[Effect of 1,2,3,4-tetrahydroimidazo[4,5-c]pyridine and 1,2,3,4-tetrahydroisoquinoline derivatives on the behavior and the brain receptor system in rats].

Adducts obtained via the interaction of formaldehyde with histidine (1,2,3,4-tetrahydroimidazo[4, 5-c]pyridine-3-carboxylic acid (I)), tyrosine (7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (II)), and dopamine (6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (III)) influence the behavior and the state of the brain receptor system of rats upon chronic administration (10-day treatment at a daily dose of 50 mg/kg, i.p.). All the compounds studied decrease the horizontal and (to a lower extent) vertical motor activity and increase the quiescence period duration. On the other hand, the effects of compounds tested on the vegetative reactions were different: compounds I and III increased, whereas compound II decreased these reactions. Using the radioligand binding method, it was established that the treatment with compound I led to a decrease in the density of benzodiazepine receptors (B max of [3H]-flunitrazepam was 78% of the control level) and to a significant (148%) increase in the density of specific binding sites for [3H]-spiperone (reflecting the total density of dopamine (D2) and serotonin (5-HT2) receptors. The chronic administration of compound III produced a reliable decrease (76% of the control level) only in the density of benzodiazepine receptors. None of the tested compounds influenced the affinity of receptors with respect to the radioactive ligands used.

[Differences in the anxiety level of 2 rat strains can be determined by the density of benzodiazepine receptors in the brain]. / Razlichiia v urovne trevozhnosti u dvukh linii krys mogut opredeliat'sia plotnost'iu benzodiazepinovykh retseptorov v mozge.

The object of the present work was detection of the genetic differences in the anxiety level evaluated in a number of behavioral tests and according to the characteristics of benzodiazepine receptors binding in the brain of rats of two inbred strains, WAG/G and Fischer-344. In all experimental situations ("conflict open field test", "mink chamber", "light-dark chamber", "Vogel's test", "elevated plus maze") Fischer-344 rats demonstrated a higher anxiety level than that of WAG/G rats. The concentration of benzodiazepine receptors in the brain was much higher in WAG/G than in Fischer-344 rats. Benzodiazepine receptor affinity had no strain differences. The results of our experiments show the important role of the primary genetic characteristics of the animals in the formation of their response to stress. Apparently, rats with an initially more active endogenic benzodiazepine system of the brain respond less emotionally to stress stimuli and demonstrate a lower anxiety level receptors.

[Tropoxin--a new serotonin antagonist and potential antimigraine agent]. / Tropoksin--novyi antagonist serotonina i potentsial'noe protivomigrenevoie sredstvo.

The search for serotonin antagonists with cerebrovascular activity was conducted among newly synthesized aromatic and heteroaromatic ethers of tropinone oxim. One of these compounds, namely, hydrochloride-3(3,4,5-trimethoxybenzoiloxiimino-1)-8-methyl-8-a zab icyclo [3,2,1] octane, called tropoxin, prevented the development of serotonin-induced constriction of cerebral vessels in vitro and in vivo experiments. This effect was demonstrated also in experiments with oral administration of the drug. Tropoxin was found to possess affinity for 5-HT2 receptors of the rat brain. Tropoxin surpasses the anti-migraine drug methysergide in antiserotonin cerebrovascular activity. This allows tropoxin to be recommended for study as a means for the treatment of migraine.

[The genetic characteristics of the brain alpha 2-adrenergic and S2-serotoninergic systems in the realization of the tail-jerk pain reflex and its morphine suppression in rats]. / Geneticheskie osobennosti al'fa 2-adrenergicheskoi i S2-serotoninergicheskoi sistem golovnogo mozga v realizatsii bolevogo refleksa otdergivanii khvosta i podavlenii ego morfinom u krys.

Experiments were conducted on two inbred rat strains--WAG/G and Fischer-344. The WAG/G rats were found to increase the density of brain cortical mu-opiate and alpha 2-adrenergic receptors, short latency of tail immersion from hot water, decreased analgesic action of 5 mg/kg of intraperitoneal morphine and pronounced analgesic action of 10 micrograms of intracerebral ventricular clonidine The Fischer-344 rats increased S2-receptor affinity, protracted pain latency, increased the analgesic action of morphine (5 mg/kg i.p.), serotonin (0.5 microgram i.c.v.), and ketanserine (1 microgram i.c.v.). The intracerebral ventricular administration of clonidine, serotonin, yohimbine, and ketaserine significantly increased the analgesic action of morphine in the two strains. It is suggested that a prompt pain response and increased analgesic action of morphine in Fischer-344 rats may be determined by higher affinity of serotoninergic receptors, but a slow pain reflex and decreased morphine-induced analgesia of WAG/G rats may be caused by the high density of brain cortex alpha 2-adrenergic receptors.

