[EXPERIMENTAL PHARMACOKINETICS AND PHARMACODYNAMICS OF GB-115 DIPEPTIDE ANXIOLYTIC SUBSTANCES].

Pharmacokinetics and pharmacological activity of GB-115 dipeptide anxiolytic after oral administration in the form of crystalline and micronized substances was studied in albino male rats. In contrast to crystalline, the micronized substance exhibited better pharmacokinetic parameters and higher bioavailability. In the "elevated plus maze" test, GB-115 in micronized form at a dose 0.3 mg/kg demonstrated pronounced anxiolytic properties during prolonged period as compared to crystalline substance at the same dose. The obtained data allow the micronized substance of GB-115 to be recommended for inclusion in pharmaceutical composition of new dipeptide anxiolytic drug formulations.

[Neurotensin NT (8- 13) dipeptide analog dilept increases the pain threshold and decreases the severity of morphine withdrawal syndrome in rats].

The pain threshold effects of a neurotensin NT (8 - 13) dipeptide analog (dilept), morphine, and their combination have been studied using the tail flick test in rats. The animals of another experimental group were administered with morphine in increasing doses (10 - 20 mg/kg, i.p.) for 5 days in order to induce the state of dependence. The physical dependence on morphine was evaluated in the open-field test by monitoring 16 specific behavioral signs of withdrawal syndrome (WS) induced by the opioid receptor antagonist naloxone, after which the WS total index was calculated. It was established, that dilept (1.6 mg/kg, i.p.) produced a mild analgesic effect via increasing the pain threshold by 34% (p < 0.01), did not effect on the morphine analgesic effect, and decreased the expression of morphine WS by 29.1 and 37.5% (p < 0.01) after a single or subchronic administration, respectively. These behavioral effects of dilept were accompanied by normalization of dopamine and serotonin turnover in the hypothalamus, frontal cortex, and striatum of experimental animals.

[The absence of tolerance and withdrawal syndrome after the treatment with the new L-tryptophane-containing dipeptide anxiolytic GB-115].

Effects of GB-115, an anxiolytic L-triptophan-containing dipeptide, based on the endogenous tetrapeptide cholecystokinin, were evaluated during and after withdrawal of its long-term administration to rats in comparison with diazepam. It was shown using the "elevated plus-maze" test (EPM) that GB-115 retained its anxiolytic properties after i/p injections at a daily dose of 0.1 mg/kg fo r 30-days. Discontinuation of dipeptide administration 24h and 48 hours after the onset of the experiment did not lead to behavioral (increased anxiety, aggression) and convulsive (decreased corazol sensitivity) manifestations of withdrawal syndrome. In contrast, the withdrawal ofdiazepam (4.0 mg/kg/day, ip, 30 days) induced the anxiogenic response in EPM, reduction of the aggression threshold, and enhancement of convulsive readiness. Significant differences between GB-115 and diazepam effects on the levels of dopamine, norepinephrine, and their metabolites after chronic administration and withdrawal were restricted to striatum.

[Afobazole decreases severity of morphine withdrawal syndrome: experimental evidence].

Effect of afobazole upon morphine dependency has been studied in rats upon the administration of incremental doses of morphine (10-20 mg/kg, i.p.) for 5 days. The state of dependency was evaluated by monitoring sixteen specific behavioral indices of "spontaneous" (24 h after the last morphine injection) or naloxone-induced withdrawal syndrome. The effect of afobazole (a single dose of 5 mg/kg injected before the test or subchronically for 5 days) was estimated through its influence upon the total index of withdrawal syndrome, which was calculated using the set of behavioural signs. It is established that afobazole upon either single or subchronic injections significantly decreased the expression of spontaneous morphine withdrawal syndrome. The effect was also statistically significant but less pronounced in the case of naloxone-induced withdrawal syndrome. The obtained data suggest that afobazole can be considered as potential effective drug for the correction of various clinical symptoms of morphine withdrawal syndrome.

[Design and synthesis of cholecystokinin-4 dipeptide analogues with anxiolytic and anxiogenic activities].

