Effects of non-peptide angiotensin II-receptor antagonists on pentylenetetrazol kindling in mice.

The effects of non-peptide AT1- and AT2-receptor antagonists DuP 753 (losartan) and PD 123319 on the intensity of pentylenetetrazol (PTZ)-kindled seizures in mice were studied. PTZ was injected intraperitoneally at a subconvulsive dose of 40 mg/kg at 48 h until the appearance of clonic seizures. DuP 753 administered intracerebroventricularly (i.c.v.) tended to decrease seizure intensity. Successive administration of ineffective doses of DuP 753 (losartan) and AT2 (angiotensin II) significantly decreased seizure intensity. PD 123319 (i.c.v.) decreased seizure intensity. Combination of ineffective doses of PD 123319 and AT2 also significantly decreased seizure intensity. The results suggest the role of AT2 receptor and its subtypes in PTZ-kindled seizures as well as an action of DuP 753 and PD 123319 similar to the action of AT2, an AT2-receptor agonist.

Further evidence for the interactions between angiotensin II and GABAergic transmission in pentylenetetrazol kindling seizures in mice.

The effects of the GABAergic drugs nipecotic acid, Gabrene, baclofen and metatolylcarbamide (MTC), when given alone or in combination at subthreshold doses with AT II also at a subthreshold dose effective on PTZ-kindling in mice were studied. PTZ-kindling was provoked by intraperitoneal (i.p.) injections of PTZ (40 mg/kg) every other day in male albino mice until clonic seizures appeared. Nipecotic acid (100 and 200 micrograms/mouse intracerebroventricularly [i.c.v.]) tended to decrease seizure intensity. Gabrene (25, 50, 100 and 250 mg/kg i.p.) inhibited PTZ-kindled seizures. Baclofen at a doses of 2.5 and 5 mg/kg i.p. tended to decrease seizure intensity and at a dose of 10 mg/kg was ineffective at all. MTC (50 and 75 mg/kg i.p.) tended to decrease and at a dose of 100 mg/kg significantly decreased seizure intensity. Combinations of subthreshold dose of AT II (0.05 micrograms/mouse i.c.v.) and subthreshold doses of nipecotic acid (100 micrograms/mouse) or Gabrene (10 mg/kg) or baclofen (10 mg/kg) or MTC (50 mg/kg) significantly decreased the intensity of PTZ-kindled seizures in mice. The observed potentiation of the anticonvulsive activity on PTZ-kindling suggests interactions of AT II receptors with GABA receptors (GABAA, GABAB or both), effected through allosteric mechanisms.

Effects of cytidine diphosphate choline on rats with memory deficits.

The effects of cytidine diphosphate choline (CDP-choline, CAS 987-78-0) on learning and memory in rats with memory deficits were examined using behavioral methods of active avoidance with punishment reinforcement (shuttle-box), passive avoidance with punishment reinforcement (step-through and step-down), and active avoidance with positive (alimentary) reinforcement (staircase-maze). In the majority of experiments CDP-choline was applied orally at doses of 10-50 or 100 mg/kg daily for 7 days before the training session. The experiments were carried out on young-adult (aged 5 months) and old (aged 22 months) rats and on rats with a low capability for retention of learned behavior. Memory deficits were induced by the muscarinic cholinoceptor antagonist scopolamine (in young and old rats and mice), by the alpha 2-adrenoceptor agonist clonidine, by electroconvulsive shock, and by hypoxy. Memory deficits were also induced in rats offspring of dams that had been exposed to alcohol during pregnancy and lactation. The results suggest that CDP-choline acts as a memory-enhancing drug and that its effect is particularly pronounced in animals with memory deficits.

Interactions between angiotensin II, diazepam, clonazepam and di-n-propylacetate in pentylenetetrazol kindling seizures in mice.

The effects of AT II alone and in combinations with the anticonvulsants diazepam, clonazepam and di-n-propylacetate (depakine) on PTZ-kindling in mice were studied. PTZ-kindling was provoked by intraperitoneal (i.p.) injections of PTZ (40 mg/kg) every other day in male albino mice until clonic seizures appeared. AT II in doses 0.1 and 1 microgram/mouse intracerebronventricularly (i.c.v.) decreased the intensity of seizures in PTZ-kindled mice. Diazepam (0.25 and 1 mg/kg i.p.), clonazepam (0.05 and 0.1 mg/kg i.p.) and depakine (75 mg/kg) inhibited PTZ-kindled seizures. Combinations of ineffective doses of AT II (0.05 microgram/mouse) and ineffective doses of diazepam (0.1 mg/kg) or clonazepam (0.01 mg/kg) or depakine (50 mg/kg) significantly decreased the intensity of seizures in PTZ-kindled mice. The seizure-decreasing effect of diazepam, clonazepam and depakine on PTZ-kindling in mice, which was potentiated by AT II, suggests interactions of AT II receptors with GABA and benzodiazepine receptors or with the GABA-benzodiazepine receptor-ionophore complex, probably effectuated through alsoteric mechanisms. A more efficient coupling of the GABA-benzodiazepine receptor-ionophore complex with AT II receptors might also be the reason for the decrease of the intensity of seizures in PTZ-kindled mice.

