Neurokynurenines (NEKY) as common neurochemical links of stress and anxiety.

The following NEKY have been studied: 1-kynurenine (KYN), 3-hydroxyKYN (3HKYN), kynurenic (KYNA), anthranilic (ANT), 3-hydroxyANT (3HANT), quinolinic (QUIN), picolinic (PICA), xanthurenic (XAN), nicotinic (NIC) acids, 3-indole-pyruvate (IPA), nicotinamide (NAM). NEKY antagonize the central effects of precursors of serotonin (tryptophan and 5-HTP), and tryptamine as well. Seizures induced by central administration of KYN and QUIN are prevented by centrally injected dopamine and diminished by noradrenaline and adrenaline. KYN, 3HANT, PIC and NIC potentiate oxotremorine hypothermia mediated by acetylcholine. Central administration of GABA, glycine or taurine, as well as proline and melatonin, prevented seizures induced by QUIN and KYN. Behavioral inhibitory effects of these amino acids are diminished by pretreament with KYN, 3HKYN and QUIN. Elevation of concentrations of corticosteroids is resulted in rise of level of NEKY due to hormonal induction of liver tryptophan pyrrolase and brain 2,3 dioxigenase. NEKY, in their turn, activate both enzymes. Thus, a "vicious circle" is formed and it supports an elevated level of NEKY for a long time, hours and days. Long-lasting increased concentrations of NEKY in tissues can lead to significant after-effects and numerous pathogenic consequences. One can not exclude that a rise of the level of some NEKY, e.g. KYNA, IPA, PIC and XAN, may play an "adaptogenic" role in stress antagonizing some pathologic effects of KYN and QUIN, e.g. anxiogenic, neurotoxic and proconvulsive. It has been demonstrated that the excitatory NEKY, KYN, 3HKYN, QUIN, possess an anxiogenic activity in the standard animal models of anxiety. NEKY with opposite neuroactivities, namely KYNA, IPA, PICA and XAN, have a pharmacological profile of anxiolytics and antagonize both anxiogenic NEKY and standard anxiogens, like caffeine, pentylenetetrazole and yohimbine. Major emphasis is made on KYN as a putative endogenous anxiogen. Studies on the interaction of NEKY with other endogenous metabolites involved in anxiety (beta-phenylethylamine, cholecystokynine, melatonin) are in progress.

[Anxiety models on mice: experimental evaluation and criticism of the method]. / Modeli trevogi na myshakh: otsenka v éksperimente i kritika metodiki.

The analysis of publications in the field of experimental psychopharmacology (in particular, anxiety models) shows a lack of data concerning the general methodological problems such as reproducibility and reliability of data. There are only a few works where important characteristics concerning solution pH, sham injections, body temperature, locomotion indices (basal and injection-modulated), etc, are reported. Figures on the illumination level in experimental chambers are generally missing. Three simplest, fastest, and most commonly used anxiety models (dark-light compartments, social isolation test, elevated plus-maze) are considered with special attention to the mistakes and artifacts most frequently encountered in registration of the experimental animal behavior and in the data interpretation.

[The mechanisms of the placebo effect]. / O mekhanizmakh platsebo-éffekta.

The lecture deals with the experimental and clinical data on the frequency and instability of placebo effects, the notions of the probable role of motivation of the treatment, psychological factors of expectancy and inspiration, conditional-reflex processes, stable pathological condition, activation of the opioidergic system, and appearance and sustenance of the placebo effects.

[A decreased frequency of peeking out from the dark compartment--the only constant index of the effect of anxiogens on the behavior of mice in a "light-darkness" chamber]. / Umen'shenie chastoty vygliadyvanii iz temnogo otseka--edinstvennyi postoiannyi pokazatel' vliianiia anksiogenov na povedenie myshei v kamere "svet-temnota".

Special measurements of the effects of anxiolytics and anxiogens on the commonly used parameters of behavior of mice in a dark-light chamber (the rate of transitions and time spent in a dark and light compartments) demonstrated their low reproducibility in consecutive experiments. Therefore, these indices are not reliable (Lapin, 1992). One more parameter was tested in the present study. A decrease in the rate of leanings out of the dark compartment appeared to be a constant effect of standard anxiety-inducing drugs: caffeine, pentylenetetrazole, yohimbine, and a putative endogenous anxiogen phenylethylamine. Increase in the rate of leanings out, like increase in the rate of transitions and shortening of the time spent in a dark compartment produced by anxiolytics diazepam, chlordiazepoxide, hydroxyzine, phenibut and baclofen were not significant in the majority of experiments. That is why these effects of anxiolytics are not reliable for measuring the activity of anxiolytics in a dark-light chamber.

Antagonism of kynurenic acid to anxiogens in mice.