A new series of dipeptide analogues of the general formula Ph(CH2)nCO-NH(CH2)mCO-Trp-NH2 (n = 1, 3-5; m = 1-3) was designed based on the structure of the endogenous tetrapeptide cholecystokinin-4 (CCK-4) and the topochemical Shemyakin-Ovchinnikov-Ivanov principle. The L-tryptophan derivatives exhibited anxiolytic properties and the D-tryptophan derivatives, anxiogenic properties. The dipeptide Ph(CH2)5CO-Gly-L-Trp-NH2 (GB-115) with the activity in rats of 0.05-0.2 mg/kg after oral and intraperitoneal administration was chosen for further studies as a promising anxiolytic agent.

Anxiolytic activity of endogenous nootropic dipeptide cycloprolylglycine in elevated plus-maze test.

Testing in an elevated plus-maze revealed dose-dependent anxiolytic activity of piracetam analog cycloprolylglycine. Intraperitoneal injection of this agent (0.05 mg/kg) 9-fold prolonged the time spent in open arms compared to the control, without affecting the total motor activity. This effect was stereo-selective: D-enantiomer in doses of 0.05 and 0.1 mg/kg was inactive. Therefore, cycloprolylglycine is similar to piracetam in not only nootropic, but also anxiolytic activity. The existence of an endogenous system responsible for the co-regulation of memory and anxiety is hypothesized.

[An assessment of the individual sensitivity of Wistar rats to the development of morphine dependence]. / Otsenka individual'noi chuvstvitel'nosti krys linii Vistar k formirovaniiu zavisimosti k morfinu.

A search was made for behavioral and physiological indicators which could serve predictors of the individual sensitivity of Wistar rats to the development of physical morphine dependence. Animals with high sensitivity to the development of dependence initially demonstrated intensive ambulation and low motor rearing in the "open field" and had low nociception. Stable animals exhibited high ambulation and motor rearing with insignificant grooming activity as compared to other rats. It has been revealed that rats sensitive to the development of dependence demonstrate higher anxiety in the Vogel test as compared to the stable ones. The findings obtained allowed one to derive a number of equations to predict Wistar rats' individual sensitivity to the development of physical morphine dependence.

[The withdrawal syndrome and lipid peroxidation during the chronic administration of narcotic analgesics to rats]. / Sindrom otmeny i perekisnoe okislenie lipidov pri khronicheskom vvedenii krysam narkotichyeskikh anal'getikov.

Diverse behavioral disorders and the intensity of lipid peroxidation (LPO) of biological membranes were estimated in different rat tissues after the 7-day administration and subsequent withdrawal of morphine or promedol. 24 hours after the withdrawal of the analgetics the demonstrated a high initial level of motor activity in the open field. Naloxone, an antagonist of opiate receptors, potentiated motor activity and the intensity of withdrawal syndrome (by 160%) in rats with morphine rather than promedol dependence. The behavioral disorders in dependent animals were accompanied by LPO activation in liver and brain membranes.

[Neurotropin suppression of the manifestations of the naloxone-provoked withdrawal syndrome in morphine-dependent rats]. / Podavlenie neirotropinom proiavlenii provotsirovannogo naloksonom sindroma otmeny u morfinzavisimykh krys.

Neurotropin was developed by Nippon Zoki Pharmaceutical Co. Ltd. It is produced by inoculating vaccine virus into rabbits and the effective substances are extracted from neuro-immuno inflamed cutaneous tissue. In the present study it was found that intraperitoneally administered neurotropin potently inhibits naloxone-precipitated withdrawal syndrome in morphine-dependent rats. Also we get the experimental evidence that neurotropin increases morphine action but has no positive-reinforcing properties. These data indicate the possibility of testing neurotropin as a medicine for treating opiate-abused patients.

[Self-stimulation characteristics and endogenous ethanol in rats of different sexes]. / Osobennosti samostimuliatsii i éndogennyi étanol u krys raznogo pola.

It has been shown in experiments on rats that in females, the threshold of self-stimulation of the lateral hypothalamus was 1.5-2 times higher than in males. Besides, the rate of self-stimulation with subthreshold currents was 57% higher in the estrus than in the diestrus. Measurement of the blood level of endogenous ethanol and animals' mass on daily self-stimulation for 8-10 weeks permitted making correlations with analogous parameters in rats of both sexes preferring ethanol to water for a long time. In both cases, the levels of endogenous ethanol, which were higher in females than in males, were lower than in intact animals. In addition, there was an increase in the body weight (only in males). The latter circumstance evidences a greater damaging action of prolonged self-stimulation on the females' body.