Combined Irradiation by Gamma Rays and Carbon Nuclei Increases the C/EBP-ß LIP Isoform Content in the Pituitary Gland of Rats.

C/EBP-ß, a basic leucine zipper transcription factor, has important roles in the regulation of the body immune and inflammatory responses. Wistar rats subjected to combined irradiation were characterized by an increase in the content of the C/EBP-ß LIP isoform in the pituitary gland. The obtained data indicate that moderate doses of ionizing radiation to initiate the endoplasmic reticulum stress response and are likely to initiate C/EBP-ß-mediated cell death according to the apoptotic scenario. This study also confirms the earlier hypothesis about the alterations of the hypothalamic-pituitary-adrenocortical axis in response to moderate doses of ionizing radiation.

[An effect of cabergoline on alcohol consumption and DRD2 expression in the brain of rats with chronic alcohol intoxication]. / Vliyanie kabergolina na potreblenie alkogolya i ekspressiyu gena DRD2 v mozge krys s khronicheskoi alkogol'noi intoksikatsiei.

AIM: Cabergoline is a high selective agonist of dopamine D2 receptors (D2R). The activation of D2R plays an important role in the regulation of dopamine transmission, the imbalance of which is thought to underlie the development of alcohol motivation. To examine this possibility, cabergoline effects on alcohol consumption and brain DRD2 expression in rats with chronic alcohol intoxication were studied. MATERIAL AND METHODS: Male Wister rats were studied using the following methods: modelling of chronic alcohol intoxication, testing in «10% alcohol vs water¼ choice regimen, quantitative RT-PCR. RESULTS: Systemic administration of 0.5 mg/kg of cabergoline significantly decreases alcohol intake in alcohol-preferring rats. At the same time, cabergoline elevates the DRD2 expression in the midbrain and striatum of high-alcohol-preferring rats but not in intact (alcohol-naïve) animals. CONCLUSION: The involvement of cabergoline in the DRD2 expression may lead to the decrease in alcohol motivation. These findings indicate that cabergoline needs further investigations as a new potential medication for alcohol use disorder.

[Effect of a cholecystokinin tetrapeptide analogue on opioid reception under acute and chronic morphine administration].

Effects of a modified CCK-4, a tetrapeptide fragment of cholecystokinin, on opioid reception and cAMP level were studied. The modified CCK-4 changed the ligand binding of the opioid receptors of mu- and sigma-types in vitro. In vivo, it prevented changes in opioid reception caused by a single morphine injection or by morphine withdrawal after its long-term introduction. The CCK-4 analogue did not exert any effect in the state of intoxication after a long-term introduction of morphine or even promoted the morphine effect. The introduction of the CCK-4 analogue alone or together with morphine changed the forskoline-stimulated level of cAMP. These changes depended on the brain structure and the duration of the introduction of morphine and the CCK-4 analogue. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2006, vol. 32, no. 3; see also http://www.maik.ru.

[Biological activity of cholecystokinin-(30-33) tetrapeptide analogs].

Analogues of the endogenous peptide corresponding to the 30-33 sequence of cholecystokinin (Trp-Met-Asp-Phe-NH2) were synthesized, and their biological activity was studied. It was shown that, in rats, the N-succinylated Nle2 analogue of this tetrapeptide exhibits increased anxiolytic properties in the dark-bright chamber test and an enhanced alcohol intake by both the control animals and the long-time alcohol-dependent animals under the conditions of free choice. Introduction of an isopropyl residue into the C-terminal amide of the Nle2 analogue resulted in the appearance of anxiolytic and antialcohol activity and the ability to increase the morphine analgesic effect in the tail-flick test on rats. The two synthesized analogues retained an affinity to cholecystokinin receptors.

[Involvement of the neuropeptide cholecystokinin in the mechanisms of regulation of emotions and craving]. / Uchastie neiropeptida kholetsistokinina v mekhanizmakh reguliatsii émotsii i vlechenii.

The paper presents an idea on the organization and functions of the cholecystokinin (CCK) system. Particular emphasis is laid on the modulating influence of CCK on dopamine neuromediation in the mesolymbic structures of the brain, which are linked with the regulation of emotions and craving. Experimental and clinical studies have indicated that CCK and its preparations arrest the major manifestation of the withdrawal syndrome, including pathological craving for alcohol, and anxiety. In the post-withdrawal period, these drugs also effectively suppress alcohol craving. The designed new tetrapeptide, a CCK analogue, selectively inhibits anxiety in animals with this emotional disorder, which is followed by normalization of dopamine exchange and GABA-system functions. It is concluded that by interacting with the dopamine-system, CCK takes a direct part in the regulation of emotions and craving.

Relationship between alcohol motivation and ethanol sensitivity and blood and brain catecholamine content in the progeny of rats preferring and nonpreferring alcohol.

A system of neurochemical signs indicating predisposition to high ethanol consumption is formed in the third generation descendants of ethanol-preferring male rats. Risk-group males are detected (with 95% probability) by the content of dopamine and norepinephrine and their ratio in the brain. Alcohol motivation depends on blood epinephrine content reflecting individual sensitivity to stress.

Effect of acute alcohol administration on cerebral tyrosine hydroxylase mRNA level in mice with different ethanol sensitivity.

The levels of tyrosine hydroxylase mRNA in different brain regions of inbred mice with different sensitivity to alcohol were evaluated. This parameter was also measured 2, 4, and 6 h after single intraperitoneal injection of ethanol. We revealed interstrain differences in expression of tyrosine hydroxylase gene in the cerebral cortex, hypothalamus, and locus ceruleus. Single ethanol injection caused different changes in tyrosine hydroxylase gene expression and reduced the interstrain differences. We conclude that the system of long-term regulation of tyrosine hydroxylase gene is involved in the mechanisms of congenital alcohol sensitivity.

