Some biological mechanisms of the inborn predisposition to alcoholism.

The children of alcoholism patients have a high biological risk of this illness, mental and emotional disorders, and behavioral disturbances. The offspring of white mongrel rats with chronic alcohol intoxication were investigated in order to study the neurochemical mechanisms of these phenomena. The content of DA in blood and blood plasma, the characteristics of GABA and the opiate receptors of the brain, the activity of DBH, COMT, MAO, the content of cAMP and cGMP in brain tissue, as well as the expression of the gene c-fos were studied. Changes in the brain content of DA and qualitative and quantitative changes in MAO (an increase and solubilization of MAO A and B activity in the liver) were identified in the offspring of alcoholic rats. A tendency was also observed in the brain toward a decrease in the activity of DBH and COMT and an increase in the activity of cAMP and cGMP. The baseline expression of the gene c-fos in the offspring of male alcoholic rats did not differ from the norm; however, a powerful increase in the expression of the gene c-fos did appear in response to the administration of 2 g/kg of ethanol, in the absence of this effect in the control. A view is presented on the significant role of changes in the functions of the DA system in the genesis of pathology in the offspring of parents with chronic alcohol intoxication, as well as on the possible influence of the prolonged consumption of alcohol on the function of the genome.

[The biological mechanisms of a congenital predisposition to alcoholism]. / Nekotorye biologicheskie mekhanizmy vrozhdennoi predraspolozhennosti k alkogolizmu.

In descendants of white rats with chronic alcoholic intoxication, the contents of DA in the brain and blood plasma, characteristics of GABA and opiate brain receptors, the contents of cAMP and other substances were studied as well as the c-fos gene expression. The data obtained suggest a considerable role of the changes in the DA system functions in the genesis of pathology in these descendants.

[Natural modulators of the function of the amine oxidase system in the body]. / O prirodnykh moduliatorakh funktsii sistemy aminoksidaz v organizme.

In cerebrospinal fluid (CSF) obtained from patients with chronic alcoholism natural modulators of monoamine oxidase (MAO) activity, containing in human mitochondrial and microsomal fractions or in rat brain mitochondria, have been found. These modulators, which were previously unknown, did not affect the activity of partially purified diamine oxidase from human placenta with 14C-putrescine as a substrate. The MAO modulators from CSF were thermostable (during 3 min at 100 degrees), penetrated through dialysing membrane thus differing from high molecular modulators of MAO previously described. In the system containing membrane bound MAO from human placenta, where the MAO-A is predominating, the modulators studied mostly inhibited deamination of 14C-serotonin. However, in the system containing membrane bound MAO from rat brain with prevalence of the MAO-B, the modulators from human CSF caused either inhibition or stimulation of oxidative deamination of 14C-serotonin or 14C-beta-phenylethylamine used as substrates. The modulators studied were not similar to tribulin (isatin) or quinolinic acid in their effects on catalytic properties of the amine oxidases investigated.

Studies on mitochondrial metabolic processes in offspring of alcoholized rats--I. Evidence for altered activity and sensitivity to monoamine oxidase-dependent control by biogenic amines of some membrane-bound enzymes.

In the liver mitochondrial fraction of the first generation offspring of alcoholized male rats, decreased activities of monoamine oxidase (MAO) types A and B, rotenone-insensitive NADH-cytochrome c-reductase and succinate dehydrogenase were observed. The MAO-dependent inhibition of rotenone-insensitive NADH-cytochrome c-reductase and succinate dehydrogenase by biogenic amines, incubated with the mitochondrial fraction, was altered in the offspring of alcoholized animals as compared with control rats. The sensitivity of these enzymatic activities towards the inhibitory effect of 5-methoxyindol-3-ylacetaldehyde was markedly increased in the offspring of alcoholized male rats. The data obtained suggest the existence of a genetically determined predisposition of the mitochondrial metabolic processes in the offspring of the alcoholized rats to the effects of ethanol and to the toxic effects of acetaldehyde, formed during ethanol metabolism.

Mechanisms of pathological influence of parent alcoholism on the progeny: possible means of prophylaxis.

