[Protective effect of selank on the model of mnestic function violation induced by pharmacological blockade of protein synthesis].

We have studied the ability of peptide anxiolytic selank (Thr-Lyz-Pro-Arg-Pro-Gly-Pro) to compensate for mnestic dysfunction caused by the administration of actinomycin D, which inhibits protein synthesis by blocking DNA-dependent RNA polymerase. The experiments were performed on white rats with acquired adaptive ability of spatial visual orientation in a 16-door labyrinth. The learning was based on the avoidance of electric skin irritation at alternating sites of escape reaction (site reflex). Selank (0.5 mg/kg, i.p.) prevented or compensated for actinomycin D (250 mg/kg, i.p.) induced violation of the process of acquisition, improvement, and consolidation of memory trace during the development of a complex site reflex. The drug administration also reduced the time required for acquisition of the adaptive ability of spatial visual orientation in the labyrinth and restored the actinomycin D violated process of re-learning upon a change in the alternation of escape sites under free-choice conditions.

[The role of opioid system in peculiarities of anti-anxiety effect of peptide anxiolytic selank].

Peculiarities of the anxiolytic effects of selank (heptapeptide analog of taftsin) under reduced activity of opioid system upon acute administration of naloxone have been studied in BALB/C and C57BL/6 inbred mice with high and low levels of anxiety, with passive and active emotional stress reaction phenotypes in the open field (OF) test. Selank (0.25 mg/kg, i.p.) per se exhibited anxiolytic effect in BALB/C mice by increasing the general locomotor activity, with no effects on the behavior of C57BL/6 mice in the OF test. Naloxone (1.0 mg/kg, i.p.) per se evoked swift runaway in OF peripheral areas in BALB/C mice while "freezing" the reaction in C57BL/6 mice with active response to stress under the same conditions. Pretreatment with naloxone attenuated the sensitivity to selank in BALB/C mice whereas the response to anxiolytic effects of peptide was increased in C57BL/6 mice. The data obtained reveal a new target for selank in CNS and indicate significance of the activity of enkephalin-opioid system in individual sensitivity to selank.

[Experimental optimization of learning and memory processes by selank].

The effect of selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro), which is a synthetic derivative of the endogenous tetrapeptide tuftsin (stable with respect to tissue peptidases), on the learning and memory processes and metabolism of serotonin (5-HT) have been experimentally studied on Wistar rats. The animals were trained with food reward in 30 trials per day. Selank (300 microg/kg) or saline were injected after the 10th trial. Elaboration of conditioned reflex with food reward was continued 30 min later. Retention was tested 24 h, 7 and 30 days after treatment. A single injection of selank activated the metabolism of 5-HT in the hypothalamus and caudal brain stem for 30 min to 2 h. It was established that selank induces an increase in memory trace stability during 30 days. These findings provide direct evidence that selank, when injected during consolidation phase, can enhance memory storage processes. Nootrope activity of the selank is probably caused by its obvious effect on the level of serotonin and its metabolite in the brain.

[Comparison of the effects of selank and tuftsin on the metabolism of serotonin in the brain of rats pretreated with PCPA].

Effects of the peptide drugs selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro) and tuftsin (Thr-Lys-Pro-Arg) on the metabolism of serotonin (5-hydroxytryptamine, 5-HT) in the brain of Wistar rats preliminarily treated with the 5-HT-synthesis inhibitor p-chlorophenylalanine (PCPA, 320 mg/kg, i.p., 4 days before experiment) have been studied on a group of 87 matured rats. It is established that selank enhances the 5-HT metabolism in the brain stem 30 min after injection to animals pretreated with PCPA. In contrast to selank, tuftsin induced no changes in the 5-HT metabolism in the brain stem and decreased it in the neocortex on the same time scale. The data obtained suggest that the peptide drug selank can be used for the correction of disturbances induced by a decrease in 5-HT metabolism.

[Effects of heptapeptide selank on the content of monoamines and their metabolites in the brain of BALB/C and C57Bl/6 mice: a comparative study].

