[Adaptive changes in sigma and phencyclidine receptors during the long-term use of haloperidol and raclopride in rats]. / Adaptatsionnye izmeneniia na sigma- i fentsiklidinovykh retseptorakh pri dlitel'nom primenenii galoperidola i rakloprida u krys.

The experiments on male albino rats have shown that 15 days haloperidol (0.5 mg/kg) and raclopride (1 mg/kg) treatment, but not acute administration, causes the increase of density of sigma receptors in the brain. The number of phencyclidine receptors was also elevated, but this increase was not statistically evident. The behavioral effects of ketamine (5 mg/kg) were evidently decreased after long-term haloperidol and raclopride treatment. The motor stimulation and stereotyped behavior induced by apomorphine (0.15 mg/kg) were increased only after treatment of haloperidol, but not raclopride. It seems probable that repeated neuroleptic (haloperidol and raclopride) treatment causes the hyposensitivity of sigma and phencyclidine receptors, despite the increase of their number. It is possible that this change is related to the depolarization inactivation of dopamine neurons caused by repeated neuroleptic administration.

[The participation of CCK-8-ergic mechanisms in the regulation of emotional behavior in rodents]. / Uchastie KhTsK-8-ergicheskikh mekhanizmov v reguliatsii émotsional'nogo povedeniia u gryzunov.

Effects of CCK-8 receptor agonists caerulein and pentagastrin and CCK-8 receptor antagonist proglumide on exploratory and locomotor activity of mice and rats were studied. Systemic administration of caerulein (500 ng/kg 1 mcg/kg) decreased significantly the exploratory activity of mice in elevated plus-maze. This anxiogenic-like action of caerulein was attenuated by acute pretreatment with proglumide (1 and 15 mg/kg) but not with diazepam (up to 0.75 mg/kg). Proglumide slightly increased the exploratory activity of rats in plus-maze; on the other hand, caerulein and pentagastrin potently decreased the measures of exploration in this test. Caerulein (10-100 mcg/kg) and proglumide (1 and 15 mg/kg) inhibited 3H-pentagastrin binding in mice brain in in vivo experiments. The data obtained indicate that CCK-8-ergic mechanisms in brain play an important role in the generation of anxiety states in rodents.

[Species differences in the behavioral effects of cerulein--an agonist of the receptors of the octapeptide cholecystokinin--in white mice and rats]. / Vidovye razlichiia v povedencheskikh éffektakh tseruleina--agonista retseptorov oktapeptida kholetsistokinina--u belykh myshei i krys.

It has been shown in the behavioural experiments that combined pretreatment with haloperidol (0.25 mg/kg) and caerulein (40 micrograms/kg), and to a lesser extent pretreatment with caerulein alone caused long-term reversal of amphetamine (2 mg/kg) induced hyperexcitability in rats. Administration of proglumide (50 mg/kg), an antagonist of CCK-8 receptors, did not reverse long-term antiamphetamine effect of caerulein. In mice pretreatment with caerulein (50 and 100 micrograms/kg) alone or in combination with haloperidol (0.25 mg/kg) caused hypersensitivity to the behavioural effect of amphetamine (3 mg/kg). Intraventricular (I ng), but not systemic (100-500 micrograms/kg) administration of caerulein selectively antagonized seizures in mice induced by intraventricular administration of quinolinic acid (5 micrograms) and N-methyl-D-aspartate (0.2 microgram). Pretreatment with proglumide (50 mg/kg) reversed the anticonvulsive effect of caerulein in mice. In rats, caerulein failed to affect the seizures caused by intraventricular administration of quinolinic acid. The results of the present study demonstrate the existence of obvious interspecies differences in the behavioural effects of caerulein, the agonist of CCK-8 receptors, in mice and rats.

[Antagonism of caerulein, a CCK-8 receptor agonist, to the behavioral effects of ketamine in mice and rats]. / Antagonizm tseruleina, agonista KhTsK-8 retseptorov k povedencheskim éffektam ketamina u myshei i krys.

It has been established in experiments on male mice and rats that caerulein antagonized the behavioural effects of ketamine, an agonist of phencyclidine receptors. Caerulein (75-375 micrograms/kg) and haloperidol (0.1-1.5 mg/kg) suppressed the stereotyped behaviour and motor excitation induced by ketamine (30 mg/kg) in mice. Caerulein and haloperidol failed to affect ketamine-induced ataxia. Caerulein (10 micrograms/kg) and the opioid antagonist naloxone (5 mg/kg) completely blocked the amnestic action of ketamine (30 mg/kg) in passive avoidance experiments on rats. It seems likely that the suppression of the behavioural effects of ketamine by caerulein is related to its functional antagonism with dopamine and opioid receptors.

