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1.  Acetate-Dependent Mechanisms of Inborn Tolerance to Ethanol 
Aims: To clarify the role of acetate in neurochemical mechanisms of the initial (inborn) tolerance to ethanol. Methods: Rats with low and high inborn tolerance to hypnotic effect of ethanol were used. In the brain region homogenates (frontal and parietal cortex, hypothalamus, striatum, medulla oblongata) and brain cortex synaptosomes, the levels of acetate, acetyl-CoA, acetylcholine (AcH), the activity of pyruvate dehydrogenase (PDG) and acetyl-CoA synthetase were examined. Results: It has been found that brain cortex of rats with high tolerance to hypnotic effect of ethanol have higher level of acetate and activity of acetyl-CoA synthetase, but lower level of acetyl-СCoA and activity of PDG. In brain cortex synaptosomes of tolerant rats, the pyruvate oxidation rate as well as the content of acetyl-CoA and AcH synthesis were lower when compared with intolerant animals. The addition of acetate into the medium significantly increased the AcH synthesis in synaptosomes of tolerant, but not of intolerant animals. Calcium ions stimulated the AcH release from synaptosomes twice as high in tolerant as in intolerant animals. Acetate eliminated the stimulating effect of calcium ions upon the release of AcH in synaptosomes of intolerant rats, but not in tolerant animals. As a result, the quantum release of AcH from synaptosomes in the presence of acetate was 6.5 times higher in tolerant when compared with intolerant rats. Conclusion: The brain cortex of rats with high inborn tolerance to hypnotic effect of ethanol can better utilize acetate for the acetyl-CoA and AcH synthesis, as well as being resistant to inhibitory effect of acetate to calcium-stimulated release of AcH. It indicates the metabolic and cholinergic mechanisms of the initial tolerance to ethanol.
doi:10.1093/alcalc/agr014
PMCID: PMC3114548  PMID: 21349883
2.  A Major QTL for Acute Ethanol Sensitivity in the Alcohol Tolerant and Non-Tolerant Selected Rat Lines 
Genes, brain, and behavior  2009;8(6):611-625.
The Alcohol Tolerant and Alcohol Non-Tolerant rats (AT, ANT) were selectively bred for ethanol-induced ataxia as measured on the inclined plane. Here we report on a quantitative trait locus (QTL) study in an F2 intercross population derived from inbred AT and ANT (IAT, IANT) and a follow-up study of congenics that were bred to examine one of the mapped QTLs. Over 1200 F2 offspring were tested for inclined plane sensitivity, acute tolerance on the inclined plane, duration of the loss of righting reflex (LORR), and blood ethanol at regain of the righting reflex (BECRR). F2 rats that were in the upper and lower 20% for inclined plane sensitivity were genotyped with 78 SSLP markers. Significant QTLs for inclined plane sensitivity were mapped on chromosomes 8 and 20; suggestive QTLs were mapped on chromosomes 1, 2, and 3. Highly significant QTLs for LORR duration (LOD=12.4) and BECRR (LOD=5.7) were mapped to the same locus on chromosome 1. Breeding and testing of reciprocal congenic lines confirmed the chromosome 1 LORR/BECRR QTL. A series of recombinant congenic sub-lines were bred to fine-map this QTL. Current results have narrowed the QTL to an interval of between 5 and 20 Mb. We expect to be able to narrow the interval to less than 5 Mb with additional genotyping and continued breeding of recombinant sub-congenic lines.
doi:10.1111/j.1601-183X.2009.00496.x
PMCID: PMC2880637  PMID: 19500156
Alcohol tolerance; Genetics; Selected lines; Loss of righting reflex
3.  Neurotoxicity and Metabolism of the Catecholamine-Derived 3,4-Dihydroxyphenylacetaldehyde and 3,4-Dihydroxyphenylglycolaldehyde: The Role of Aldehyde Dehydrogenase 
Pharmacological reviews  2007;59(2):125-150.
