[Behavioral and neuroreceptor effects of the racetam derivative GIZh-290 in mouse experimental attention deficit model]. / Povedencheskie i neiroretseptornye éffekty proizvodnogo ratsetama GIZh-290 s ispol'zovaniem éksperimental'noi modeli defitsita vnimaniia.

Behavioral and neurochemical effects of the new racetam derivative GIZh-290 were studied in a mouse attention deficit model (the ED-Low animals subpopulation selected during preliminary behavioral typing in the "closed enriched cross maze" test). Subchronic administration of GIZh-290 (1 mg/kg, 3 mg/kg and 5 mg/kg, intraperitoneally, for 6 days), increased the initially low level of attention in ED-Low animals; the highest selectivity was observed at a dose of 3 mg/kg. Radioligand analysis showed that at this dose, the drug changed density (Bmax) of D2 and GABAB receptors as markers in the pre-frontal cortex of the ED-Low subpopulation to Bmax values observed in the ED-High subpopulation. In the prefrontal cortex of the ED-Low rodents treated with GIZh-290 in dose of 3 mg/kg, there was a normalization of tissue concentrations of both dopamine itself (DA) and its intra- and extracellular metabolites (DOPA/DA and HVA/DA). The obtained results indicate the effectiveness of the studied drug for pharmacotherapy of attention deficit in experimental modeling and impact on potential molecular targets identified in the study.

[Influence of pantogam and atomoxetine on attention stability and distribution of dopamine D2 and GABAB receptors in the attention deficit mouse model]. / Vliianie pantogama i atomoksetina na ustoichivost' vnimaniia i raspredelenie dofaminovykh D2 i GAMKV-retseptorov u myshei s model'iu defitsita vnimaniia.

The closed enriched cross maze test was employed as a new experimental model of the attention deficit disorder (ADD) for evaluation of the behavioral and neurochemical effects of the nootropic drug pantogam (100 mg/kg, intraperitoneally) and atomoxetine hydrochloride (3 mg/kg, intraperitoneally) administered subchronically to CD-1 outbred mice. Two subpopulations of rodents differed spontaneously in attention to enriched compartments (ED-Low and ED-High), were estimated on the basis of time spent by the mice in the empty or enriched compartments. The ED-Low and ED-High mice insignificantly differed in parameters associated with anxiety, exploratory efficacy and motor activity. Subchronic administration of both drugs in selected doses produced corrective effect on animal behavior seen as a selective increase in the ED-ratio values in the ED-Low subpopulation. Differences in the distribution of dopamine D2 and GABAB receptors (Bmax) between placebo-treated ED-Low and ED-High mice were found in the prefrontal cortex using the radioligand binding method. The neuroreceptor effects of atomoxetine were seen in prefrontal cortex of ED-Low mice as decrease in the Bmax values of D2 receptors by 14%. Pantogam in the prefrontal cortex of ED-Low subpopulation showed a decrease in the Bmax values of D2 receptors by 22% and an increase for GABAB receptors by 44%. Therefore, subchronic administration of pantogam had a positive corrective effect on the behavior parameters and the density of the studied receptor subtypes in animals with severe attention deficit.

Dental Microwear and Mesowear of the Microtus Voles Molars before and after Experimental Feeding of Owls.

In small mammals, the degree of micro- and mesowear of molars depends on the feed hardness, abrasiveness, and some other characteristics. Analysis of micro- and mesorelief of the paleontological material is used for reconstruction of some animal diet parameters. Small mammals pass through a series of complex transformations on the way from the objects of biocenosis to paleontological objects. Bone remains underwent transformations during accumulation and fossilization. In particular, bone remains from ornithogenous deposits were exposed to the bird digestive system elements. We have experimentally studied changes in some parameters of the narrow-headed vole (Microtus gregalis) molars derived from the owl pellets. Comparison of the same samples before and after exposure to the digestive system of the polar owl (Nyctea scandiaca) and eagle owl (Bubo bubo) showed that the tooth enamel microrelief undergoes serious changes and therefore, provides no information on the intravital diet of voles. A different degree of preservation of the characteristics of the mesorelief was shown. Depending on this, an assessment of their applicability to paleoreconstructions was given.

[COMPARISON OF PHARMACOLOGICAL EFFECTS OF HEPTAPEPTIDE SELANK AFTER INTRANASAL AND INTRAPERITONEAL ADMINISTRATION TO BALB/c AND C57BL/6 MICE.]