The effect of heptapeptide selank on the content of neurotransmitter monoamines and its metabolites in the brain structures of BALB/C and C57Bl/6 line mice under conditions of the open-field test were studied. Significant interstrain differences in the content of norepinephrine (NE), dopamine (DA), serotonin (5-HT) as well as in the levels of their metabolites in hippocampus, hypothalamus, striatum and frontal cortex of C57Bl/6 and BALB/C mice were demonstrated. In particular, the content of 5-HT and its metabolite 5-oxyindolacetic acid (5-HIAA) in hippocampus of BALB/C mice (with passive stress response) was higher than in the same structure of C57Bl/6 (stress-susceptible) animals. The injection of selank (0.3 mg/kg) led to an increase in the NE level in the hypothalamus of both mice strains. At the same time, selank produced opposite effects on the content of DA metabolites: the concentrations of dioxyphenylacetic (DOPAC) and homovanillic (HVA) acids were found to increase in frontal cortex and hippocampus of C57Bl/6 mice, while the same parameters in BALB/C mice were demonstrated to decrease. Selank induced a decrease in 5-HT and 5-HIAA levels in the hippocampus of BALB/C mice, but did not affect these parameters in C57Bl/6 animals. The obtained results are indicative of selectivity of the anxiolytic effects of selank.

[Effects of heptapeptide selank on genetically-based and situation-provoked symptoms of depression in behavior in WAG/Rij and Wistar rats, and in BALB/c mice].

A synthetic derivative of the endogenous peptide tuftsin heptapeptide selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro) possesses an anxiolytic and psychostimulant effect, and represents a working element of a new peptide drug having completed the third phase of the clinical testing as a selective anxiolytic. The neurobiochemical spectrum of selank action combines mechanisms which are characteristics of antidepressants and psychostimulants: activation of the brain monoaminergic systems, dopamine synthesis and turnover, and modulation of the tyrosine hydroxylase activity. The aim of this study was to investigate the effect of selank in a new model of inherited (genetically-based) symptoms of depression in behavior of inbred WAG/Rij rats in comparison with its effect on situation-provoked symptoms of depression in behavior of BALB/c mice. Outbred Wistar rats constituted control group. Selank in high doses (1000-2000 microg/kg), after repeated injection counteracted symptoms of depression in behavior of WAG/Rij rats (increased immobilization in the forced swimming test and decreased sucrose intake or preference (anhedonia)). Selank in low doses (100 and 300 microg/kg) after single injection reduced the duration of immobility of BALB/c mice in the forced swimming test, but did not exert significant effect after repeated injection or after injection in high doses (600 and 900 microg/kg). Selank did not affect the level of general locomotor activity and anxiety in WAG/Rij rats, and did not exert substantial effect on the behavior of control Wistar rats. The results demonstrate the presence of antidepressant component in the spectrum of neuropsychotrophyc activity of selank and indicate the higher reliability of a new experimental model of depression (the WAG/Rij rats) as compared to the standard forced swimming test for the determination of antidepressant activity of a pharmacological drug.

[Compensatory effect of selank on the mnestic functions disturbed by neurotoxic damage of the noradrenergic system of the rat brain].

It has been shown that the peptide anxiolytic drug Selank recovers learning and memory impaired by damage of the noradrenergic (NA) brain system in Wistar rats after injection of the NA-synthesis inhibitor disulfiram, administration of neurotoxic compound 6-OHDA, or a combined induction of hypoxic hypoxia and hypercapnia. The main component of the Selank action is the stimulation of the search reflex aimed to distinguish an adequate adaptive response in the first trials of the learning session. The enhancement of memory consolidation and retrieval shows evidence for stimulation of the brain motivation mechanisms impaired by the NA system damage.

[Selank-induced normalizing effects on the integrative brain activity and biogenic amine level disorders due to antenatal hypoxia].

