Biomedical subjects

E Konstantinova

Publications and source records attributed to E Konstantinova.

At least 19 recordsLinked to original sources

PubMed2000

Memory effects of the Ca2+ and 5-HT antagonists dotarizine and flunarizine.

In experiments on Wistar and Long Evans rats, using behavioral methods for passive (step-down and step-through) and active (shuttle-box two-way avoidance with punishment reinforcement) the newly synthesized diphenyl-methyl-piperazine derivative with Ca2+ and 5-HT antagonistic action dotarizine (DOT) administered repeatedly at oral doses of 50 and 10 mg/kg in some cases improve memory process. Under the same experimental conditions the chemically related to dotarizine Ca2+ antagonist flunarizine significantly facilitated retention. In old (Long Evans and Wistar) rats DOT in large dose decreases values of learning criterion. Probably this is a manifestation of the inherent to drugs with nootropic action "therapeutic window". Earlier investigations of the same and other authors suggest the participation of serotonergic neurotransmission in the mechanism of the memory effects of the drug DOT.

Animals↗

PubMed1998

Does nitric oxide participate in the mechanism of action of dotarizine?

Behavioral and nociceptive effects of dotarizine (DOT) and other substances acting on migrainous attacks and nitric oxide (NO) metabolism were studied in comparative experiments on rats. Behavioral effects were evaluated by the changes induced in ambulations and rearings of rats in the Opto-Varimex apparatus; effects on nociception were determined by the changes of pain threshold in growing mechanical pressure on one of the rat paw. The data showed that (1) NO did not participate directly in the mechanism of the behavioral actions of DOT. A role could be ascribed to the modulating influence of DOT on the changes in NO formation induced by other agents; (2) the NO system did not participate in the mechanisms of the responses to the painful mechanical pressure on the rat paw; (3) the behavioral effects of the substances with facilitating or inhibitory action on the migrainous process (m-CPP and ergotamine) and the influence of substances proved to affect NO formation (L-arginine, histamine, L-NAME) on these effects suggest a role for NO as a modulating but not a basic factor in the mechanisms of action of these pro- and antimigrainous substances; and (4) the behavioral effects of DOT were similar to the effects of the antimigrainous drug ergotamine and different from the promigrainous drug meta-chlorophenyl-piperazine (m-CPP)--which suggest an antimigrainous activity of dotarizine.

Animals↗

PubMed1995

Participation of different 5-HT receptors in the memory process in rats and its modulation by the serotonin depletor p-chlorophenylalanine.

The memory effects of agonists and antagonists of some serotonin (5-HT) receptor subtypes were examined in experiments on rats using an active avoidance method (shuttle-box). The 5-HT receptor antagonists NAN 190 (1 mg/kg i.p.) and pindolol (6 mg/kg i.p.) improved some indices for memory; the 5-HT2 and 5-HT3 receptor antagonists ritanserin (1 mg/kg i.p.) and ondansetron (0.1 mg/kg i.p.) exerted a favourable effect on the mastering of active avoidance performance. The tryptophan hydroxylase inhibitor para-chlorophenylalanine (300 mg/kg i.p.) alone produced no significant changes in the indices for retention of learned behaviour but in combination with the 5-HT-receptor agonists and antagonists influenced some of their effects. The results obtained show different participation of 5-HT1A, 5-HT2 and 5-HT3 receptors in the mechanisms of the memory process; the nature of this involvement is modulated by the brain level of serotonin.

Animals↗

PubMed1995

Effects on nociception of the Ca2+ and 5-HT antagonist dotarizine and other 5-HT receptor agonists and antagonists.