[Uniform regulation of central and peripheral benzodiazepine binding sites by GABA receptor agonists in rats]. / Odinakovaia reguliatsiia tsentral'nykh i perifericheskikh mest sviazyvaniia benzodiazepinov agonistami retseptorov GAMK u krys.

Central and peripheral benzodiazepine binding sites were studied in vitro after the administration of GABAA and GABAB agonists. Cerebral cortex and kidney homogenates were used in this study. Muscimol (1.5 mg/kg, intraperitoneally) pretreatment significantly increased the affinity of benzodiazepine binding sites not only in the cerebral cortex but also in the kidneys. Similar changes were obtained with (-) and (+) baclofen (5 mg/kg, intraperitoneally), with the only exception that (-) baclofen in addition to changes in the affinity caused a marked decrease in the number of binding sites in both structures studied. The mechanism of action of GABA agonists on peripheral benzodiazepine binding sites is discussed.

[Changes in the behavioral and biochemical effects of cerulein, an analog of cholecystokinin octapeptide, after prolonged administration of haloperidol]. / Izmenenie povedencheskikh i biokhimicheskikh éffektov tseruleina, analoga oktapeptida kholetsistokinina, posle dlitel'nogo vvedeniia galoperidola.

In experiments on male mice and rats, long-term haloperidol administration (0.25 mg/kg twice a day during 15 days) significantly changed behavioural effects of caerulein, an agonist of CCK-8 receptors. As a rule, the effects of caerulein were reduced or inverted; only long-term antagonism with amphetamine motor excitation in rats increased after the cessation of haloperidol administration. The decrease or inversion of caerulein's effects was connected with reduction of high-affinity dopamine2- and low-affinity CCK-8 receptors' density, reflecting the inhibition of some interneurons' activity in subcortical forebrain structures after haloperidol treatment. A more pronounced inhibition of dopamine's release by caerulein was the reason for the increased antiamphetamine action after long-term haloperidol treatment. It seems possible that both above mechanisms are involved in the antipsychotic action of haloperidol.

[Decreased sensitivity of cholecystokinin receptors in the brain as affected by the prolonged administration of haloperidol]. / Ponizhenie chuvstvitel'nosti kholetsistokininovykh retseptorov v mozge pod vliianiem dlitel'nogo vvedeniia galoperidola.

The authors have used behavioural and radioreceptor methods of investigation, that helped to find correlates of the behavioural phenomena on the receptor level.

[Nonuniform effect of prolonged haloperidol administration on the GABA(A) and benzodiazepine receptors in different parts of the brain]. / Neodinakovoe vliianie dlitel'nogo vvedeniia galoperidola na GAMK(A)- i benzodiazepinovye retseptory v raznykh otdelakh mozga.

The experiments on male mice and rats have revealed reversed behavioral effects of muscimol and Ro 15-1788 after 15 days of haloperidol (0.25 mg/kg, twice daily) treatment. Muscimol (0.75 mg/kg), which depressed motor activity in saline-pretreated mice, stimulated it after discontinuation of long-term haloperidol administration. Ro 15-1788 stimulating effect in saline-pretreated rats gave way to sedative effect following haloperidol withdrawal. Simultaneously, the number of 3H-muscimol and 3H-flunitrazepam binding sites was decreased in forebrain, but increased in hindbrain. It was suggested that GABAA and benzodiazepine receptors in forebrain and hindbrain play opposite (inhibiting and stimulating, respectively) functional roles in the regulation of behaviour.

[Changes in the sensitivity of brain dopamine and serotonin receptors during the prolonged administration of carbidine]. / Izmenenie chuvstvitel'nosti dofaminovykh i serotoninovykh retseptorov mozga pri dlitel'nom vvedenii karbidina.

Male Wistar rats were treated chronically with either carbidine (10 mg/kg/day) or haloperidol (1 mg/kg/day) for 23 consecutive days. On days 4-5 after the treatment discontinuation the animals were challenged with apomorphine HCl (0.5 mg/kg) or 5-OTP (150 mg/kg i. p) in combination with pargiline (40 mg/kg i. p) and stereotype responses were scored. In carbidine-treated rats the intensity of stereotype sniffings was increased after apomorphine treatment. In contrast, animals treated with haloperidol exhibited more intensive gnawing after apomorphine in comparison to vehicle-treated rats. 5-OTP-induced head twitches were increased only in carbidine-treated rats. Prolonged carbidine treatment in contrast to haloperidol induced a decrease in 5H-spiperone and 3H-LSD binding in the frontal cortex, with the density of D-2 receptors in the striatum practically unchanged. It is concluded that neuroleptic carbidine in contrast to classical neuroleptics has a more selective effect in serotonin (S-2) receptors and antidepressive properties of this compound may be due to the down-regulation of S-2 receptors in the brain.