Polymorphism of dopamine D2 and D4 receptor genes and Slavic-surnamed alcoholic patients.

The association between alcoholism and the Taq1 "A" and "B" polymorphic alleles at the DRD2 gene and 48-bp tandem repeat in exon 3 of dopamine D4 receptor (DRD4) gene in 42 unrelated Slavic-surnamed patients and 76 normal controls was examined. The frequency of the A1 allele was higher in alcoholic patients and in alcoholic patients with a family history of alcoholism than in controls (χ²= 3.45, p < 0.001 and χ²)= 3.97, p < 0.001, respectively). Moreover, the frequency of the A1 allele was higher in alcoholics with a family history of alcoholism than in alcoholics without a family history (χ²= 3.33, p < 0.001).The results of association analysis for both the Taq1 "B" and DRD4 alleles were negative for alcoholics in general, subgroups of alcoholics and normal controls. However, the 7-repeat allele (DRD4*7R) of DRD4 gene occurred at significantly higher frequency in alcoholics with a family history of alcoholism compared with those without a family history (χ²= 3.42, p < 0.01).The results indicate that the A1 allele of the DRD2 gene is associated with susceptibility to alcoholism in general.The A1 allele, as well as the DRD4*7R allele, is significantly prevalent among alcoholics with a family history, in comparison with alcoholics without a family history, reflecting different roles of genetic factors in development of alcoholism.

[The current status of the drug abuse problem in Russia]. / Sovremennoe sostoianie problemy narkomanii v Rossii.

The statistic data evidence for rapid increase of the number of narcomanias, especially in juveniles and young people nowadays in Russia. The spectrum of psychoactive preparations used became also wider. On the basis of medico-biological studies the conception concerning main pathogenetic mechanisms of the development of psychoactive substances dependence was formulated. Enzyme immuno assays either for diagnosis of long-term opiate administration or for determination of blood serum methadone level were elaborated. Clinical studies demonstrated pathomorphism of the symptoms of dependence upon well-known narcotics. Clinical pattern of dependence upon new psychoactive preparations which cause dependence syndrome was also investigated. New differentiated methods of treatment of various types of narcomanias are proposed. There is underlined that a comprehensive program of narcomanias prophylaxis in Russia is needed.

[The effect of cholecystokinin octapeptide on ethanol-induced changes in motor activity and in dopamine metabolism in the nucleus accumbens of the rat brain]. / Vliianie kholetsistokinina-oktapeptida na vyzvannye étanolom izmeneniia dvigatel'noi aktivnosti i metabolizma dofamina v prilezhashchem iadre mozga krys.

The effect of intraventricular injection of cholecystokinin-octapeptide (CCK-8) in doses of 0.1875; 0.375; 0.75 and 1.5 micrograms/rat on the extracellular level of dopamine (DA) and its metabolites (DOPAC and HVA) after intraperitoneal injection of 1.5 g/kg ethanol was studied by microdialysis in n. accumbens of the brain of freely moving rats. CCK in a dose of 0.75 mg had no effect on the DA level, but significantly reduced the ethanol-induced increased DOPAC and HVA level. The effect of intraventricular injection of 0.75 microgram/rat CCK-8 on the motor activity of rats after intraperitoneal injection of ethanol (1.5 g/kg) was studied by the open field method. CCK-8 blocked the ethanol-induced inhibition of rat motor activity.

[The efficacy and mechanisms of action of lerivon in alcoholism]. / Effektivnost' i mekhanizmy deistviia lerivona pri alkogolizme.

Clinico-biological examination of 50 alcoholic patients was carried out. 30 patients were treated with lerivon (L) during 1 month. 15 control patients received amitriptylin for 1 month and 15 patients received relanium for 7 days. It was determined that L was quite effective in treatment of depression in alcoholic patients. The main L effects were anxiolytic, antidepressive and hypnotic. The drug also decreased alcohol addiction, had vegetostabilising and sedative effects. The conclusion was made on pathogenetic action of L in alcoholism: It influences upon dopaminergic mediation in catecholamine system. Administration of L permitted to normalize neurochemical processes underlying alcohol addiction and depression. L was well tolerated. Side effects complications, drug addiction were not registered.

Influence of ethanol administration on the activity and compartmentation of rat liver monoamine oxidases.

Single-dose ethanol administration to rats caused inhibition of liver mitochondrial monoamine oxidases (MAO) A and B, and an increase in susceptibility of MAO A (but not MAO B) to limited proteolysis. Chronic ethanol feeding resulted in a less distinct alteration in catalytic activity and susceptibility to proteolysis of mitochondrial MAO, but increased the amount of soluble MAO. The sensitivity of membrane-bound MAO to inhibitors (imipramine and chlorpromazine), action of which depends on their lipophilicity and/or hydrophobicity, remained unchanged, compared with controls. Increased amounts of soluble MAO seen after chronic ethanol feeding probably reflect an impairment of insertion of newly synthesized enzyme molecules into the outer mitochondrial membrane, rather than solubilization of MAO from it.

[Neuromediator systems in the mechanisms of remission and recurrence in alcoholism]. / Neiromediatornye sistemy v mekhanizmakh remissii i retsidiva pri alkogolizme.

Experiments on chronically alcoholic rats have revealed profound changes in the properties of the brain dopamine, serotonin, GABA and opiate systems 48 hours and 2 months of alcohol deprivation. With this, a single administration of ethanol showed its increased sensitivity of striatal and hippocampal receptors both during short- and long-term alcohol deprivation, the properties of these receptors tended towards recovery. It may be suggested that the above changes in the receptor apparatus of the neurotransmitter systems underlie the mechanism of remission and recurrence in alcoholism.