The effects of Selank synthetic analog of Tuftsin, representing the heptapeptide forming Thr-Lys-Pro-Arg-Pro-Gly-Pro, on behavior and serotonin/noradrenalin concentrations in brain were investigated in adult rats exposed to hypoxia during 14-16 days of gestation. It was revealed that injection of Selank (300 mkg/kg, i/p) increased 2--3-fold (p < 0.01) the sensory attention, facilitated 1.5-fold the learning capacity (p < 0.01), normalized exploratory activity in the open field and hole board, and recovered the balance of serotonergic and noradrenergic brain system activity. The data obtained demonstrate the possibility of Selank to compensate for long-lasting negative effects of antenatal hypoxia on integrative brain activity and brain monoamine level.

[Selank and short peptides of Taftsin derivatives in regulation of adaptive behavior of animals in stress]. / Selank i korotkie peptidy semeistva taftsina v reguliatsii adaptivnogo povedeniia pri stresse.

Effects of 10 peptides, tuftsin and Selank derivatives upon behavior during emotional stress induced by conflict situation, were studied in Balb/c and C57BL/6 male mice with genetically determined opposite types of emotional stress reaction, in white male mice and in Wistar male rats divided into different groups according to the type of emotional reactivity. Positive effects of some peptides upon the adaptive behavior of animals in stress situation were demonstrated. Individual physiologically important effects depending on molecular structure of the peptides under study and/or their fragments, possible products of degradation, were revealed. The results obtained confirm the perspectives of aimed synthesis of peptides with definite pharmacological activity, which are not ksenobiotics and will have no side effects.

[The effect of bromantane on the behavior of inbred mouse strains with different phenotypes of emotional stress reaction]. / Vliianie bromantana na povedenie inbrednykh linii myshei s razlichnymi fenotipami émotsional'no-stressovoi reaktsii.

Per os administration of bromantan (2-[n-bromphenyl]-aminoadamantan) in doses of 40-50 mg/kg prevents the fixed posture reaction and reduces the level of defecation in Balb/c mice in the "open field" test and activates their behavior in the "elevated plus maze" test. It increases the motor activity of C57B1/c mice in both tests. It is concluded that an anxiolytic effect is present in the spectrum of pharmacological properties of bromantan.

[The anxiolytic action of an analog of the endogenous peptide tuftsin on inbred mice with different phenotypes of the emotional stress reaction]. / Izuchenie protivotrevozhnogo deistviia analoga éndogennogo peptida taftsina na inbrednykh myshakh s razlichnym fenotipom émotsional'no-stressovoi reaktsii.

The anxiolytic effect of the synthetic analogue of the endogenous peptide tuftsin (Thr-Lys-Pro-Arg-Pro-Gly-Pro) was studied in inbred mice Balb/c (C) and C57B1/6 (B6) with different heritable types of emotional-stress reaction. In C strain with genetically high level of anxiety and "passive" type of behaviour under conditions of avoidable and unavoidable stress (open field, elevated plus-maze, light-dark chamber) the heptapeptide prevented manifestations of anxiety being administered intraperitoneally in a wide range of active doses (200-3000 mcg/kg). The drug did not change the behaviour of B6 mice with low level of anxiety and active type of emotional-stress reaction. The described effect is comparable with tranquilizing-activatory action of low doses of benzodiazepine tranquillizers, however, in contrast to the latter, the heptapeptide has no side inhibitory behavioural effects even in high doses. The heptapeptide may be considered as a promising new anxioselective drug without side inhibitory behavioural effects which are typical for benzodiazepine tranquillizers.

[The pharmacogenetic concept of the anxio-selective effect]. / Farmakogeneticheskaia kontseptsiia anksioselektivnogo éffekta.

Hereditary variations in the effects of benzodiazepine tranquilizers depending on the phenotype of an emotional stress reaction (ESR) are described. The membrane-receptor relationship showed differences between C57B1/6 with an "active" ESR phenotype and Balb/c with a "passive" ESR at the GABA benzodiazepine receptor complex level. The pharmacological results evidenced the selective anxiolytic properties of the novel drug aphobazole (2-[2-morpholyno)ethylthio]-5-ethoxybenzimidazole dihydrochloride) which produced an activating anxiolytic action in Balb/c mice whereas no behavioral changes were observed in C57B1/6 mice.