The effects of the Ca2+ and 5-HT1 and 5-HT2 receptor antagonist dotarizine and of some other agonists and antagonists of different 5-HT receptor subtypes administered alone or in combination with the 5-HT uptake inhibitor fluoxetine (FLU) on nociception were studied, using a foot-pressure method (analgesy-meter testing). Dotarizine (DOT) administered at a dose of 50 mg/kg for 3 days orally significantly increased the pain threshold. Fluoxetine (FLU) administered at a dose of 10 mg/kg for 3 days also significantly increased the pain threshold. The combination of DOT and FLU abolished the analgesic effects of the two drugs. The 5-HT1A and 5-HT1B/1C receptor agonists buspirone and m-CPP decreased the pain threshold. The antagonists of 5-HT1A(NAN-190),5-HT1/5-HT2(methysergide), 5-HT2 (ritanserin), and 5-HT3 (ondansetron) receptors as well as the agonists of 5-HT2(DOI) and 5-HT3 (mCPBG) receptors increased the pain threshold. Fluoxetine at a single dose of 10 mg/kg differently influenced the effects of the 5-HT agonists and antagonists on nociception. Comparison of the effects of dotarizine with the effects of some of the agonists and antagonists of 5-HT receptor subtypes on the nociceptive and other actions suggests the possibility of a therapeutic value of dotarizine as an antimigraine drug.

Animals↗

PubMed1995

Anxiolytic effects of dotarizine, a possible antimigraine drug.

In experiments on rats in elevated plus-maze and in Opto Varimex apparatus, used for studying exploratory behavior, we observed that dotarizine (DOT), a drug with Ca2+ and 5-HT1/5-HT2-receptor antagonistic action, exerted effects suggesting anxiolytic action. The 5-HT uptake inhibitor fluoxetine (FLU) produced mainly anxiogenic effects. The simultaneous administration of DOT and FLU weakened the anxiolytic effect of DOT. The effects of the 5-HT1B/5-HT1C receptor agonist with promigraine action, m-chlorophenylpiperazine (m-CPP), indicated anxiogenic action, which was increased to a certain extent when it was combined with FLU. Some of the other 5-HT-receptor agonists and antagonists tested showed anxiogenic action and others anxiolytic action. In most cases, these effects were changed when they were administered simultaneously with FLU. DOT increased general locomotor activity and when combined with FLU this effect tended to decrease. In contrast, m-CPP decreased general locomotor activity and this effect was potentiated by FLU. DOT at the two doses used did not significantly change the rate of development of habituation, while m-CPP, buspirone and ondansetron increased it. The behavioral effects of DOT observed in all cases opposite to the same effects of the promigraine drug m-CPP suggest an antimigraine action of DOT.

Animals↗

PubMed1994

Behavioral effects of the Ca2+/5-HT antagonist dotarizine.

The diphenyl-methyl-piperazine derivatives with Ca(2+)-antagonistic effect dotarizine (DOT), Fl-6020 and flunarizine were investigated in experiments on rats. The substances tested were administered repeatedly at an oral dose of 50 mg/kg. Behavioral methods were used to study the exploratory activity when the animals were placed in an environment that was unfamiliar to them (the chamber of the Opto Varimex apparatus), the elevated plus-maze method for examining the effect on anxiety, and the method of recording changes in motor activity (using the Automex II apparatus). DOT was found to increase motor activity and to have an anxiolytic effect. Combination of DOT--a compound with Ca(2+)--and 5-HT2-receptor antagonistic action--and the 5-HT-receptor agonists and antagonists used (buspirone, NAN190, pindolol, ritanserin and ondansetron) resulted in such changes in the development of habituation and in anxiety, which suggest that the modulating effects of DOT depend but partly on its typical interaction with the 5-HT2 receptor. Apparently, the Ca(2+)-antagonistic action of DOT plays a definite role, changing its biological activity depending on the 5-HT receptor subtype at the level of which the interaction is taking place.

Animals↗

PubMed1993

Memory effects of standardized extracts of Panax ginseng (G115), Ginkgo biloba (GK 501) and their combination Gincosan (PHL-00701).

In experiments on young (aged 3 months) and old (aged 26 months) rats, using some conditioned-reflex methods with punishment or positive reinforcement for active and passive avoidance (shuttle-box, step-down, step-through, and water maze), we studied the effects of the standardized extracts of Panax ginseng (G115), Ginkgo biloba (GK501) and their combination Gincosan (PHL-00701). The extracts were administered orally for 7 days before training at three increasing doses: 17, 50, and 150 mg/kg for G115; 10, 30, and 90 mg/kg for GK501; and 27, 80, and 240 mg/kg for PHL-00701. The two extracts and their combination improved the retention of learned behavior. This effect varied considerably with the extracts, with the dose and with the behavioral method used. The results suggest that the Panax ginseng G115 and the Ginkgo biloba GK501 extracts possess properties similar in every respect to those of nootropic drugs. The favorable effects on learning and memory of the combination of G115 plus GK501 and the other pharmacological activities inherent in the extracts characterize this combination, offered as Gincosan as a particularly promising drug in geriatric practice.