In a dark-light chamber in mice, kynurenic acid (KYNA, 200 mg/kg, i.p.), an endogenous neuroactive metabolite of tryptophan, attenuated the most stable effect of anxiogens in this model of anxiety--a decrease in the rate of leanings-out of the dark compartment --induced by caffeine, pentylenetetrazole and yohimbine, but not by beta-phenylethylamine (PEA). KYNA by itself did not alter behavior of mice in the chamber, in contrast to what has been observed in an elevated plus-maze, another model of anxiety, where KYNA had an anxiolytic pharmacological profile.

[The intracerebral route of kynurenine administration is one of the reasons for the resistance of kynurenine-induced seizures to diazepam]. / Vnutrimozgovoi put' vvedeniia kinurenina--odna iz prichin rezistentnosti kinureninovykh sudorog k diazepamu.

It has been shown many times that in experiments on mice systemic administration of anticonvulsive doses of diazepam caused a 15-20-fold higher effect against the endogenous convulsant kynurenine (injection into the brain ventricles) than against corasol (systemic injection). In the present work diazepam (0.5-2.0 mg/kg, intraperitoneal injection) prevented convulsions induced in nonbred and C57B1/6 mice by equally effective doses of corasol injected subcutaneously (80 mg/kg) better than in injection into the brain ventricles (500 micrograms). In injection of the three drugs into the ventricles diazepam (0.5-10 micrograms) relieved to a similar degree convulsions induced by equally effective doses of corasol (500 micrograms) and kynurenine (50 micrograms). It follows from this that the unique resistance the kynurenine convulsions to diazepam is due to the fact that only kynurenine is injected into the brain ventricles whereas all the other convulsants compared with it are administered systemically. It is suggested that besides the route of administration, the more significant dependence of kynurenine convulsions on GAMA(B) receptors and the activity of the brain dopaminergic system is responsible for the difference in the diazepam sensitivity of kynurenine and corasol convulsions.

[The initial level of motor activity determines the directivity of the motor effect of apomorphine]. / Iskhodnyi uroven' dvigatel'noi aktivnost' opredeliaet napravlennost' motornogo éffekta apomorfina.

In male mice of BALB/c and SHR strains with the highest base level of locomotion and rearings apomorphine (5 mg/kg) decreased these forms of motor activity while in C57BL/6 mice with the lowest base level of motor activity apomorphine increased it. In mice of C57BR and C3H/A strains with intermediate base level there was a tendency for an increase in activity. Extinction of exploratory motor activity in BALB/c as a result of four consecutive testings in the same experimental chamber with hourly intervals induced a decrease in activity of the animals by half. Being injected against this background the same dose of apomorphine (5 mg/kg) twice increased locomotion and rearings in these mice.

[The pharmacological differences between kynurenine- and korazol-induced seizures (the participation of GABA-B receptors and dopamine)]. / Farmakologicheskie razlichiia mezhdu kinureninovymi i korazolovymi sudorogami (uchastie GAMKB-retseptorov i dofamina).

In experiments of male SHR (nonbred) and C57B1/6 mice [correction of rats] bicucullin intensified corasole-induced convulsions but had no effect on kynurenine convulsions, removed the anticonvulsive effect of phenibut against kynurenine and did not affect the anticonvulsive effect of diazepam against corasole. Phenibut and baclofen reduced the anticonvulsive effect of diazepam against corasole and caffeine. Haloperidol increased kynurenine-induced convulsions and had no effect on those caused by corasole. Dopamine removed the effect of haloperidol. Haloperidol and 6-oxydopamine weakened the sedative effect of phenibut. Blockade of GAMAB-receptors and weakening of dopaminergic activity are important in the mechanisms of kynurenine convulsions, and blockage of GABAA-receptors unrelated to it is important in the mechanisms of corasole convulsions. A functional antagonism in anticonvulsive activity may exist between these receptors. Bicucullin may probably have an effect both on GABAA- and GABAB-receptors.

Anticonvulsant activity of melatonin against seizures induced by quinolinate, kainate, glutamate, NMDA, and pentylenetetrazole in mice.

Melatonin was tested in an ongoing attempt to find the endogenous antagonists of quinolinic acid, an endogenous convulsant. Among a great number of metabolites that have been tried before, only a few were found (cerulein and quinaldic acid in mice and kynurenic acid in rats). In SHR (bred from Swiss) male mice, intracerebroventricular (i.c.v.) pretreatment with melatonin (1.25-10.0 microg) attenuated (in the descending order of potency) the convulsant effect of i.c.v. administered kainate, quinolinate, glutamate, N-methyl-D-aspartate, and pentylenetetrazole. Melatonin was ineffective against i.p. administered pentylenetetrazole. Systemically (intraperitoneal, i.p.) administered melatonin (12.5-100.0 mg/kg) attenuated the convulsant effect of quinolinate, while the action of other convulsants used remained unaltered. It is suggested that melatonin could be tried against grand mal seizures in epileptic patients.