Comparative studies on the influence of ONK (N(5-hydroxynicotinoil) glutamic acid), piracetam and meclofenoxate on the learning- and memory-impairing effect of scopolamine, clonidine, and methergoline.

The effects of the new compound N(5-hydroxynicotinoil)glutamic acid (ONK) in comparison with the well-known nootropic drugs piracetam and meclofenoxate on cognitive functions impaired by scopolamine, clonidine or methergoline were examined in albino rats and mice. The changes in learning and memory were studied by the two-way active avoidance "shuttle-box", passive avoidance "step-down" in rats and passive avoidance "step-through" in mice. The present results showed that ONK (50 mg/kg) injected intraperitoneally (i. p.), piracetam (800 mg/kg) and meclofenoxate (100 mg/kg) administered orally once daily for 5 days before training completely antagonized the scopolamine-provoked amnesia in step-through-trained mice. ONK (50 mg/kg) administered i. p., piracetam (600 mg/kg) and meclofenoxate (100 mg/kg) administered orally once daily for 5 days before training abolished the memory-impairing effect of clonidine in shuttle-box-trained rats and the amnestic effect of methergoline in step-down trained rats. The observed antiamnestic effects of the nootropic drugs studied are probably realised through their influence on cholinergic, noradrenergic and serotoninergic neurotransmission. The favourable effect of ONK on cognition might be of interest for therapeutic practice.

Memory effects of a group of newly-synthesized pyrrolidine derivatives with putative nootropic effect.

The original pyrrolidine derivatives with putative nootropic effect: para-chloro-phenoxyacetyl-2-pyrrolidinone (Mf-P), 1-adamantanyl-2-pyrrolidinone (A-P), 2-oxo-1-pyrrolidine-3,7-dimethylxanthine (A-T) and para-benzoyl-1,4-dipyrrolidinone (p-P), were studied. Toxicological screening performed on mice demonstrated the low toxicity of the compounds. Five- or seven-day oral administration of the substances to rats in a dose of 100 mg/kg weight facilitated the learning process and improved the memory of the rats with most of the conditioned-reflex methods used. Application of Mf-P to 2- and 24-month-old rats for 8 days induced changes in the levels of some biogenic monoamines in the brain structures studied. The results obtained, as well as the results of other studies in this laboratory, show that the pyrrolidine derivatives studied, which can be considered to be original new aniracetam analogues, improve the memory process. This effect varies strongly depending on the regime of application of the compounds studied, on the memory capacity of the experimental animals and on the experimental method used. The changes in the brain neurotransmission induced by the substances studied play an essential role in their mechanism of action.

Influence of nootropic drugs on the learning- and memory-impairing effect of diethyldithiocarbamate in albino rats.

The effects of four nootropic drugs (piracetam, aniracetam, meclofenoxate and fipexide) on the impaired cognitive functions by the dopamine-beta-hydroxylase inhibitor diethyldithiocarbamate (DDC) were investigated in albino rats. The changes in learning and memory were studied by the two-way active avoidance with punishment reinforcement (shuttle box). DDC injected intraperitoneally at a dose of 300 mg/kg in the course of the 5-day shuttle box training significantly impaired learning and retention. The 10-day treatment (5 days before and 5 days during training) with piracetam 600 mg/kg, aniracetam 50 mg/kg, meclofenoxate 100 mg/kg and fipexide 10 mg/kg completely abolished the learning- and memory-impairing effect of DDC. The role of the NA-ergic neurotransmitter system for the DDC-induced disturbances in cognition as well as for the protective effects of nootropic drugs was discussed.

Effects of meclofenoxate and Extr. Rhodiolae roseae L. on electroconvulsive shock-impaired learning and memory in rats.

In experiments on albino rats, the authors studied the effects of meclofenoxate and Extr. Rhodiolae roseae on the memory-impairing action of convulsant electroshock. "Step-down" passive avoidance training with negative reinforcement was used to trace the changes in memory. Meclofenoxate administered i.p. in a dose of 100 mg/kg body weight for five days prevented the retrograde amnesia observed after convulsant electroshock upon retention testing on the 3rd and 24th hr after the end of the training session. The Rhodiola extract administered orally in a dose of 0.10 ml/rat for 10 days, which in other experimental approaches improved learning and memory, remained ineffective here. The role of biogenic monoamines in the learning- and memory-improving effects of meclofenoxate is considered on the basis of earlier studies by the authors.

