• Energy Research
• CA close
• Neuroinformatics close

Alcohol is a neuroactive molecule that is able to exert variable and often detrimental effects on the developing brain, resulting in a broad range of physiological, behavioural, and cognitive phenotypes that characterize ‘fetal alcohol spectrum disorders’ (FASD). Factors affecting the manifestation of these phenotypes include alcohol dosage, timing of exposure, and pattern of maternal alcohol consumption; however, the biological processes that are vulnerable to ethanol at any given neurodevelopmental stage are unclear, as is how their disruption results in the emergence of specific pathological phenotypes later in life. The research included in this thesis utilizes a C57BL/6J (B6) mouse model to examine the changes to gene expression and behaviour following a binge-like exposure to ethanol during synaptogenesis, a period of neurodevelopment characterized by the rapid formation and pruning of synaptic connectivity that correlates to brain development during the human third trimester. B6 pups were treated with a high dose (5 g/kg over 2 hours) of ethanol at postnatal day 4 (P4), P7, or on both days (P4+7). Mice were evaluated using a battery of behavioural tests designed to assess FASD-relevant phenotypes, and showed delayed achievement of neuromuscular coordination, hyperactivity, increased anxiety-related traits, and impaired spatial learning and memory. Gene expression analysis identified 315 transcripts that were altered acutely (4 hours) following ethanol exposure. Up-regulated transcripts were associated with cellular stress response, including both pro- and anti-apoptotic molecules, as well as maintenance of cell structural integrity. Down-regulated transcripts were associated with energetically costly processes such as ribosome biogenesis and cell cycle progression. Genes critical to synapse formation were also affected, as well as genes important for the appropriate development of the hypothalamic-pituitary-adrenal axis. Additionally, gene expression changes within the adult brain of mice treated with ...

The results of our recent investigations have suggested that tolerance and cross-tolerance development to motor-impairing and hypothermic effects of ethanol was slowed when brain serotonin (5-HT) was extensively depleted by treatment with p-chlorophenylalanine (p-CPA). These findings have been extended by the observation that p-PCA also slowed the development of tolerance to motor-impairing effects of barbital whether tolerance was tested repeatedly in the same animal or in separate subgroups being tested only once. Additional support was provided by the demonstration that intracerebral injection of 5,7-dihydroxytryptamine (-DHT), which is known to deplete 5-HT markedly, also slowed the development of tolerance to motor-impairing and hypothermic effects of ethanol. In addition, when brain 5-HT level was elevated by administration of L-tryptophan, the rate of tolerance development to ethanol, as measured by motor impairment and hypothermia, was accelerated. In contrast to 5,7-DHT, intracerebral injection of 5,6-DHT was surprisingly found to accelerate the development of tolerance to ethanol. Upon further investigation, however, it was determined that the 5,6-DHT treatment depleted brain 5-HT levels by only 20% and, in addition, resulted in the development of supersensitivity. These results further confirm and extend the generality of our observations that 5-HT may be involved in the development of tolerance and cross-tolerance to sedatives. The possibility of a non-specific vs. specific effect of the serotoninergic system (as well as other aminergic systems) in tolerance and neuroplasticity deserves further investigation. The possible significance of these findings and the role of 5-HT (and noradrenaline) in the mechanism of tolerance are discussed in terms of analogy to enzyme or receptor mechanism.

Research has suggested that catalase plays a role in mediating ethanol's psychopharmacological effects. It has been shown that acatalasemic (C3H-A) mice differing in the activity of this enzyme consume larger amounts of ethanol. It has also been reported that when catalase activity is pharmacologically reduced, via 3-amino-1,2,4-triazole (AT), rats reduce their intake and preference for ethanol. The present research attempted to investigate AT's effects in nonselected mice. Swiss Webster mice were randomly assigned to groups of four per cage and further assigned to either a 5%, a 10%, or a 15% ethanol exposure condition. Mice were given a choice between water and increasing 1% concentrations of ethanol starting with 2%. Following five days of baseline, mice were injected daily with either AT (0.5 g/kg) or saline for five days. Results showed that AT significantly reduced ethanol consumption across treatment, but not posttreatment days. Results could not be explained by differences in total fluid intake. These results suggest a role for brain catalase in ethanol consumption across a variety of strains and species and further support the involvement of centrally formed acetaldehyde in the mediation of ethanol's psychopharmacological effects.

Alcohol is one of the most widely used substances. Alcohol use accounts for 5.1% of the global disease burden, contributes substantially to societal and economic costs, and leads to approximately 3 million global deaths yearly. Alcohol use disorder (AUD) includes various drinking behavior patterns that lead to short-term or long-lasting effects on health. Ethanol, the main psychoactive molecule acting in alcoholic beverages, directly impacts the GABAergic system, contributing to GABAergic dysregulations that vary depending on the intensity and duration of alcohol consumption. A small number of interventions have been developed that target the GABAergic system, but there are promising future therapeutic avenues to explore. This review provides an overview of the impact of alcohol on the GABAergic system, the current interventions available for AUD that target the GABAergic system, and the novel interventions being explored that in the future could be included among first-line therapies for the treatment of AUD.

The studies presented above add further support to the notion that one of ethanol's most important sites of activity may be the plasma membrane of cells. In addition, they provide an example of how ethanol's effects on these membranes may affect the function of protein molecules associated with nerve cell membranes such as the receptive sites for the putative excitatory neurotransmitter L-glutamic acid. The result of chronic ethanol administration is an apparently enhanced sensitivity to glutamate action in the CNS as measured by either the increases in L-glutamate binding activity or the increased Ca2+ mobilization as a result of glutamate interaction with the synaptosomal membranes. Both of these processes exhibit an enhancement of the maximum response with little or no change in the KD for binding of L-glutamic acid to its receptor site. Finally, it was demonstrated by means of in vivo experiments that there is an apparent sensitization to glutamate during the induction of ethanol dependence, and that this enhanced sensitivity may be causally linked to some of the signs of the post withdrawal CNS hyperexcitability.

