type mice in severity of ethanol-induced acute withdrawal, conditioned taste aversion to alcohol, conditioned place preference, or sensitivity to hypnotic effect of ethanol. However, null mutant mice showed shorter duration of loss of righting reflex induced by low doses of ethanol (3.2 and 3.4 g/kg) and faster recovery from motor incoordination induced by ethanol. All three behavioral phenotypes (increased preference for ethanol, decreased sensitivity to ethanol-induced sedation, and faster recovery from ethanol-induced motor incoordination) seen in mutant mice were reproduced in wild-type mice by injection of a specific inhibitor of FAAH activity--URB597. These data suggest that increased endocannabinoid signaling increased ethanol consumption owing to decreased acute ethanol intoxication.
Lipofuscin is an end-product of lipid peroxidation which dramatically increases following ethanol consumption, as we have shown in hippocampal and cerebellar neurons. In this work, we corroborated observations indicating that supplementation of ethanol with 200 mg/l of grape seed flavanols prevents increased lipofuscin formation, an action that has been ascribed to the antioxidant properties of the flavanols. Because wine is an alcoholic beverage naturally rich in flavanols, we decided to study the effect of chronic ingestion of Port wine (PW), which also contains 20% ethanol and approximately 200 mg/l of flavanol oligomers, upon lipofuscin accumulation in the hippocampal CA1 and CA3 pyramidal neurons and in the cerebellar Purkinje cells. Six months old rats were fed with PW and results were compared with those obtained in ethanol-treated groups and pair-fed controls. After 6 months of treatment, the volume of lipofuscin per neuron was estimated using unbiased stereological methods. Treatment with PW resulted in an increase of lipofuscin in all neuronal populations studied when compared to controls and to rats treated with ethanol supplemented with flavanols. No differences were observed when comparisons were made with ethanol drinking rats. We conclude that PW, despite containing 20% ethanol and flavanols, does not prevent ethanol-induced lipofuscin formation as previously found in animals drinking ethanol plus flavanols. The reduced antioxidant capacity of PW might depend on the type and amount of flavanols present and on its content in sugars.