Aldehydes are highly reactive molecules formed during the biotransformation of numerous endogenous and exogenous compounds, including biogenic amines. 3,4-Dihydroxyphenylacetaldehyde is the aldehyde metabolite of dopamine, and 3,4-dihydroxyphenylglycolaldehyde is the aldehyde metabolite of both norepinephrine and epinephrine. There is an increasing body of evidence suggesting that these compounds are neurotoxic, and it has been recently hypothesized that neurodegenerative disorders may be associated with increased levels of these biogenic aldehydes. Aldehyde dehydrogenases are a group of NAD(P)+-dependent enzymes that catalyze the oxidation of aldehydes, such as those derived from catecholamines, to their corresponding carboxylic acids. To date, 19 aldehyde dehydrogenase genes have been identified in the human genome. Mutations in these genes and subsequent inborn errors in aldehyde metabolism are the molecular basis of several diseases, including Sjögren-Larsson syndrome, type II hyperprolinemia, γ-hydroxybutyric aciduria, and pyridoxine-dependent seizures, most of which are characterized by neurological abnormalities. Several pharmaceutical agents and environmental toxins are also known to disrupt or inhibit aldehyde dehydrogenase function. It is, therefore, possible to speculate that reduced detoxification of 3,4-dihydroxyphenylacetaldehyde and 3,4-dihydroxyphenylglycolaldehyde from impaired or deficient aldehyde dehydrogenase function may be a contributing factor in the suggested neurotoxicity of these compounds. This article presents a comprehensive review of what is currently known of both the neurotoxicity and respective metabolism pathways of 3,4-dihydroxyphenylacetaldehyde and 3,4-dihydroxyphenylglycolaldehyde with an emphasis on the role that aldehyde dehydrogenase enzymes play in the detoxification of these two aldehydes.
doi:10.1124/pr.59.2.1
PMCID: PMC2647328  PMID: 17379813
4.  Putative role of brain acetaldehyde in ethanol addiction 
Current drug abuse reviews  2008;1(1):3-8.
The putative contribution of brain acetaldehyde (AcH) to ethanol (EtOH) tolerance and dependence (addiction) is reviewed. Although the role of AcH in EtOH addiction has been controversial, there are data showing a relationship. AcH can be formed in the brain tissues through the peroxidatic activity of catalase and by oxidation via other oxidizing enzymes such as cytochrome P-4502E1. Significant formation of AcH occurs in vitro in brain tissue at concentrations of EtOH that can be achieved by voluntary consumption of EtOH by rodents. AcH itself possesses reinforcing properties, which suggests that some of the behavioral pharmacological effects attributed to EtOH may be a result of the formation of AcH, and supports the involvement of AcH in EtOH addiction. Modulation of aldehyde dehydrogenase (ALDH) and brain catalase activity can change EtOH-related addictive behaviors presumably by changing AcH levels. Moreover, some condensation reaction products of AcH may promote some actions of EtOH and its consumption. On the basis of the findings, it can be concluded that AcH may mediate some of the CNS actions of EtOH including tolerance and dependence, although further exploration the involvement of AcH in EtOH addiction is warranted.
PMCID: PMC2613359  PMID: 19122804
Acetaldehyde; Ethanol; Brain; Addiction; reinforcement
5.  Short-term Selection for Acute Ethanol Tolerance and Sensitization from an F2 Population Derived from the High and Low Alcohol Sensitive Selectively Bred Rat Lines 
Alcohol (Fayetteville, N.Y.)  2007;41(8):557-566.
Previous studies have identified quantitative trait loci (QTL) in the inbred High and Low Alcohol Sensitive Rat (IHAS1 and ILAS1) strains. The original development of the strains involved selection for ethanol sensitivity based on duration of the loss of the righting reflex (LORR) following a standard dose of ethanol. This paper confirms some of these QTL using a short-term selection procedure based on the difference between the blood ethanol level at loss and regain of the righting response. An F2 population of rats was developed by a reciprocal cross of IHAS1 and ILAS1 rats. Selection for 5 generations was carried out using delta-blood ethanol concentration (dBEC) as the selection trait, where dBEC = BECLR (BEC at loss of righting reflex) – BECRR (BEC at regain of righting reflex). The lines were labeled Tolerant (TOL) or Sensitive (SENS). Approximately one-third of the offspring for each generation in each line were genotyped using DNA markers that had been previously found to be linked to QTL on chromosomes 1, 2, 5, 12, and 13. By the fifth generation of selection, the lines showed a very large difference in dBEC, BECRR, and duration of LORR; BECLR showed little segregation during the selection, and latency to lose the righting reflex showed none. IHAS allele frequency increased in the SENS line for markers on chromosomes 1, 5, 12, and 13 while ILAS allele frequency increased in the TOL line. These results were in good agreement with the two previous QTL studies. On chromosome 2, the selection resulted in an accumulation of ILAS alleles in both lines. This study provides independent confirmation of the location of QTL on chromosomes 1, 5, 12, and 13 for ethanol sensitivity. It also suggests that genetic differences in duration of LORR are mediated primarily by the dBEC phenotype.