Pharmacological effects of intraperitoneal (i.p.) and intranasal (i.n.) administration of heptapeptide selank (300 µg/kg/day for 5 days), known to possess anxiolytic and nootropic properties, were compared by studying the elevated-plus-maze behavior of inbred BALB/c and C57BL/6 mice and measuring the binding of markers to NMDA and GABA receptors of brain. The anxiolytic and nootropic efficiency of selank administered via both routes was observed only in BALB/c mice, which were characterized by initially reduced exploratory activity and higher levels of anxiety as compared to C57BL/6 mice. In BALB/c mice, i.p. selank increased the number of [G-(3)H]SR 95531 binding sites with GABA-receptors in the frontal cortex by 38%, without change in binding to NMDA receptors in the hippocampus. On the contrary, i.n. selank led to an increase in the density of [G-(3)H]MK-801 binding sites by 23% with no effect on GABA receptors. It is suggested that the differences in pharmacological spectra observed for the two routes of selank administration are determined by specific features of drug pharmacokinetics and biotransformation as well as by the dynamics of formation of the anxiolytic and nootropic effects of selank.

[The dynamics of behavioral and neuroreceptor effects after acute and long-term noopept administration in C57BL/6 and BALB/c mice].

The effect of acute, 7-fold and 14-fold noopept (1 mg/kg/day) administration on the dynamics of anxiolitic and nootropic behavioral effects in cross-maze, as well as their correlations with NMDA- and BDZ-receptor density was studied in inbred mice strains, differing in exploratory and emotional status--C57BL/6 and BALB/c. The dipeptide failed to affect the anxiety and exploration activity in C57BL/6 mice at each of 3 steps of experimental session. In this strain the B(max) values of [3H]-MK-801 and [3H]-Flunitrazepam binding changed only after single administration. In respect to BALB/c mice noopept induced both the anxiolitic and nootropic effects reaching their maximum on 7th day. In BALB/c strain the dynamics of hippocampal NMDA-receptor binding corresponds to the dynamics of exploratory efficacy whereas the dynamics of BDZ-receptors in prefrontal cortex was reciprocally to dynamics of anxiety level.

[The influence of piracetam on behavior and brain receptors in C57BL/6 and BALB/c mice: nootropic and anxiolytic effects].

The influence of acute and long-term piracetam administration on the dynamics of rapid (non-specific, anxiolytic) and slow (specific, nootropic) behavioral drug effects, as well as on their interrelation with NMDA- and BDZ-receptors was studied in inbred mice strains differing in cognitive and emotional status--C57BL/6 and BALB/c. The BALB/c strain contained 17% less [3H]-flunitrazepam binding sites in frontal cortex and 22% less [3H]-MK801 binding sites in hippocampus as compared to those in C57BL/6 mice. Based on these data, BALB/c strain was used as a model of psychopathology, combining increased anxiety and cognitive deficit. Under the action of single, 7-fold, and 14-fold piracetam i.p. injections (200 mg/kg body weight, daily), a fast increase in NMDA-receptor density and slow escalation of the specific nootropic effect was observed in BALB/c mice. Non-specific anxiolytic effects in these mice increased for the first 1 - 7 days without any changes in BDZ-binding and then decreased to initial values accompanied by decrement of brain receptor concentration. Thus, in BALB/c mice, a slowly manifested specific nootropic action of piracetam develops, following an increase in NMDA receptor density, whereas the non-specific anxiolytic effect precedes the fast-paced changes in BDZ-binding site density.

[Effects of nootropic drugs on behavior of BALB/c and C57BL/6 mice in the exploratory cross-maze test].

Exploratory behavior, locomotor activity, and anxiety in inbred mice of C57BL/6 and BALB/c strains subchronically treated with placebo or various types of nootropic (cognition enhancing) drugs (piracetam, phenotropil, noopept, semax, pantogam, nooglutil) have been evaluated using the exploratory cross-maze test. It was found that BALB/c mice in comparison to C57BL/6 mice are characterized by greater anxiety and lower efficiency of exploratory behavior in the previously unfamiliar environment. All tested drugs clearly improved the exploratory behavior in BALB/c mice only. In BALB/c mice, piracetam, phenotropil, noopept, and semax also reduced anxiety, while phenotropil additionally increased locomotor activity. Thus, the nootropic drugs displayed clear positive modulation of spontaneous orientation in the mice strain with initially low exploratory efficiency (BALB/c) in the cross-maze test. Some drugs (pantogam, nooglutil) exhibited only nootropic properties, while the other drugs exhibited both nootropic effects on the exploratory activity and produced modulation of the anxiety level (piracetam, fenotropil, noopept, semax) and locomotor activity (fenotropil).

