Effects of flunarizine and nitrendipine on electroconvulsive shock- and clonidine-induced amnesia.

This study was designed to examine the calcium channel blockers flunarizine and nitrendipine for their ability to prevent electroconvulsive shock (ECS)- or clonidine-induced deterioration of the inhibitory avoidance performance (step-down) in rats. Flunarizine (10 mg/kg) and nitrendipine (40 mg/kg) were found to prevent the ECS- or clonidine-provoked amnesia after oral administration for 12 days. The mechanisms of action of the two drugs are considered. The results of this study further suggest that calcium antagonists might be useful in the treatment of cognitive disorders.

Memory impairment induced by combined disturbance of noradrenergic and dopaminergic neurotransmissions: effects of nootropic drugs.

The effect of the combined application of the alpha 2-adrenoreceptor agonist clonidine and of the dopaminergic blocker haloperidol on the memory processes was tested on albino rats. The changes in the memory were studied using the following methods: two-way active avoidance with negative reinforcement (shuttle-box) and passive avoidance (step-through). Both clonidine (0.05 mg/kg) and haloperidol (0.5 mg/kg), injected intraperitoneally immediately after the end of the training session, slightly impaired retention in the memory tests used with both training methods. Their combined application, however, caused a marked amnesia. This amnesia model was used to study the effects of the nootropic drugs: adafenoxate and the newly-synthesized compound benzoyl-1, 4-dipyrolydinone (p-P). Administered orally in a dose of 100 mg/kg for 5 days prior to the training session, both adafenoxate and p-P fully eliminate the amnesia caused by the combined application of clonidine and haloperidol. The paper discusses the role of the noradrenergic and dopaminergic neurotransmitter systems for the amnestic effect of the clonidine + haloperidol combination, as well as for the favourable effect on the cognitive functions of the tested nootropic drugs adafenoxate and p-p.

Interactions of angiotensin II and GABA-ergic agents at the threshold of convulsive reactions.

The effects of angiotensin II (AT II), GABA, muscimol (administered i.c.v.) and of amino-oxiacetic acid (AOAA) and baclofen (administered i.p.), as well as of the combinations of AT II with these substances and bicuculline, were studied with respect to the threshold of the convulsive seizures induced by timed intravenous infusion of pentylenetetrazol (PTZ) in mice. It was found in the experiments that the threshold-increasing effect of GABA, muscimol and AOAA was potentiated by AT II (applied in a dose which did not change essentially the convulsive threshold). The potentiated effect of GABA, muscimol and AOAA on the convulsive threshold, when applied in combination with AT II, was antagonized by bicuculline. The threshold-increasing effect of baclofen was not affected substantially by AT II; in this case bicuculline had no effect. On the basis of the results obtained it may be assumed that AT II performs the functions of an antocoid predominantly for the GABA-A receptors in the central nervous system.

Comparative effects of centrophenoxine on the picrotoxin convulsive-seizure threshold in non-irradiated and irradiated mice.

A comparative study is made of the effect of centrophenoxine (CP) on the picrotoxin convulsive-seizure threshold (PCST) in non-irradiated and irradiated 3 and 7 days previously male mice. It is found that the CP appliked intracerebroventricularly in doses of 200 and 400 micrograms/mouse (weight 18-22 g), increases PCST. In non-irradiated mice the PCST-increasing effect of CP occurs rapidly (5 min) and it is brief (it can be observed until the 15th min). When the irradiation is performed three days previously, the PCST-increasing effect of CP is prolonged (it is observed until the 6th hour after its application). When the irradiation is performed seven days previously the characteristic features of the PCST-increasing effect of CP are similar to those in the early stage (3 days), the only difference being that the duration of the effect is prolonged to 120 min. Generally, these specificities of the CP effect are valid for all three phases of the convulsive seizure (general excitation, clonic convulsive seizure and tonic convulsive seizure.

Apomorphine stereotypies and transmitter mechanisms in the striatum. I. Changes in the apomorphine stereotypies caused by drugs acting on the GABA-ergic, dopaminergic and cholinergic transmission.

Experiments on male albino mice were carried out in order to determine the effects of drugs connecting with the GABA-ergic, dopaminergic and cholinergic transmission, on apomorphine stereotypies. The agents acting on GABA-ergic transmission are found to reduce the intensity of apomorphine stereotypies in the following order (arranged from strongest to weakest effect and expressed in doses of microgram per mouse: GABA (100), aminooxyacetic acid (5), diazepam (20), picrotoxin (1), GABA (10), semicarbazide (30), picrotoxin (0.1). The agents acting on the dopaminergic transmission also reduce apomorphine stereotypies in the following order: haloperidol (20;2), L-DOPA (500 mg/kg, i. p.), alpha-methylparatyrosine (150 mg/kg, i. p.) diethyldithiocarbamate (200). The strongest antagonistic effect in the two groups of agents studied was found for haloperidol. The agents acting on the cholinergic transmission (agonists and antagonists of muscarinic and nicotinic cholinoreceptors) have no significant effect on apomorphine stereotypies. It is assumed that the striatum is not the only brain structure responsible for apomorphine stereotypies.

Apomorphine stereotypies and transmitter mechanisms in the striatum. II. Interactions between GABA-ergic and cholinergic transmission.

The interactions between the GABA-ergic and cholinergic transmissions in the striatum of male mice are determined through microinjection in the striatum of agents influencing these types of transmission in cases of apomorphine stereotypies. It is found that the agents acting on the cholinergic transmission (agonists and antagonists of the muscarinic and nicotinic cholinoreceptors), antagonize considerably the reducing effect on apomorphine stereotypies of the agents acting on GABA-ergic transmission. Conversely, the agents acting on GABA-ergic transmission (pre- and post-synaptic) intensify or weaken the effects of the agents acting on the cholinergic transmission with respect to apomorphine stereotypies, though the difference is not entirely significant. The influence of the effects of the agents acting on the GABA-ergic transmission in cases of apomorphine stereotypies is thought to be due to the antagonistic action of the striatal cholinergic neurones on the GABA-ergic neurones, while the latter interact with the striatal dopaminergic neurones either directly or through the mediation of substantia nigra. The lack of direct interactions between the GABA-ergic and the cholinergic neurones in the striatum explains the weak influence on cholinergic transmission exerted by the agents acting on the GABA-ergic transmission with respect to apomorphine stereotypies.

Effect of p-chlorophenylalanine on the central nervous excitability threshold and on the activity of some central depressants.

The effect of p-chlorophenylalaine (pCPA)on the central nervous excitability threshold for the neurostimulants pentetrazol, picrotoxin and strychnine inflused intravenously was evaluated in male albino mice. The effect of pCPA pretreatment was also studied in mice treated both with the neurostimulants and with central depressants meta-tolylcarbamide (MTC), phenacemide (phenylacetylurea, Phenurone) or phenobarbitol sodium (PBS). pCPA applied alone or together with MTC, phenacemide and pbs lowered the central nervous excitability threshold for the three central stimulants used in the majority of the experiments.