[The characteristics of the anxiolytic action of taftsin and its analog TP-7 on behavior and serotonin metabolism in the brain of rats with chronic deprivation of serotoninergic system activity]. / Osobennosti anksioliticheskogo deistviia taftsina i ego analoga TP-7 na povedenie i obmen serotonina v mozge krys s khronicheskoi deprivatsiei aktivnosti serotoninergicheskoi sistemy.

The effect of taftcine (Thr-Lys-Pro-Arg) and its analog TP-7 (Thr-Lys-Pro-Arg-Pro-Gly-Pro) on rat behavior and serotonin brain exchange was studied in 95 adult male Wistar rats neonatally administered with 5,7-dihydroxytriptamine. Intracutaneous administration of both peptides (300 micrograms/kg) was found to result in weakening perception of stress situations; an increase in stability of investigation behavior and normalization of serotonin level in the brain of rats with chronic deprivation of serotoninergic system activity. Anxiolytic and psychostimulant activities of TP-7 are more pronounced than those of tafcine.

[The peptidergic modulation of learning a motor food-acquiring conditioned-reflex habit]. / Peptidergicheskaia moduliatsiia obucheniia dvigatel'nomu pishchedobyvatel'nomu uslovnoreflektornomu navyku.

The experimental data were given obtained at studying the influence of different dozes of synthetic heptapeptide (on tafcine basis) on learning to complex instrumental habit in dogs. Effectiveness of intranasal application of peptide on earlier stages of learning and also its ability to restore the lost habit was shown. Vegetative ensuring of learning at its modulation by peptide was studied.

[Enhanced resistance to emotional stress through the use of D-phenylalanine]. / Povyshenie ustoichivosti k émotsional'nomu stressu s pomoshch'iu D-fenilalanina.

Stress-protective action was studied of D-phenylalanine, having an ability to decrease destruction of endogenic enkefalins. In the experiments stability of the experimental (receiving D-phenylalanine) and control groups of male rats of August line to emotional stress was compared in conditions of immobilization stress by parameters of animals survival rate, adrenal glands hypertrophy development, involution of thymus, pathologic changes in lungs (abscesses development), ulcero-dystrophic disturbances in stomach, and also the activity and kinetic properties of enzyme tyrosin-hydroxylase in the hypothalamus were determined. It was shown that by several of the mentioned physiological parameters the D-phenylalanine significantly increased the animals stability to the emotional stress and decreased tyrosinhydroxylase activity which participates in activation of katecholaminergic processes.

[The role of endogenous enkephalins in the regulation of bone marrow hematopoiesis in stress]. / Ob uchastii éndogennykh énkefalinov v reguliatsii kostno- mozgovogo krovetvoreniia pri stresse.

A study was made of the effect of the enkephalinase inhibitor D-phenylalanine on hematopoiesis during the immobilization stress. The long-term treatment with D-phenylalanine before the immobilization stress resulted in a significant increase of plasma ley-enkephalin in mice during the first day after exposure. Later the inhibition of bone marrow hyperplasia was recorded. There were no changes in hematopoiesis provided D-phenylalanine was injected after the immobilization. It is suggested that endogenous enkephalins may take part in the regulation of hematopoiesis at the early period of the stress reaction formation.

[The role of the brain monoaminergic systems in the effects of tuftsin and its analog on animal emotional behavior]. / O roli monoaminergicheskikh sistem mozga v éffektakh taftsina i ego analoga na émotsional'noe povedenie zhivotnykh.

The effects of tuftsin and its analogue TP-1 (300 micrograms/kg) on the animal adaptive behaviour in emotionally different situations, the level of biogenic amines and their metabolites 10, 30 min., 2 and 6 hrs after injection of these substances were studies. The TP-1 induced an increase in the memory traces stability better than tuftsin in emotionally negative situation. A single injection of the peptides induced changes in NA, DA and their metabolites contents for 30 min. to 2 hrs. In contrast to tuftsin, the TP-1 activated the metabolism of 5-HT in the hypothalamus and caudal brainstem without changing the NA turnover. The data obtained suggests that a stronger psychotropic activity of the TP-1 seems to be caused by its obvious effect on biogenic amines and their metabolites level in the brain.