[Influence of hemantane and doxycycline on MPTP-evoked behavior violations in C57BL/6 mice].

The effects of anti-parkinsonian drug hemantane [(2-adamantyl)hexamethylenimine] (10 mg/kg, p. o.) and/or antibiotic drug doxycycline (100 mg/kg, p. o.), as well as that of neurotoxin 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP) (4 x 20 mg/kg, i. p.) were studied in elevated plus maze test on C57BL/6 mice. On second day after injection, MPTP decreased the locomot or activity in comparison to saline. Acute administration of hemantane or doxycycline failed to influence locomotion in mice, while their combination normalized motor activity. The results obtained confirm the role of inflammatory processes in parkinsonism and suggest expediency of combined pharmacotherapy of neurodegenerative diseases.

[Toxicity of ethyl-3-(8-fluoro-2-methyl-2,3,4,5-tetrahydropyrido[4,3-b]indol-5-yl)-propionate dihydrochloride possessing antiallergic properties].

The toxicity of new gamma-carboline derivative [ethyl 3-(8-fluoro-2-methyl-2,3,4,5-tetrahydro-1H-gamma-carbolin-5-yl)-propionate dihydrochloride, CD-008-040] has been studied.

[Anti-allergic properties of a novel ethyl 3-(8-fluoro-2-methyl-2,3,4,5-tetrahydropyrido[4,3-b]indol-5-yl)propionate dihydrochloride].

The influence of ethyl-3-(8-fluoro-2-methyl-2,3,4,5-tetrahydro-1H-gamma-carboline-5-yl)propionate dihydrochloride belonging to the class of gamma-carbolines on the allergic reactions (inflammation and systemic anaphylaxis) has been studied on laboratory animals. It was established that the given substance administered in a dose of 5 - 20 mg/kg exhibits a pronounced antiallergic action. Unlike many other antihistamine drugs, this gamma-carboline derivative probably does not produce sedative effect.

[Substituted 2,3,4,5-tetrahydro-1H-gamma-carbolines: new antagonists of histamine H1 receptors].

The properties of 2,3,4,5-tetrahydro-1H-gamma-carbolines containing acid, ether, and amido-substituents, were assessed as potential antagonists of histamine H1 receptors (H1R), capable of blocking histamine-induced calcium fluxes in SK-N-SH cells. The structure--activity relationship for their antagonistic activity is discussed. Among the gamma-carbolines used in the study, the antihistamine activity considerably depends on the nature of substituents in positions 2, 5, and 8 of the heterocycle. The most active antagonist, ethyl 3-(2-methyl-8-fluoro-2,3,4,5-tetrahydro-1H-gamma-carboline-5-yl)propionate, with high affinity to the H1R (Ki = 6.5 nM), produces no adverse effects on motor activity of mice in doses 1-40 mg/kg, which shows the absence of a sedative effect.

[Effects of nicotinic cholinoreceptor ligands and nootropic drugs on the spontaneous exploratory activity in a labyrinth in mice].

We have studied the effects of nicotine (0.125, 0.25, and 0.5 mg/kg) and mecamylamine (0.5, 1.5, and 3 mg/kg) in comparison to reference cognition-enhancing drugs piracetam (100 and 300 mg/kg) and meclofenoxate (20, 50, and 100 mg/kg) administered to male C57BL mice intraperitoneally 30 min prior to behavioral test. The behavioral drug effect was evaluated as influencing the activity in visiting arms of a closed plus-maze. Piracetam (300 mg/kg) and meclofenoxate (100 mg/kg) improved the exploratory activity. Mecamylamine (0.5 mg/kg) also improved the exploratory activity, while nicotine (0.5 mg/kg) deteriorated it.

[Effects of piracetam and meclofenoxate on the brain NMDA and nicotinic receptors in mice with different exploratory efficacy in the cross maze test].

A population of outbred mice of the ICR strain was divided into two subpopulations according to their high (EH mice) or low (EL mice) exploratory efficacy in the closed cross maze test. In addition, the EH and EL mice differed in the number of binding sites of (i) [G-3H]-MK-801 with NMDA receptors from hippocampus and (ii) [G-3H]-nicotine with nicotine cholinoreceptors (nACh) from neocortex. A subchronic administration of the cognition enhancer piracetam (200 mg/kg, once per day for 5 days) increased by 70% the number of binding sites of NMDA receptors in the EL mice. At the same time, this treatment decreased the density of neocortical nACh receptors in both EL and EH mice (by 55% and 40%, respectively). A subchronic administration of the cognition enhancer and anti-oxidant meclofenoxate (100 mg/kg, once per day for 5 days) also decreased the density of neocortical nACh receptors in both EL and EH mice (by 48% and 20%, respectively). However, meclofenoxate also increased by 41% the number of binding sites of NMDA receptors in the EH mice.