[The pharmacological properties of karazedin]. / O farmakologicheskikh svoistvakh karazedina.

The original agent 1,2,3,4,5,5a,6,10b-octahydroazepino-[4,5-b]indole (carazedine), an analog of the highly active antipsychotic drug carbidine, was synthesized. This agent was found to have various psychotropic activities and to be superior to carbidine, as shown by a number of tests, and combine properties typical of neuroleptics and tranquilizers. The toxicity of carazedine and carbidine was equal.

[A method for the quantitative assessment of the withdrawal syndrome in morphine-dependent rats]. / Metod kolichestvennoi otsenki sindroma otmeny u morfinzavisimykh krys.

The evaluation of strength of morphine withdrawal syndrome in rats after the 17th day i. p. morphine administration is proposed as calculation of individual indexes in "open field" test. It is found, that injection 1, 5 or 10 mg/kg of morphine 30 min before testing, decreases the withdrawal syndrome in dose dependent manner. Disappearance of particular withdrawal signs took place in different doses of morphine pretreatment. According to this effect all the signs were divided into four groups and signs of each group were given by the specificity coefficient (from 0 to 3). The total individual index of the withdrawal syndrome was calculated as a sum of particular signs, multiplied by the particular coefficient. Specificity of significant signs decrease according to the order: "wet dog" shakes, diarrhea, writhings, dyspnea, paw shakes, ptosis, piloerection and teeth chattering.

[Differences in the characteristics of opiate and catecholaminergic receptors of the striatum and cerebral cortex of rats of Fisher-344 and WAG/GSto strains may cause differences in reinforced action of morphine]. / Razlichiia kharakteristik opiatnykh i katekholaminergicheskikh retseptorov striatuma i kory golovonogo mozga krys linii Fisher-344 i WAG/GSto mogut obuslovlivat' razlichiia v polozhitel'no-podkrepliaiushchem deistvii morfina.

It has been shown that Fischer-344 rats more than WAG/GSto inbred rats preferred to consume the solution of morphine. In intravenous self-administration testing, Fischer-344 rats had a higher rate of reinforced responses that resulted in morphine infusion. Bmax values for mu- and alpha 2-adrenoreceptors were significantly higher in the cortex of WAG/GSto rats. The sensitivity of the serotonin and dopamine receptors in the cortex and striatum of WAG/GSto rats was lower than that in Fischer-344 rats. These findings suggest that the difference between morphine consumptions in two inbred rat strains may be due to individual genetic patterns determining opioid and catecholamine receptors binding in the brain.

[Interaction of piracetam with 3H-imipramine binding sites and the GAMA-benzodiazepine receptor complex of brain membranes]. / Vzaimodeistvie piratsetama s mestami spetsificheskogo sviazyvaniia 3H-imipramina i GAMK-benzodiazepinovym retseptornym kompleksom membran golovnogo mozga.

Piracetam at a concentration of 10(-6) M was shown to behave as a noncompetitive inhibitor of 3H-imipramine specific binding to rat brain membranes. At the same time piracetam failed to influence specific binding of 3H-mianserin to membranes of guinea-pig cerebellum, which is indicative of its inability to suppress histamine H1 receptors, a component of 3H-imipramine specific binding sites. At a concentration of 10(-4) M piracetam does not change specific binding of 3H-flunitrazepam to rat hippocampal membranes in the absence of GABA, but in the presence of 5 X 10(-5) M GABA, like atypical tranquilizer mebicar, acts as a competitor of 3H-flunitrasepam binding. Though Ro-15 1788 did not suppress anxyolytic piracetam (and mebicar) effect, our results give evidence of a possible involvement of GABA-benzodiazepine supramolecular complex in the anxiolytic activity of piracetam.

[Effect of chronic administration of antidepressants on the binding of 3H-imipramine with mouse brain synaptic membranes]. / Vliianie khronicheskogo vvedeniia antidepressantov na sviazyvanie 3H-imipramina s sinapticheskimi membranami golovnogo mozga myshi.