[Role of serotonin and dopamine receptors in the mechanism of action of haloperidol and pirenperone]. / Rol' serotoninovykh i dofaminovykh retseptorov v mekhanizme deistviia galoperidola i pirenperona.

The effects of haloperidol, a typical neuroleptic, and pirenperone, a selective blocker of serotonin-2-receptors, were studied and compared. Acute administration of haloperidol had effects mainly in dopaminergic models, whereas pirenperone was active only in serotoninergic models. Chronic administration of both drugs made the systems indicated hypersensitive. This effect may be important in the mechanism of action of neuroleptic drugs.

[Stimulation by cerulein--an analog of the octapeptide cholecystokinin--of 3H-spiroperidol binding after the long-term administration of neuroleptics]. / Stimuliatsiia tseruleinom--analogom oktapeptida kholetsistokinina--sviazyvaniia 3H-spiroperidola posle dlitel'nogo vvedeniia neiroleptikov.

It has been established in experiments on white male rats that prolonged administration (twice a day for 14 days) of haloperidol (0.25 mg/kg) and pyreneperone (0.25 mg/kg) resulted in the reduced interaction between 3H-spiroperidol and low affinity binding sites for apomorphine in subcortical structures, whereas 3H-spiroperidol binding with high affinity binding sites for apomorphine increased both in the frontal cortex and subcortical structures of the forebrain. After prolonged administration of neuroleptics the displacing effect of cerulein, an analog of cholecystokinin octapeptide, was replaced by the stimulant action on 3H-spiroperidol binding. It is assumed that increased interaction between 3H-spiroperidol and high affinity binding sites for apomorphine on dopamine2- and serotonin2-receptors underlies the antipsychotic action of neuroleptics after their prolonged administration. Cholecystokinin octapeptide is a necessary factor for realization of this action of neuroleptics.

[Effect of an imidazobenzodiazepine (RO 15-1788) on aggressive behavior in mice]. / Vliianie imidazobenzodiazepina (RO 15-1788) na agressivnoe povedenie myshei.

Imidazobenzodiazepine (Ro 15-1788, 5 mg/kg) similarly to a lose dose of apomorphine (0.1 mg/kg) decreased the intensity of footshock aggression in male rats. Ro 15-1788 significantly potentiated the antiaggressive action of apomorphine. Pirenperone (0.01 mg/kg) potentiated the effect of both drugs, whereas haloperidol (0.01 mg/kg) had an opposite action. After long-term treatment with apomorphine and Ro 15-1788 the tolerance to their antiaggressive action developed. This change was in agreement with increased serotonin metabolism in the forebrain. Unlike the action on aggressive behavior, Ro 15-1788 similarly to haloperidol (0.05 mg/kg) decreased the motor depressant effect of apomorphine (0.01 mg/kg) in mice. This effect correlated with the lowered serotonin metabolism after Ro 15-1788 administration. Unlike apomorphine, Ro 15-1788 reversed catalepsy induced by haloperidol (0.25 mg/kg). Administration of pirenperone (0.03 mg/kg) and destruction of serotoninergic terminals by p-chloroamphetamine (2 X 15 mg/kg) significantly potentiated the sedative action of apomorphine. It appears that different action of Ro 15-1788 on behavioral effects of apomorphine is related to different influence of Ro-1788 on serotoninergic processes in the striatum and limbic structures.

[Role of serotonin2 receptors in regulating aggressive behavior]. / Rol' serotonin2-retseptorov v reguliatsii agressivnogo povedeniia.