[The correlation between brain weight and behavior changes in response to ethanol administration in laboratory mice]. / Korreliatsiia vesa mozga i izmenenii povedeniia v otvet na vvedenie étanola u laboratornoi myshi.

The effects of ethanol injections on the F2 offspring of the cross between large-brain (LB) and small-brain (SB) mouse strains selected for high and low relative brain weights, respectively, have been studied. The parental strains have significantly differed in brain weight for many generations. The effects of ethanol (2.4 g/kg) have been compared in four subpopulations of mice that differ pairwise in brain weight. One pair of subpopulations has been isolated from the hybrid group and the other, from generation 22 of selection of the parental strains. The results of ANOVA have demonstrated that brain weight is related to the response to ethanol injections. The parameters of stereotyped behavior, which increased in after ethanol injections and reflected the decrease in exploratory activity) were different in mice with high and low relative brain weights. The pattern of behavioral changes after ethanol injections is the second (after increased learning ability) behavioral trait found to be correlated with brain weight.

[Rapid tolerance to ethanol and high voluntary alcohol consumption in mice selected for brain weight]. / Bystraia tolerantnost' k étalonu i dobrovol'noe potreblenie bol'shikh doz alkogolia u myshei, selektirovannykh po vesu mozga.

Mice of two strains selected for small and large brain weight (SB and LB, respectively) had free access to 10% alcohol and water within three months. At the end of this period, they consumed alcohol in daily dose of 6.9 +/- 0.9 and 7.5 +/- 0.8 g/kg, respectively. After a period of imposed three-day abstinence, the alcohol consumption by the mice of these strains increased by 68.6 and 49.3%, respectively. Exploratory behavior of independent groups of mice from these strains was studied in the closed cross-maze. The animals were injected with ethanol (2.4 g/kg, i.p.) or vehicle twice with a weekly interval. In SB mice, the first ethanol administration increased the total time of maze exploration and the number of stereotyped visits. The second ethanol administration did not increase the time of exploration but increased the number of stereotyped visits even to the greater extent. The latter indicates the development of rapid tolerance and sensitization of these behaviors to the drug, respectively. The ethanol administration inhibited exploratory patrolling behavior and defecations. In LB mice, both the first and second ethanol administrations increased the number of stereotyped visits and decreased the exploration time and the number of defecations. The results do not support the psychomotor stimulant hypothesis of alcohol addiction. It is proposed that SB and LB mice may serve as models for Cloninger's types 1 and 2 alcoholics and may be useful for investigation of neuropharmacological mechanisms of stimulatory and inhibitory effects of ethanol.

Behavioral screening of two mouse lines selected for different brain weight.

1. Several behavioral tests were used to compare two lines of mice selected for large (LB) and small brain (SB) weight on the basis of brain/body weight ratio values. 2. An elevated pain sensitivity as well more intense startle response was shown in SB mice in comparison with LB mice. 3. In inescapable situations of slip funnel and tail suspension tests, analogues of the Porsolt swim test, higher immobility scores in SB mice suggest an increased level of fear and/or anxiety the stress situations. 4. The SB mice demonstrated higher levels of locomotion in open field and cross-maze tests. In the latter test, the SB mice also showed increased tendency for stereotyped alternation of two arms during maze exploration. 5. Acute administration of a moderate dose of ethanol (3 g/kg) had opposite effects on the total time of cross-maze exploration: this measure increased in the SB and decreased in the LB line. By contrast, the tendency for stereotypy was similarly increased and the efficacy of maze exploration decreased in both lines.

Haloperidol administered subchronically reduces the alcohol-deprivation effect in mice.

