[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.

[Modulating effect of cerulein on benzodiazepine receptors]. / Moduliruiushchee vliianie tseruleina na benzodiazepinovye retseptory.

Subcutaneous administration of caerulein (100-500 micrograms/kg) significantly reduced the development of picrotoxin (8 mg/kg) seizures in male mice. The same doses of caerulein inhibited 3H-flunitrazepam binding in in vivo experiments. Proglumide, an antagonist of cholecystokinin receptors, in low dose (5 mg/kg) potentiated the effects of caerulein (100 micrograms/kg), whereas the administration of proglumide in high dose (25 mg/kg) reduced the action of caerulein on 3H-flunitrazepam binding and picrotoxin seizures. Caerulein (5-1000 nM) decreased 3H-flunitrazepam binding in in vitro experiments only after supplementation of the binding medium with 120 mM NaCl and 5mM KCl. The results suggest the possible interaction of caerulein with chloride ionophor. It seems probable that the direct interaction of caerulein with chloride ionophor in involved in the inhibitory effect of caerulein on picrotoxin seizures and 3H-flunitrazepam binding.

[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.

[Effect of repeated haloperidol and apomorphine administration on the development of tolerance for catalepsy and dopamine receptor hypersensitivity in mice]. / Vliianie povtornogo vvedeniia galoperidola s apomorfinom na vyrabotku tolerantnosti k katalepsii i giperchuvstvitel'nosti dofaminovykh retseptorov u myshei.

It has been shown in experiments on mice that repeated administration of haloperidol (20 days) in doses of 0.1 and 5.0 mg/kg provoked an increase in the tolerance to the drug cataleptic effect. When administered in a higher dose (5.0 mg/kg), the drug increased 3H-spiroperidol binding with the striatal membranes 72 hours after withdrawal. Repeated administration of apomorphine in doses of 0.1 and 1 mg/kg combined with haloperidol antagonized the development of the tolerance and reduced the hypersensitivity of dopamine receptors, observed after withdrawal of haloperidol in a dose of 5.0 mg/kg. The low apomorphine dose also potentiated the haloperidol-induced catalepsy.

[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.

[Effect of the GABA receptor blockader bicuculline on the action of fenibut and diazepam]. / Vliianie blokatora GAMK-retseptorov bikukullina na éffekty fenibuta i diazepama.

Fenibut (100 mg/kg) suppressed the motility and emotional reactivity but did not possess any antiaggressive properties, whereas diazepam (2.5 mg/kg) did increase the motility and reduced aggressiveness in rats. Bicuculline (1.25 mg/kg) itself did not cause any behavioral changes, although it was capable of antagonizing the effects of diazepam and to potentiate those of fenibut. Bicuculline attenuated the GABA rise but did not influence the increased content of HVA and DOPAC after fenibut. The importance of the bicuculline-insensitive mechanisms in the action of fenibut and bicuculline-sensitive ones in the action of diazepam is discussed.

Intrastriatal injection of kainic acid prevents the development of postsynaptic dopamine receptor hypersensitivity after chronic haloperidol treatment.

Rats injected intrastriatally with kainic acid (KA), in contrast to sham-treated (control) animals, showed no tolerance toward catalepsy induced by chronic haloperidol treatment (28 days). After termination of chronic haloperidol treatment in control animals, apomorphine-induced stereotypy was significantly enhanced as compared to chronic saline-injected controls. Rats injected with kainic acid and treated with chronic haloperidol or saline showed no differences in apomorphine stereotypy. These results show that the development of tolerance and behavioural hypersensitivity after chronic neuroleptic treatment is mediated via striatal postsynaptic receptors sensitive to kainic acid lesions.

[Influence of the intracaudate administration of kainic acid on the effects of the prolonged use of haloperidol and apomorphine on rats]. / Vliianie vnutrikaudatnogo vvedeniia kainovoi kisloty na éffekty dlitel'nogo primeneniia galoperidola i apomorfina u krys.

In rats injected with kainic acid into the dorsal part of the caudate nucleus, the chronic treatment (for 20 days) with haloperidol (1 mg/kg) did not induce hypersensitivity of dopamine receptors. However, kainic acid produced no effect on hypersensitivity of the receptors after long-term administration of apomorphine (1 mg/kg). It is suggested that in the CNS there exist at least two types of dopamine receptors one of which is involved in the hypersensitivity mechanism after long-term administration of neuroleptics (post-synaptic receptors), while another one in the hypersensitivity to the effects of long-term administration of dopaminomimetics (presynaptic receptors).

[Effect of intracaudate administration of kainic acid on the activity of the dopaminergic system]. / Vliianie vnutrikaudatnogo vvedeniia kainovoi kisloty na aktivnost' dofaminergicheskoi sistemy.

The injection of kainic acid into dorsal part of the rat striatum destroys the neuronal perikarya and dendrites in the site of injection. Within 10 days the concentration of striatal dopamine and its metabolites (homovanillic acid and 3,4-dihydrohyphenylacetic acid) increased, suggesting activation of the nigro-striatal dopaminergic system. The increase of dopaminergic activity is due to the generation of GABA-ergic striato-nigral loop. The administration of apomorphine and haloperidol in kainic-treated rats showed that apomorphine exerted its effect on the dopamine metabolism presumably via the presynaptic receptors while haloperidol acted on both pre- and postsynaptic receptors. The use of kainic acid as a means for the study of regulation of dopaminergic system activity is proposed.

[Effect of chronic administration of lithium chloride on the development of dopamine receptor sensitivity during morphine withdrawal in rats]. / Vliianie khronicheskogo vvedeniia khlorida litiia na razvitie giperchuvstvitel'nosti dofaminovykh retseptorov pri otmene morfina u krys.

The morphine withdrawal syndrome was studied in male Wistar rats. Spontaneous aggressiveness, enhanced apomorphine aggressiveness, lowered pain threshold and decreased dopamine turnover were observed after withdrawal of 10-day treatment with the increasing doses of morphine (30-300 mg/kg). These changes attested to the increased sensitivity of dopamine receptors. Administration of morphine in conjunction with lithium chloride in a dose of 2 mekv/kg prevented the development of dopamine receptor hypersensitivity. Also, this method did not produce the increased spontaneous and apomorphine aggressiveness or the decreased dopamine turnover. Meanwhile the pain threshold remained lowered.