doi:10.1016/j.alcohol.2007.10.001
PMCID: PMC2185819  PMID: 18047909
Genetics; quantitative trait loci; ethanol tolerance; selected lines; inbred rats
6.  Ethanol Metabolism and Effects: Nitric Oxide and its Interaction 
Current clinical pharmacology  2007;2(2):145-153.
Ethanol (EtOH) in alcoholic beverages is consumed by a large number of individuals and its elimination is primarily by oxidation. The role of nitric oxide (NO) in ethanol’s effects is important since NO is one of the most prominent biological factors in mammals. NO is constantly formed endogenously from L-arginine. Dose and length of EtOH exposure, and cell type are the main factors affecting EtOH effects on NO production. Either acute or chronic EtOH ingestion affects inducible NO synthase (iNOS) activity. However it seems that EtOH suppresses induced-NO production by inhibition of iNOS in different cells. On the other hand, it is clear that acute low doses of EtOH increase both the release of NO and endothelial NOS (eNOS) expression, and augment endothelium-mediated vasodilatation, whereas higher doses impair endothelial functions. EtOH selectively affects neuronal NOS (nNOS) activity in different brain cells, which may relate to various behavioral interactions. Therefore, there is an excellent chance for EtOH and NO to react with each other. Effects of EtOH on NO production and NOS activity may be important to ethanol modification of cell or organ function. Nitrosated compounds (alkyl nitrites) are often found as the interaction products, which might be one of the minor pathways of EtOH metabolism. NO also inhibits EtOH metabolizing enzymes. Furthermore, NO is involved in EtOH induced liver damage and has a role in fetal development during ethanol exposure in pregnancy. The mechanisms underlying these effects are only partially understood. Hence, the current discussion of the interaction of ethanol and NO is presented.
PMCID: PMC2562584  PMID: 18690862
Ethanol; Nitric oxide; Nitric oxide synthase; Interaction; Metabolism
7.  Modulation of GABAA receptors in Cerebellar Granule Neurons by Ethanol: A Review of Genetic and Electrophysiological Studies 
Alcohol (Fayetteville, N.Y.)  2007;41(3):187-199.
Cerebellar granule neurons receive inhibitory input from Golgi cells in the form of phasic and tonic currents that are mediated by postsynaptic and extrasynaptic GABAA receptors, respectively. Extrasynaptic receptors are thought to contain α6βxδ subunits. Here we review studies on ethanol (EtOH) modulation of these receptors, which have yielded contradictory results. Although studies with recombinant receptors expressed in Xenopus oocytes indicate that α6β3δ receptors are potently enhanced by acute exposure to low (≥3 mM) EtOH concentrations, this effect was not observed when these receptors were expressed in Chinese hamster ovary cells. Slice recordings of cerebellar granule neurons have consistently shown that EtOH increases the frequency of phasic spontaneous inhibitory postsynaptic currents (sIPSCs), as well as the tonic current amplitude and noise. However, there is a lack of consensus as to whether EtOH directly acts on extrasynaptic receptors or modulates them indirectly; i.e. via an increase in spillover of synaptically released GABA. It was recently demonstrated that an R to Q mutation of amino acid 100 of the α6 subunit increases the effect of EtOH on both sIPSCs and tonic current. These electrophysiological findings have not been reproducible in our hands. Moreover, it was shown the α6-R100Q mutation enhances sensitivity to the motor-impairing effects of EtOH in outbred Sprague-Dawley rats, but this was not observed in a line of rats selectively bred for high sensitivity to EtOH-induced motor alterations (Alcohol Non-Tolerant rats). We conclude that currently there is insufficient evidence conclusively supporting a direct potentiation of extrasynaptic GABAA receptors following acute EtOH exposure in cerebellar granule neurons.
doi:10.1016/j.alcohol.2007.04.004
PMCID: PMC1986723  PMID: 17521847
GABA; ethanol; extrasynaptic; presynaptic; granule

Results 1-7 (7)