Subchronic (14 days) administration of chlorimipramine and zimelidine, and a new morpholine derivative produces different effects on 3H-imipramine binding with synaptic membranes of the mouse brain. Chlorimipramine increases the concentration of the binding sites (Bmax), zimelidine raises both the Bmax and the dissociation constant, while the new morpholine derivative does not significantly change these characteristics. It has been demonstrated that the changes in the Bmax that occur during prolonged administration of chlorimipramine depend on the method for the obtaining of membrane brain preparations.

[Analysis of acute and chronic effects of antidepressive agents in a learned helplessness model in mice]. / Analiz ostrogo i khronicheskogo éffekta antidepressantov na modeli depressii povedeniia ("learned helplessness") u myshei.

In experimental learned helplessness in mice determined by preliminary inavoidable aversive exposure, activity of tricyclic antidepressants (desipramine, chlorimipramine, amitryptyline), type A MAO inhibitors (pyrazidol), and atypical (zimelidine, trazodon, befuralin) antidepressants as well as that of potential antidepressants (LIS-30, DZK-153) were determined upon chronic administration. The tricyclic compounds, befuralin and DZK-153 removed learned helplessness only after 14 days of administration. The substances with a predominant serotoninomimetic action (zimelidin, trazodon in high doses, pyrazidol, LIS-30) showed high efficacy following 6 days of administration. Single administration of the substances under study did not make it possible to disclose their specific antidepressant activity.

[Use of the swimming test for demonstrating antidepressive activity of drugs during single and repeated administration]. / Primenenie plavatel'nogo testa dlia vyiavleniia antidepressivnoi aktivnosti pri odnokratnom i khronicheskom vvedenii veshchestv.

After placing rats or mice into the cylinders filled with water the animals after initial period active swimming, take the immobilization position the time of which is minimized by administering antidepressants. Experiments were made with random-bred, tetrahybrids CBWA, and C57BL/6, BALB/c, CBA, F1 CBA/c55BL mice. Tetrahybrids CBWA appeared to be an optimal species for making experiments. The use of the "swimming test" made it possible to identify the activity of tricyclic (desipramine, chlorimipramine, amitryptyline) and atypical antidepressants (befuralin, zimelidine, trazodon), that of pyrazidol (type A MAO inhibitor) and of a number of new compounds--derivatives of benzofuran and morpholine upon single and chronic administration. To define the method specificity, use was made of the neuroleptic haloperidol, the tranquilizer diazepam, and of nembutal, which did not exhibit any activity in the test in question. Psychostimulants (amphetamine, caffeine) dramatically increased the time of active swimming. The effect lasted throughout all the 30 minutes of testing, which is not characteristic for antidepressants.

[Effect of chronic use of antidepressants on the state of benzodiazepine receptors in the mouse brain]. / Vliianie khronicheskogo primeneniia antidepressantov na sostoianie benzodiazepinovykh retseptorov golovnogo mozga myshi.

A study was made of the effect of a two-week administration of chlorimipramine, zimelidine and a morpholine derivative on benzodiazepine receptors of the mouse brain. The animals which received antidepressants demonstrated a significant increase in the binding sites of 3H-flunitrazepam without any changes in the dissociation constant as compared to control. The data on the evoked aggressiveness and latency of tonic corasole convulsions in the antidepressant-treated animals support the functional importance of the discovered changes in benzodiazepine receptors.

[Comparative study of the psychotropic activity of tuftsin and its analogs]. / Sravnitel'noe izuchenie psikhotropnoi aktivnosti taftsina i ego analogov.

Tuftsin and its Leu1 and D-Arg4 analogs displayed stimulating activity in experimental behavioral despair in mice. In rats with different types of emotional reactions and with destroyed catecholamine terminals (6-OHDA treatment), tuftsin increased exploratory activity, with fear manifestations being decreased and avoidance behavior improved. This was shown while testing the rats in the "open field" and according to the ability to accomplish an extrapolation task of avoiding critical stress-situation. Leu1-tuftsin increased the emotional stress and sharply hindered the avoidance reaction, while D-Arg4-tuftsin modulated the behavior of the animals with increased emotional reactivity and made the avoidance behavior prompter. Pentapeptide, an inhibitor of tuftsin stimulation of phagocytosis, had no significant effect on the behavior. Modifications in the structure of tuftsin resulted both in the changes in phagocytosis-stimulating activity and the appearance of other psychotropic effects.