Quipazine and pirenperone , the drugs interacting with serotonin2 -receptors, more readily displaced 3H-spiroperidol from its binding sites in the frontal cortex than in the striatum. Pirenperone (0,07-0,3 mg/kg), antagonist of serotonin2 -receptors, selectively decreased the intensity of apomorphine aggressiveness. The antiaggressive action of haloperidol (0,01-0,2 mg/kg) was in correlation with its antistereotypic activity. Long-term administration of naloxone (0,5; 15,0 mg/kg), together with apomorphine (0,5 mg/kg) reduced the number of head-twitches caused by quipazine (2,5 mg/kg). The administration of quipazine 48 hours after the last injection of naloxone and apomorphine caused spontaneous aggressiveness that did not differ from apomorphine aggressiveness. Intracerebroventricular injection of cholecystokinin tetrapeptide (CCK-4) markedly enhanced the foot-shock aggression. The same dose of CCK-4 also decreased the intensity of quipazine (2,5 mg/kg) head-twitches. Compared to haloperidol, pirenperone was a more selective antagonist of CCK-4. After long-term apomorphine treatment (0,5 mg/kg during 10 days, twice daily), the effect of CCK-4 on aggressive behaviour was markedly enhanced. It is possible that two subtypes of serotonin2 -receptors exist in the brain and have opposite action on the aggressive behaviour. CCK-4 may play the role of an endogenous modulator of sensitivity of serotonin2 -receptors involved in the control of aggressiveness.

[Various methods of overcoming secondary resistance to treatment developing in relation to adaptation to psychotropic drugs during long-term treatment (clinico-experimental study)]. / Nekotorye metody preodoleniia vtorichnoi terapevticheskoi rezistentnosti, formiruiushcheisia v sviazi s adaptatsiei k psikhotropnym sredstvam pri dlitel'nom lechenii (kliniko-éksperimental'noe issledovanie).

Clinical and experimental studies into the phenomenon of adaptation to neuroleptic agents and into the methods of its overcoming were carried out. An experimental study of the long-term administrations of haloperidol revealed the formation of adaptation to the drug which can be overcome by a zigzag-like sharp elevation of the dosage followed by rapid reduction to the baseline level. The trial of this method under clinical conditions showed that it was expedient to use on a large scale the experimental findings on the specific features of the formation and prevention of the secondary therapeutic resistance.

[Effect of multiple daily administration of fenibut and diazepam on GABA and benzodiazepine receptors in the mouse brain]. / Vliianie mnogodnevnogo vvedeniia fenibuta i diazepama na retseptory GAMK i benzodiazepinov v mozge myshei.

It was shown in experiments on mice that 25 hours after chronic treatment with fenibut (100 mg/kg, twice daily for 10 days) was discontinued the number of benzodiazepine and GABAA (bicucullin-sensitive) receptor sites was increased and 48 hours after treatment discontinuation the number of GABAB (bicucullin nonsensitive) sites was decreased. The enhanced binding to GABAA and GABAB receptor sites and the decreased binding to benzodiazepine receptors was observed 24 hours after discontinuation of chronic treatment with diazepam (5 mg/kg, twice daily). Forty-eight hours after diazepam chronic treatment was discontinued the number of benzodiazepine receptor sites was increased. The involvement of the increased benzodiazepine receptor sensitivity in the mechanism of therapeutic activity of fenibut is suggested.

[Role of benzodiazepine receptors in regulating aggressive behavior]. / O roli benzodiazepinovykh retseptorov v reguliatsii agressivnogo povedeniia.

In experiments of male Wistar rats, it was established that a long-term apomorphine treatment caused changes in density of benzodiazepine receptors in forebrain structures opposite to those elicited by acute administration. The changes in benzodiazepine binding correlated with decrease of antiaggressive effect of diazepam and Ro 15-1788 after long-term apomorphine administration. The action of apomorphine on the benzodiazepine receptors was not direct, as apomorphine did not change the benzodiazepine agonist-antagonist interaction, and naloxone, opiate blocator, was a more powerful antagonist of antiaggressive action of diazepam than Ro 15-1788. The involvement of the two types of benzodiazepine receptors in the regulation of aggressive behavior is suggested, the first being apparently linked with GABA and opiate receptors and the other one--with the serotoninergic system. Ro 15-1788 was able to antagonize the effects of diazepam on the first but not on the second type of benzodiazepine receptors.

[Fenibut binding with bicuculline-insensitive GABA receptors in the rat brain]. / O sviazyvanii fenibuta s bikukullinnechuvstvitel'nymi retseptorami GAMK v mozge krys.

(+/-) Fenibut beta-phenyl-GABA) was not able to displace 3H-GABA in Na+ independent GABA binding (IC50 greater than 250 microM). Nevertheless, (+/-) fenibut and (+/-) baclofen effectively displaced 3H-GABA in Ca2+ dependent GABA binding in the presence of 50 microM (+) bicuculline. (+/-) Fenibut was less potent in this respect. It is suggested that fenibut may act via bicuculline-insensitive GABA receptors.