Aversive stimulus differentially triggers subsecond dopamine release in reward regions.

Aversive stimuli have a powerful impact on behavior and are considered to be the opposite valence of pleasure. Recent studies have determined some populations of ventral tegmental area (VTA) dopaminergic neurons are activated by several types of aversive stimuli, whereas other distinct populations are either inhibited or unresponsive. However, it is not clear where these aversion-responsive neurons project, and whether alterations in their activity translate into dopamine release in the terminal field. Here we show unequivocally that the neurochemical and anatomical substrates responsible for the perception and processing of pleasurable stimuli within the striatum are also activated by tail pinch, a classical painful and aversive stimulus. Dopamine release is triggered in the dorsal striatum and nucleus accumbens (NAc) core by tail pinch and is time locked to the duration of the stimulus, indicating that the dorsal striatum and NAc core are neural substrates, which are involved in the perception of aversive stimuli. However, dopamine is released in the NAc shell only when tail pinch is removed, indicating that the alleviation of aversive condition could be perceived as a rewarding event.

Neuronal nicotinic acetylcholine receptor binding affinities of boron-containing nicotine analogues.

A series of boron-containing nicotine (NIC) analogues 7-9 was synthesized and evaluated for binding to alpha4beta2 and alpha7 nicotinic receptors. Compound ACME-B inhibited [3H]methyllycaconitine binding to rat brain membranes with a similar potency compared to NIC (Ki = 2.4 and 0.77 microM, respectively), but was markedly less potent in inhibiting [3H]NIC binding when compared to NIC (Ki = 0.60 microM and 1.0 nM, respectively). Thus, tethering a two-carbon bridge between the 2-pyridyl and 3'-pyrrolidino carbons of NIC or 7 affords analogues that bind to the alpha7 receptor in a manner similar to NIC, but with a dramatic loss of affinity for the alpha4beta2 receptor.

Alcohol action on liver: dose dependence and morpho-biochemical correlations.

BACKGROUND: Since the duration and the dose of alcohol administration are acknowledged as factors that influence the risk of liver injury, it was interesting to compare the character and degree of liver damage following various doses and methods of alcohol administration. In addition, it was assumed to compare the degree of liver damage histologically and on the activity of marker liver enzymes in blood plasma in the same animals. METHODS AND RESULTS: The several experiments on heterogeneous stock rats with the various daily dose, duration and method of alcohol administration have been carried out. It was found, that the 9-month intake of 15.20% (v/v) ethanol solution as the only source of drinking (the consumption of absolute alcohol was about 4 g/kg/day) did not affect the normal development of animals and did not induce any harmful morphological changes in liver. Moreover, the liver parenchyma looks even better in the context of lesser inflammatory infiltration and vacuolisation of hypatocytes. The activities of the marker liver injury enzymes: alanine and aspartate amino transferases (ALT and AST), alkaline phosphatase (AP) as well as alcohol dehydrogenase (ADH) in blood were also not changed. The intragastric administration 25% (v/v) ethanol (3.5 g/kg twice a day, during 14 days) induced some morphological disturbances in the liver: an extension of blood capillaries and veins in parenchyma and insignificant increasing of the hepatocyte vacuolisation degree (from 0.7 +/- 0.1 points in control to 1.2 +/- 0.2 points in alcohol treated animals). In blood serum, a slight elevation of ADH (from 1.2 +/- 0.2 microM/min/l in control to 1.7 +/- 0.3) and AP (from 236 +/- 19 microM/min/l in control to 278 +/- 25) activities were found. The liquid alcohol diets (mean consumption of absolute alcohol was 14-18 g/kg/day, during a month) induced the more pronounced liver injury: extension of the liver blood vessels, inflammatory infiltration (from 1.1 +/- 0.1 points in control to 2.0 +/- 0.3; P, 0.05) and destruction of hepatocytes (from 0.5 +/- 0.01 points in control to 1.2 +/- 0.1; p < 0.05). Another liquid alcohol diet (mean consumption of absolute alcohol was 20-24 g/kg/day, during a month) induced the expressive hepatocyte vacuolisation (from 0.5 +/- 0.1 points in control to 1.5 +/- 0.2; p < 0.05). In both the experiments, the weaker staining of hepatocyte cytoplasms, basophilia in particular, were found. The activity of blood plasma ADH was insignificantly increased by 47% and 134% and that of AP--by 15% and 38%. The activity of ALT insignificantly increased in the third experiment only and AST remained unchanged. Some correlations among the morphological and biochemical indexes were found in the above experiments: between the degree of hepatocytes vacuolisation and the blood ADH or AP activities (r = 0.62; p < 0.01 and r = 0.54; p < 0.05), accordingly. The oxyphilia intensity correlated with the AST activity (r = 0.64; p < 0.01) and the intensity of hepatocyte basophilia with the ADH activity (r = 0.67; p < 0.01). The negative correlation was also found between the degree of extension of liver blood vessels and the activity of AST (r = -0.57; p < 0.05). CONCLUSIONS: The data obtained confirm the earlier observations concerning the dependence of the degree of liver injury on the dose and manner of alcohol administration as well as great individuality in the liver response to alcohol in heterogeneous stock rats. There are the significant correlations between the some morphological and biochemical markers of alcohol liver injury; among the biochemical markers studied, the ADH activity was the most sensitive.