Aging↗

PubMed1992

Effect of CDP-choline on learning and memory processes in rodents.

The effects of cytidine (5') diphosphocholine (CDP-choline) on learning and memory were studied using conditioned reflex methods for passive avoidance and active avoidance with punishment reinforcement (step-through, step-down, shuttle box and maze), for active avoidance with alimentary reinforcement (staircase maze), and the Morris water maze. The majority of experiments involved comparative studies of the nootropic drugs meclofenoxate and/or piracetam. CDP-choline was administered orally, in some of the experiments also intraperitoneally, at doses of 10-500 mg/kg body weight once or twice daily for 5 or 7 days. In separate cases only single doses were administered. Trainings started one hour after the last dose of the drugs. Retention tests were given 3 h, 24 h, 7 days or 10 days after training. The results obtained with the different methods document CDP-choline's ability to improve learning and memory in rats and mice. No essential differences in the effects of CDP-choline were established upon oral and intraperitoneal administration of the drug. The learning- and memory-facilitating effects of CDP-choline were similar to those of meclofenoxate and piracetam. The results of the present study permit us to define CDP-choline as a substance capable of improving cognitive levels.

Animals↗

PubMed1991

Modulation of the effects on learning and memory of nootropic drugs and central stimulants when applied together.

In experiments on rats using passive avoidance with punishment reinforcement (step-through) and two-way active avoidance with punishment reinforcement (shuttle-box), we examined the effects on acquisition and retention of different combinations of the nootropic drugs meclofenoxate (Mf), citicholine (CCh), piracetam (Pc), the structural analogues of aniracetam p-P and p-F, standardized extract from ginseng roots (PG) and the psychostimulants caffeine (Caf) and amphetamine (Amph). Favorable effects (more pronounced improvement of learning and/or memory as compared to that caused by the drugs when given alone) were in some cases obtained by the combination Mf+Caf, Pc+Caf, CCh+Caf, p-F+Caf, Mf+CCh, as well as by the combination Mf+PG applied to rats with electroconvulsive shock-induced amnesia. However, in some cases the combined administration of two drugs with favorable effects on memory did not led to summation or potentiation but rather to disappearance of these effects. This was observed under certain experimental conditions with some combinations of Caf and CCh, Mf, Pc and p-P and with some combinations of Amph and Mf. Based on our earlier results and data in the literature, we present some considerations about the role of the neurotransmitter mechanisms of action of the drugs tested as neurochemical correlates of their effects on memory. It is suggested that the unfavorable results obtained in some cases with combinations of nootropics and psychostimulants are due to the possible disturbance of selective acquisition by the psychostimulant drug.

Amphetamine↗

PubMed1991

Memory effects of a group of newly-synthesized pyrrolidine derivatives with putative nootropic effect.

The original pyrrolidine derivatives with putative nootropic effect: para-chloro-phenoxyacetyl-2-pyrrolidinone (Mf-P), 1-adamantanyl-2-pyrrolidinone (A-P), 2-oxo-1-pyrrolidine-3,7-dimethylxanthine (A-T) and para-benzoyl-1,4-dipyrrolidinone (p-P), were studied. Toxicological screening performed on mice demonstrated the low toxicity of the compounds. Five- or seven-day oral administration of the substances to rats in a dose of 100 mg/kg weight facilitated the learning process and improved the memory of the rats with most of the conditioned-reflex methods used. Application of Mf-P to 2- and 24-month-old rats for 8 days induced changes in the levels of some biogenic monoamines in the brain structures studied. The results obtained, as well as the results of other studies in this laboratory, show that the pyrrolidine derivatives studied, which can be considered to be original new aniracetam analogues, improve the memory process. This effect varies strongly depending on the regime of application of the compounds studied, on the memory capacity of the experimental animals and on the experimental method used. The changes in the brain neurotransmission induced by the substances studied play an essential role in their mechanism of action.