Modulation of the inhibitory effect of phenylethylamine on spontaneous motor activity in mice by CPP-(+/-)-3-(2-carboxypiperazin-4-YL)-propyl-1-phosphonic acid.

Beta-phenyl-ethylamine (PEA) at dose of 50 mg/kg inhibits spontaneous, motor activity in mice. CPP- (+/-)-3-(2-Carboxypiperazin-4-yl)-propyl-1-phosphonic acid, a selective and competitive antagonist of N-methyl-D-aspartate (NMDA) receptors, in doses of 0.2-10 mg/kg dose-dependently antagonizes this inhibitory effect of PEA. This effect of CPP appeared to be selective because the inhibitory action of PEA was not altered by pretreament with noncompetitive antagonists of NMDA receptors, such as dizocilpine (MK-801), phencyclidine (PCP), 1-phenylcyclohexylamine (PCA) or by antagonists of other behavioral effects of PEA such as haloperidol, baclofen and phenibut (beta-phenyl-GABA). CPP failed to antagonize the inhibitory effect of other tested drugs such as diazepam, haloperidol, baclofen and phenibut. Intracerebroventricularly administered NMDA (0.2 microM), an agonist of NMDA receptors, suppressed the antagonistic effects of CPP against PEA. This suggests that anti-PEA effect of CPP is related to NMDA receptors. Anti-PEA effect of CPP is not due to accelerated deamination of PEA in CPP-treated mice. When small doses of PEA (5 and 10 mg/kg) and CPP (0.2 and 1 mg/kg) were used, the synergism of two drugs was observed. CPP (1 mg/kg) and deprenyl (0.5 mg/kg) an inhibitor monoamine oxidase of B type (MAO-B), had additive effects on PEA-induced inhibition of locomotion. This effect was not associated with any further inhibition of activity of brain MAO-B (over the inhibition induced by deprenyl alone-by 65%) under high (80 microM) or low (4.3 microM) concentration of PEA as a substrate in the medium. Mechanism of the interaction of CPP and PEA, two drugs belonging to different groups of biologically active compounds, deserves further studies.

[GABA-ergic system in defense against excitatory kynurenines]. / GAMK-ergicheskaia sistema v zashchite ot vozbuzhdaiushchikh kinureninov.

Protection against the excitatory action of L-kynurenine and quinolinic acid in mice is related to the activation of GABA-B and dopamine receptors of the brain and to much lesser degree to the activation of GABA-A receptors. It is hardly believable that the anticonvulsant effect of phenibut (beta-phenyl-GABA), baclofen (CL-phenibut), sodium hydroxybutyrate and taurine against seizures induced by these two kynurenines is determined by alterations in metabolism of GABA.

Antagonism by CPP (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid, of beta-phenylethylamine (PEA)-induced hypermotility in mice of different strains.

In male C57BL/6, BALB/c, and SHR (bred from Swiss) mice, pretreatment with (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), a competitive antagonist of N-methyl-D-aspartate (NMDA) receptor, attenuated the hyperlocomotion induced by beta-phenylethylamine (PEA). This effect of CPP was blocked by intracerebroventricularly (ICV) administered NMDA (0.2 nM). CPP did not alter the hyperlocomotion induced by d-amphetamine. PEA rarely inhibited spontaneous motor activity in those strains. Two other competitive antagonists of NMDA, 2-amino-5-phosphonopentanoic acid (AP-5) and 2-amino-7-phosphonoheptanoic acid (AP-7), ICV at doses of 0.01-0.1 microgram, were ineffective. The noncompetitive antagonists of NMDA, dizocilpine (MK-801) and phencyclidine, at subthreshold doses of 0.1-0.5 mg/kg, potentiated the stimulant effect of PEA. In earlier studies we also observed antagonism between CPP and PEA in NIH-Swiss mice, a strain in which PEA inhibits locomotion. Relationships between the stimulant and the anxiogenic effects of PEA are discussed.

[The contrary effects of ethanol on the behavior of short- and long-sleep C57BL/6 mice in a dark-light chamber]. / Protivopolozhnye éffekty étanola na povedenie korotko- i dolgospiashchikh myshchei C57BL/6 v temno-svetloi kamere.

Marked differences in the behavior of short (SS) and long-sleep (LS) male C57BL/6 mice were found 21 h after a one-time oral administration of ethanol (0.5, 1.0, and 2.0 g/kg), namely a significant prolongation of the time spent in the light compartment, i.e., the inhibition of dark preference (of the hole reflex) was observed only in SS mice. 15 min after ethanol administration opposite changes took place the time spent in the light compartment was shortened in SS mice and prolonged in LS mice. A smaller dose of ethanol (0.5 g/kg) activated the locomotion in SS mice and inhibited it in LS mice. It seems promising to compare the behavior of SS and LS mice over a period of the ethanol withdrawal.