[Effect of supplementary vitamin administration on free amino acids in the liver and brain of rats with alcoholic intoxication]. / Vliianie dopolnitel'noi vitaminizatsii na svobodnye aminokisloty pecheni i mozga krys s alkogol'noi intoksikatsiei.

The authors studied combined action of ethanol, pyridoxine (3 mg/kg), and a mixture of thiamine (5 mg/kg), riboflavin (5 mg/kg), pyridoxine (3 mg/kg) and pantothenate (15 mg/kg) on the free amino acid reserve in the tissues of rats. Ethanol was given to the animals with a liquid semisynthetic diet (its calorific value comprised 36%) during 30 days. Both pyridoxine and the complex of vitamin B group produce normalizing action on the free amino acid pool by correcting the shifts induced by ethanol. It is especially manifested in the decreased levels of urea, isoleucine and GABA in the brain. The data obtained have shown that prevention with vitamins of shifts in the amino acid metabolism induced by ethanol, especially in respect to the central nervous system, should be recommended.

[Biochemical changes in a decrease in the voluntary consumption of alcohol by rats due to lithium chloride]. / Biokhimicheskie izmeneniia pri snizhenii dobrovol'nogo potrebleniia étanola u krys khloristym litiem.

A decrease of alcohol intake by ethanol-preferring rats under free choice conditions after intraperitoneal administration of lithium chloride (35 mg/kg) was accompanied by an activation of aldehyde dehydrogenase in the brain stem, a decrease of dopamine and salsolinol levels in the striatum and normalization of 11-hydroxycorticosteroids contents in the blood and adrenal glands.

[Interaction of simple tetrahydroisoquinolines with opiate and high-affinity dopamine (D3) receptors in the rat corpus striatum]. / Vzaimodeistvie prostykh tetragidroizokhinolinov s opiatnymi i vysokospetsificheskimi dofaminovymi (D3) retseptorami polosatogo mozga krys.

The pharmacological activities of salsolinol (Sal) and salsoline (San) were compared by their abilities to displace 3H-dopamine and 3H-D-ala2-met-enkephalinamide from specific binding sites of rat striatal membrane preparations. Sal was more potent in receptor tests than San. Consequently, methylation by using catechol-O-methyltransferase is the process of its partial inactivation. Sal affinity for D3-receptors was higher than for opiate receptors (IC50 was 1.1 mumol/l for the former and 88 mumol/l for the latter). It was concluded that dopamine-like mechanisms of action of simple tetrahydroisoquinolines are possible to exist.

[Interaction of various tetrahydroisoquinoline alkaloids with opiate receptors in the rat hypothalamus and midbrain]. / Vzaimodeistvie nekotorykh tetragidroizokhinolinovykh alkaloidov s opiatnymi retseptorami gipotalamusa i srednego mozga krys.

Using the method of competitive displacement of 3H-labelled naloxone, (D-ala2)-met enkephalinamide or (D-ala2)-D-leu-enkephalin by salsolinol, 1-methyl-6-hydroxy-1, 2, 3, 4-tetrahydro-beta-carboline or 1-methyl-6-methoxy-1, 2, 3, 4-tetrahydro-beta-carboline from opiate receptors, it was shown that the alkaloids studied were capable to cause specific interactions with rat hypothalamus and midbrain however, exhibiting distinctly less affinity as compared with morphine or its analogs. The sodium ratios, determined from the effective doses of the tetrahydroisoquinoline alkaloids corresponding to the alkaloid concentrations, which induce 50% displacement of 3H-naloxone from the opiate receptors in the presence or absence of 100 mM NaCl, have been found to be 0.75 for salsolinol and 3.6 for beta-carbolines studied. The data obtained suggest that salsolinol, similar to naloxone, is a "pure" morphine antagonist, whereas the beta-carbolines studied may be classified with the agonist-antagonist type. A considerable decrease in the affinity of mu-type opiate receptors has been found in presence of salsolinol in the incubation medium. The possible mechanisms of pharmacological action of the alkaloids and their relation to development of alcohol dependence and tolerance are discussed.

[Identification of the functional groups of yeast thiamine pyrophosphokinase]. / Identifikatsiia funktsional'nykh grupp drozhzhevoi tiaminpirofosfokinazy.

The content of free sulfhydril groups in yeast thiamine pyrophosphokinase (EC 2.7.6.2) was studied. Their blocking was found not to affect considerably the enzyme activity. N-bromsuccinimide developes the inhibitory effect only if taken in excessive concentrations, which indicates that tryptophane has no key position for the enzyme-substrate complex formation. On account of high speed of photoinactivation with Rose bengale and methilene blue, sigmoid dependence of activity loss on pH under irradiation, characteristic narrowing of the modified enzyme absorption spectrum, it is suggested that imidazole residue of the histidine is one of the functional groups of thiamine pyrophosphokinase.