During the pre-experimental phase, hybrid (CBA x C57BL) male mice having had 16 weeks free access to food, water and flavored 30% alcohol were deprived of alcohol for 3 days. The next day they were given free choice between similarly flavored water and 30% alcohol. The mice were divided into two subgroups having (HD) or lacking (LD) the deprivation-induced elevation in alcohol intake during the first 1.5 h of renewed access compared with their intake during the last 22.5 h of first postdeprivation day. In Experiment 1, alcohol naive, LD, and HD mice received daily injections of haloperidol (Haldol; 1 mg/kg) or vehicle during 14 days of abstinence. The behavior of the mice was evaluated in an exploratory cross-maze and inescapable slip funnel test a day after the 13th injection (before the 14th injection). On the first postinjection day, the mice were again given a free choice between flavored water and alcohol. In Experiment 2, all the mice were administered with vehicle during the first 13 days of abstinence. On 14th day, they received an injection of haloperidol (1 mg/kg) or vehicle and a day later were given choice between flavored water and alcohol. Unlike a single injection, the subchronic administration of haloperidol lowered the alcohol intake by HD mice with a more prominent decrease seen during the first 1.5 h than during the last 22.5 h of first postdeprivation day. The alcohol-deprivation effect in HD mice decreased by 79% after subchronic haloperidol. No significant change in alcohol intake was found in alcohol-naive and LD mice. Water intake did not vary systematically. Among the groups, the effect of subchronic haloperidol on the alcohol-deprivation effect did not parallel changes in most of the measures of exploratory or avoidance behavior. It is proposed that haloperidol administered subchronically may attenuate motivation for alcohol.

[The comparison of levels of anxiety and stress response in mice selected for low and high brain weight]. / Sravnenie urovnia trevozhnosti i stress-reaktivnosti myshei, selektirovannykh na bol'shoi i malyi ves mozga.

Emotionality, anxiety and stress reactivity were studied in mice selected for large (LW) and small (SW) brain weight. The open-field test, startle reaction, cross-maze, tail suspension and slippery funnel tests were used. It was shown that the SW mice are more active in the open field, more anxious and predisposed to the stereotyped behavior and passive reactions in stress situations. The relationship between the studied traits and brain weight and their influence on cognitive behavior are discussed.

Different behavioral patterns related to alcohol use in rodents: a factor analysis.

To estimate genetic correlations among behavioral measures from explorative crossmaze, inescapable slip funnel, as well as from drinking tests, the data from five pairs of high/low alcohol drinking rat (AA/ANA, P/NP, HAD1/LAD1, HAD2/LAD2, HIGH-IPH/LOW-IPH) and from three pairs of mouse (B10.AKM/B10.A(4R), HD/LD, Small_Brain/ Large_Brain) lines were evaluated by the use of principal component analysis. The analysis yielded a two-factor solution explaining 71.8% of total variability. Both the factors had high positive loadings on alcohol drinking. The first factor had sufficient positive loadings on latency of crossmaze exploration and total time of slip funnel immobility, whereas, there was a negative loading on slip funnel avoidance. The second factor had positive loadings on efficacy of crossmaze exploration and slip funnel escape attempts, whereas there was a negative loading on slip funnel immobility. The number of defecations in the crossmaze, time in open arms of the elevated plus-maze, time immobile during the forced-swim test, as well as intake of a saccharin solution, additionally available for a lesser number of the lines, were studied for correlations with the factor scores. The first factor of "alcohol drive with timidity and meekness" exhibited positive relation to saccharin intake. Time in the open arms of the elevated plus-maze showed significant negative correlation with a latency of crossmaze exploration. The second factor of "alcohol drive with novelty seeking and persistence" showed a negative link to crossmaze defecations and forced-swim immobility.

Effects of ethanol consumption by adolescent alcohol-preferring P rats on subsequent behavioral performance in the cross-maze and slip funnel tests.

Neonatal alcohol exposure during the first 1-2 weeks of age is known to produce subsequent behavioral hyperactivity in rats. However, little is known about the effects of alcohol exposure during adolescence on subsequent adult behavior. In the present study, male and female P rats had free access to 10% alcohol during adolescence (3-8 weeks of age). After 8 days of abstinence, their behavior was evaluated in the cross-maze and in the inescapable slip funnel tests during the 10th week of age. Two-way ANOVAs revealed significant effects of alcohol drinking on several variables. Compared to alcohol-naive rats, the alcohol-exposed group started exploration earlier (3.5 +/- 0.3 vs. 5.4 +/- 0.7 s, p = 0.03) and made fewer defecations. In the slip funnel test, the alcohol group spent more time immobile (130 +/- 7 vs. 107 +/- 5 s, p = 0.01) and less time attempting to escape out of the funnel (11 +/- 2 vs. 28 +/- 5 s, p = 0.002) than the control group. Overall, the results suggest that the effects of alcohol drinking by P rats during adolescence on subsequent behavior are to reduce novelty-induced anxiety (cross-maze test) and lower response to stress induced by an inescapable situation (slip-funnel test).