Animals↗

PubMed1987

Changes in the 5-HT-binding sites in the cerebral cortex, striatum and hypothalamus of rats during ageing and under the effect of dopaminergic agents.

The changes in the 5-HT1-binding sites, developing during ageing and under the effect of 10-day administration of L-DOPA and haloperidol, were studied in the cerebral cortex, striatum and hypothalamus of 2-, 10- and 22-month-old rats. The values of Bmax of the 5-HT1-binding sites decreased in all three brain structures studied with the ageing of the experimental animals. Both L-DOPA and haloperidol did not change the general character of the changes in the number of 5-HT1-receptors, developing during ageing, but at the same time L-DOPA reduced their density in the three age periods and in the three cerebral areas studied, while haloperidol increased their number in the 2- and 10-month-old rats. The Kd-values of the 5-HT1-receptors manifested very varied changes, determined both by ageing and by the administration of L-DOPA and haloperidol. The generalized interpretation of these results with the results obtained in earlier studies on the age-determined changes in DA2 and the enkephalin receptors, as well as of the content of biogenic monoamines and MAO-activities, made it possible to see new elements in the adaptive possibilities of the cerebral receptors. On the other hand, the results obtained in the present and earlier studies show that ageing is paralleled by deviations in the equilibrium of the cerebral transmitter systems which seem to play an important role for the development of the behavioural changes connected with ageing.

Aging↗

PubMed1986

Effects of the ergot alkaloid elymoclavine on the level and turnover of biogenic monoamines in the rat brain.

The effect of the clavine alkaloid elymoclavine, isolated from Claviceps sp cp II, on the level and turnover of biogenic monoamines in several rat brain structures was studied. Elymoclavine administered intraperitoneally (i.p.) at a dose of 5 mg/kg significantly increased the dopamine (DA) level in the striatum and hypothalamus and enhanced the DA turnover in the striatum. A significant increase was also found in the level and turnover of noradrenaline (NA) in the hypothalamus. Elymoclavine exerted an opposite effect on the level and turnover of serotonin (5-HT) in these brain structures: the 5-HT level significantly declined and the 5-HT turnover slightly decreased in the striatum and hypothalamus. In the cerebral cortex elymoclavine significantly increased the 5-HT level. Although the stimulant effect on DA receptors appears to be a dominant element in the mechanism of action of elymoclavine, it seems that this ergot alkaloid is also characterized by a plurireceptor action. The present results suggest a certain role for the elymoclavine action on the level and turnover of brain biogenic monoamines in the mechanism of its different pharmacological effects.

Animals↗

PubMed1985

Changes in brain opiate receptors in rats with isolation syndrome.

Prolonged social isolation of Wistar rats produces various neurochemical, neuroendocrine and behavioral changes. Some of isolated rats exhibit interspecies aggressive behavior (mouse-killing). It is suggested that social isolation leads to a stress-like state of rats. On the other hand, the participation of endogenous opioid mechanisms in stress is well known. We found that social isolation induced a decrease in the number of opiate receptors in rat frontal cortex, striatum, hippocampus and periaqueductal grey matter. The decrease was most pronounced in isolated aggressive rats. The affinity of opiate receptors in striatum and hippocampus was increased and in frontal cortex was decreased, these changes being more distinct in isolated aggressive than in isolated non-aggressive rats. These data suggest that social isolation of rats induces great changes in brain opiate receptor functions.

Aggression↗

PubMed1985

Effects of meclofenoxate on the level and turnover of biogenic monoamines in the rat brain.

The level and turnover of biogenic monoamines in some rat brain structures were determined after treatment with meclofenoxate at a dose of 50 mg/kg administered i.p. two times a day (9 a.m. and 5 p.m.) for 5 days. Meclofenoxate decreased dopamine (DA) turnover in the frontal cortex and striatum and highly increased it in the hypothalamus. The DA level significantly declined in the striatum, tended to decline in the cortex and significantly rose in the hypothalamus. The noradrenaline (NA) turnover and level in the cortex and striatum were decreased. Meclofenoxate decreased serotonin (5-HT) turnover in the cortex, striatum and hypothalamus and increased it in the pons. At the same time, the 5-HT level rose in the cortex, striatum and pons and declined in the hypothalamus. These results suggest the neurochemical basis of the psychotropic and neuroendocrine effects of meclofenoxate.