Mechanisms of genetically determined alcoholic motivation were studied in chronically alcohol-treated rats and their offsprings by biochemical and genetic approaches. Stimulation of the activity of membrane-bound monoamine oxidases, (e.g. in thrombocytes, brain), modification of their catalytic properties, partial solubilisation and increased sensitivity towards transitory inhibiting effect of ethanol were detected in chronically alcohol-treated rats and especially in their offsprings which were not chronically alcohol-treated. Altered content of biogenic amines in brain and disturbances of behaviour accompanied the impairments in functions of monoamine oxidases. Administration of ethanol was required to normalise the disturbances in biochemical parameters studied. Presence of ethanol in tissues may be considered as a molecular basis for development of alcoholic motivation in off-springs of chronically alcohol-treated animals. The described above biochemical alterations in the offsprings were prevented by treatment of their parents (during alcoholization) with a compound of plant origin. A distinct increase in expression of c-fos gene in brain cortex was observed in offsprings of chronically alcohol-treated rats after administration of ethanol. The impairments in regulation of c-fos gene activity in offsprings suggest that chronic alcohol treatment of animals may influence functions of genome of their offsprings which were not subjected to chronic alcohol treatment.

[Use of bacterial luciferase for determining monoamine oxidase activity]. / Ispol'zovanie bakterial'noi liutsiferazy dlia opredeleniia monoaminooksidaznoi aktivnosti.

A bioluminescence assay is proposed for measuring monoamine oxidase activity in different biological specimens (platelets, mitochondria). The assay is based on the bioluminescent reaction catalysed by bacterial luciferase and coupled to monoamine oxidase. Two modifications of the bioluminescence assay were used. In the first case, the bioluminescent system was added to monoamine oxidase preincubated with the substrates, while in the second case, all the components of the coupled enzymatic systems were directly mixed in a cell. The proposed bioluminescence assay is simple, highly sensitive and rapid, and could be especially useful for biomedical examinations.

Some neurobiological mechanisms of the effect of ethanol on offspring of chronically alcohol treated rats.

Mechanisms of genetically determined alcoholic motivation were studied in chronically alcohol treated rats and their offspring using neurochemical, physiological and genetic techniques. Stimulation of the activity of membrane-bound monoamine oxidases, (e.g., in liver or brain), modification of their catalytic properties, partial solubilisation and increased sensitivity towards the transitory inhibiting effect of ethanol were detected in chronically alcohol treated rats, especially in offspring which did not receive chronic alcohol treatment. An altered content of biogenic amines in brain and disturbances of behaviour accompanied impairments in functions of monoamine oxidases. Administration of ethanol was required to restore to normal the disturbances in the neurochemical and physiological parameters studied. The constant presence of ethanol in tissues becomes essential for returning metabolic impairments to normal and may be considered as a molecular basis for the development of alcoholic motivation in offspring of chronically alcohol treated animals. A distinct increase in the expression of the c-fos gene in the brain cortex was observed in offspring of chronically alcohol treated rats after administration of ethanol. The impairments in regulating c-fos gene activity caused by ethanol administration suggest that chronic alcohol treatment of animals may influence the functions of the genome of offspring not subjected to chronic alcohol treatment.

[Characteristics of lipid peroxidation in alcoholic intoxication]. / Ob osobennostiakh perekisnogo okisleniia lipidov pri alkogol'noi intoksikatsii.

Content of malonic dialdehyde and dynamics of its accumulation in ascorbate-dependent lipid peroxidation (LP), content of diene conjugates, lipid hydroperoxides and lipofuscin-like pigments as well as activity of antioxidant enzymes (superoxide dismutase, glutathione peroxidase and glutathione transferase) were studied in homogenates of liver, lung, heart and kidney tissues of persons suffering from chronic alcoholism during life-time, of persons lost from acute alcohol intoxication as well as of persons not abusing with alcohol during life-time and lost from accidents (control). In chronic alcoholism the rate of ascorbate-dependent LP was distinctly increased in liver tissue as compared with controls or with acute mortal alcohol intoxication, while the rate of the patterns studied was increased in lung tissue of the latter group of patients. At the same time, increase in content of lipofuscin-like pigments and a decrease in the activity of antioxidant enzymes studied were noted.

[Changes in catalytic properties of membrane-bound monoamine oxidases in alcoholic intoxication]. / Osobennosti izmenenii kataliticheskikh svoistv membranosviazannykh monoaminoksidaz pri alkogol'noi intoksikatsii.

Chronic alcohol intoxication was accompanied by qualitatively new deamination reactions of cadaverine or glucosamine in dialyzed fraction of rat liver tissue homogenate. The rate of reactions was considerably more distinct in human liver and brain tissues obtained post mortem from patients with chronic alcoholism. At the same time, impairments were observed both in deamination of biogenic monoamines by membrane-bound monoamine oxidases and in ascorbate-dependent lipid peroxidation. The qualitative modifications in catalytic properties of membrane-bound monoamine oxidase, related to reactions of deamination and lipid peroxidation, appear to be of importance in chronic alcoholism and acute lethal alcohol intoxication.