Chronic alcohol exposure affects the central nervous system, influences behavior, and induces neuroadaptive changes in vertebrate species including our own. The molecular mechanisms responsible for chronic alcohol effects have not been fully elucidated due to the complexity of alcohol's actions. Here we use zebrafish, a novel tool in alcohol research, to reveal a large number of genes that respond to chronic alcohol treatment. We demonstrate differential gene expression in response to chronic alcohol treatment using full genome DNA microarrays and find a total of 1914 genes to show a minimum of 2-fold and significant expression level change (1127 were up- and 787 were down-regulated). Approximately two-thirds of these genes had no known previous functional annotation. The results of the microarray analyses correlated well with those obtained on a selected subset of genes analyzed by quantitative real-time RT-PCR. Analyses of the differentially expressed genes with known annotations were enriched for a variety of molecular functions. Only a fraction of these known genes has been reported in the literature to be alcohol related. We conclude that the zebrafish is an excellent tool for the analysis of genes associated with alcohol's actions in vertebrates, one which may facilitate the discovery and better understanding of the mechanisms of alcohol abuse.

BackgroundThe consumption of alcohol during pregnancy can result in abnormal fetal development and impaired brain function in humans and experimental animal models. Depending on the pattern of consumption, the dose, and the period of exposure to ethanol (EtOH), a variety of structural and functional brain deficits can be observed.MethodsThis study compared the effects of EtOH exposure during distinct periods of brain development on oxidative damage and endogenous antioxidant status in various brain regions of adult female and male Sprague Dawley rats. Pregnant dams and neonatal rats were exposed to EtOH during one of the following time windows: between gestational days (GDs) 1 and 10 (first trimester equivalent); between GDs 11 and 21 (second trimester equivalent); or between postnatal days (PNDs) 4 and 10 (third trimester equivalent).ResultsEtOH exposure during any of the 3 trimester equivalents significantly increased lipid peroxidation in both the cornus ammonis (CA) and dentate gyrus (DG) subregions of the hippocampus, while also decreasing the levels of the endogenous antioxidant glutathione in the hippocampal CA and DG subregions as well as the prefrontal cortex of young adult animals (PND 60).ConclusionsThese results indicate that EtOH exposure during restricted periods of brain development can have long‐term consequences in the adult brain by dysregulating its redox status. This dysfunction may underlie, at least in part, the long‐term alterations in brain function associated with fetal alcohol spectrum disorders.

The zebrafish has been successfully employed to model and study the effects of embryonic alcohol exposure. Short exposure to low alcohol concentrations during embryonic development has been shown to significantly disrupt social behavior as well as the dopaminergic and serotoninergic systems in zebrafish. However, analysis of potential effects of embryonic alcohol exposure on other amino acid neurotransmitter systems has not been performed. Here we analyzed neurochemicals obtained from adult AB and TU strain zebrafish that were immersed in 0.00% (control), 0.25%, 0.50%, 0.75% or 1.00% alcohol solution (vol/vol%) at 24 h post-fertilization for 2 h. From whole brain extracts, we quantified glutamate, aspartate, glycine, taurine and GABA levels using high performance liquid chromatography (HPLC). We found embryonic alcohol exposure not to have any significant effect on the levels of glutamate, aspartate, glycine and GABA in both AB and TU zebrafish. AB zebrafish showed a significant elevation of taurine levels, but only in the highest alcohol dose group compared to control. These results, albeit mainly negative, together with prior findings suggest that behavioral abnormalities resulting from embryonic alcohol exposure described before for AB zebrafish may primarily be due to altered dopaminergic and serotoninergic mechanisms. Furthermore, a Principal Component Analysis conducted with all neurochemicals tested in this and in our prior study, found a strain-dependent correlation structure response to embryonic alcohol treatment, confirming that embryonic alcohol effects may be genotype dependent.

Salsolinol, a substance that may participate in the development of alcoholism, has been identified in urine and other biological samples from alcoholics. Differentials have been observed between alcoholics and controls. Salsolinol forms when dopamine reacts with acetaldehyde, which may exist in higher concentrations in the blood of alcoholics after alcohol ingestion. Hence, it was postulated that there is a relationship between level of social drinking and the elaboration of salsolinol. Salsolinol is also found in certain food and beverage products. Eighty volunteers, balanced for gender, social drinking level, ethanol dose administered and experimental diet provided urine samples 90 minutes and three hours after ethanol was consumed. Salsolinol levels were analysed in urine using high performance liquid chromatography. A 24 hour carryover effect was observed. Diet, ethanol dose and social drinking level had main and interactive effects on excreted quantities of salsolinol. Gender, situational stress and cigarette smoking had minor if any influence on salsolinol excretion. While there was no evident difference in amounts of salsolinol excreted by light and heavy drinkers in the absence of external sources of salsolinol, heavy social drinkers excreted less salsolinol than did light drinkers after consuming a "salsolinol-enriched" diet, suggesting that they differ in some aspect of absorption, distribution, or metabolism of salsolinol after drinking ethanol. Accordingly, studies that attempt to determine whether salsolinol has any relationship to drinking behaviour in humans should be particularly concerned with salsolinol that occurs in exogenous sources.