Animals↗

PubMed1984

Enkephalin receptor changes in rat brain during aging.

In experiments on 2-, 10- and 22-month-old rats, it was found that the number (Bmax) of brain enkephalin (Enk) receptors decreased with aging. The Bmax values in the cortex of 22-month-old rats decreased by 57%, in the striatum by 33% and in the hypothalamus by 84% as compared to those in 2-month-old rats. The Enk receptor sensitivity in the brain of aged rats also decreased (increased Kd). It is suggested that the changes in opiate receptors play a role in the age-related reduction of the adaptive capacity of the organism. The studies with repeated administration of L-dopa or haloperidol provided further evidence for interactions between opiate and dopaminergic systems.

Aging↗

PubMed1984

Age-related changes in rat brain dopaminergic receptors.

The number (Bmax) and affinity (Kd) of [3H] spiroperidol binding sites in the cerebral cortex, striatum and hypothalamus of 2-, 10- and 22-month old male Wistar rats (20 rats per group) injected i. p. for 10 days with saline, L-DOPA (250 mg/kg) or haloperidol (1 mg/kg) were determined in the presence of 10(-6) M unlabelled haloperidol. The Bmax values in the three brain structures studied decreased with aging in both controls and L-DOPA- or haloperidol-treated rats. The Kd values increased with age. That specific [3H] spiroperidol binding was determined through displacement of the labelled ligand by haloperidol suggested that an age-related loss of dopamine receptors occurred in the brain structures studied. However, considering the fact that in the cerebral cortex [3H] spiroperidol labels a subclass of serotonin receptors (5-HT2) rather than DA receptors, the present results, particularly those concerning the cerebral cortex, suggest an age-related decrease also in the number of 5-HT receptors in this cerebral structure.

Age Factors↗

PubMed1984

Changes in the brain biogenic monoamines of rats, induced by piracetam and aniracetam.

Single oral dose of 600 mg/kg weight piracetam, respectively 50 mg/kg aniracetam, causes essential changes in the level and turnover of dopamine (DA) and serotonin (5-HT) in some rat cerebral structures. When the animals were killed one hour after the administration of the drugs, piracetam significantly increased the DA level in the cerebral cortex and in the striatum, as well as the 5-HT level in the cortex, reducing the 5-HT level in the striatum, brain stem and hypothalamus. At the same time, under the effect of piracetam the DA turnover was accelerated in the cortex and hypothalamus and delayed in the striatum, the noradrenaline turnover was accelerated in the brain stem, the 5-HT turnover was accelerated in the cortex and delayed in the striatum, stem and hypothalamus. Under the effect of aniracetam the DA level was reduced in the striatum and hypothalamus; the 5-HT level was also decreased in the hypothalamus and increased in the cortex and striatum. Aniracetam delayed the DA turnover in the striatum and the 5-HT turnover in the hypothalamus, accelerating the 5-HT turnover in the cortex, striatum and stem. The results obtained show that the changes induced in the cerebral biogenic monoamines participate in the mechanism of action of piracetam and aniracetam, whereby it seems that the analogies and differences in their effects on the cerebral biogenic monoamines play a definite role for the observed analogies and differences in the behavioural effects of these two "nootropic" compounds.

Animals↗

PubMed1976

[Changes in the concentration of biogenic monoamines in different brain regions under the influence of centrophenoxine (experiments on rats)].

The authors administered 50 mg/body weight of centrophenoxine in white rats i.p. for five susseccive days. The content of serotonine in the cerebral cortex, brain stem and cerebellum increased statistically significant in the rats, injected with centrophenoxine. The levels of noradrenaline and dopamine in the brain stem were raised also significantly. Centrophenoxine did not alter the content of cyclic AMP and the activity of phosphodiesterase in the cerebral cortex and brain stem. These data gave foundation to the authors to suggest that in the mechanism of action of centrophenoxine a significant role is given to the changes, induced by this preparation in the content of biogenic amines in the brain stem.

Animals↗