Interactions between angiotensin II, GABA and diazepam in convulsive seizures.

In experiments on male mice, we studied the effects of gamma-aminobutyric acid (GABA), angiotensin II (AT II), administered intracerebroventricularly, diazepam, injected intraperitoneally, and combinations of GABA + AT II and diazepam + AT II on convulsive seizures induced by pentylenetetrazol (PTZ) (80 mg/kg subcutaneously) and 3-mercaptopropionic acid (3-MPA) (40 mg/kg intraperitoneally). The anticonvulsant effects of GABA and diazepam on PTZ-induced seizures were increased by AT II in doses which did not significantly influence seizures. AT II applied together with GABA or diazepam in ineffective doses provoked a strong anticonvulsant effect on both PTZ- and 3-MPA-induced seizures. These results indicate that the anticonvulsant effects of GABA and diazepam on PTZ- and 3-MPA-induced seizures might effectively be potentiated by the octapeptide AT II. It is suggested that AT II operates as an endocoid acting on GABA, respectively benzodiazepine recognition sites in the CNS.

Serotonergic mechanism in seizures kindled from the rabbit amygdala.

The effect of agents enhancing or diminishing serotonergic activity on seizures kindled from the rabbit amygdala was examined. Acute administration of 5-hydroxytryptophan (5-HTP) 10 and 25 mg/kg (administered in combination with a peripheral decarboxylase inhibitor), quipazine 1, 5 and 10 mg/kg or femoxetine 5 and 15 mg/kg which enhance serotonergic activity affected neither the intensity of behavioral seizures nor the duration of bioelectrical ones. 5-HTP 25 mg/kg and femoxetine 15 mg/kg prolonged the duration of behavioral seizures. Chronic administration of 5-HTP 25 mg/kg and femoxetine 15 mg/kg prolonged the duration of behavioral seizures. Chronic administration of 5-HTP 25 mg/kg had no effect on the development of kindled seizures. Acute administration of p-chlorphenylalanine (PCPA) 250 mg/kg reduced the intensity and shortened the duration of behavioral seizures. Cyproheptadine which blocks the postsynaptic action of serotonin shortened the duration of behavioral seizures. Chronic administration of PCPA 80 mg/kg delayed the development of kindled seizures. It is concluded that a pharmacological stimulation of the serotonergic system exerts no or little enhancing effect, whereas pharmacological inhibition of this system attenuates and delays the development of seizures kindled from the rabbit amygdala.

The effects of antidepressant drugs on the seizures kindled from the rabbit amygdala.

The effects of tricyclic antidepressants; imipramine and doxepin, and of new antidepressants; mianserin, danitracen, trazodone, viloxazine and zimelidine, on seizures kindled from the rabbit amygdala were examined. Behavioral and bioelectrical seizures were kindled by a repeated daily stimulation of unilateral amygdala with a low intensity electric current (120 microamperemeter, 1 msec, 50Hz). The following parameters of kindled seizures were analyzed: 1-intensity of behavioral seizures according to a 6-point scale, 2-duration of behavioral seizures, 3-duration of bioelectrical (EEG) seizure activity. Only imipramine inhibited all parameters of kindled seizures. Doxepin, mianserin, danitracen and trazodone affected only two parameters. Zimelidine did not induce any changes of kindled seizure, and viloxazine prolonged duration of the bioelectrical seizure activity. It is likely that inhibition of seizures kindled from the rabbit amygdala is due to noradrenaline stimulating or serotonin inhibiting properties of the drugs, but independent of the antidepressive activity.

On certain effects of dopaminergic agents in pentylenetetrazol convulsions.

In experiments with pentylenetetrazol convulsion model it has been found that L-DOPA in a dose of 50 mg/kg has no influence, while 500 mg/kg potentiate convulsions. Amantadine in a dose of 25 mg/kg and particularly markedly in a dose of 100 mg/kg potentaites convulsive seizures. Amphetamine in a dose of 0.5 mg/kg has no effect, while 5 mg/kg potentiate convulsive seizures, which is particularly pronounced in mice. Apomorphine in doses of 0.5 and 5 mg/kg has no marked effect on convulsions. Haloperidol in doses of 0.2 and 2 mg/kg does not have a pronounced effect on convulsive-seizure reactions and does not influence the effect of L-DOPA and amantadine on these reactions. The results obtained suggested a rather indirect effect of the dopaminergic system on convulsive-seizure reactivity. It is possible that the effects of some of the dopaminergic agents studied are realized through influencing the relationships between the dopaminergic system and other neurotransmitter systems (especially cholinergic, GABA-ergic and serotonin-ergic).

On certain relationships between gamma-aminobutyric acid (GABA) and adrenergic mechanisms in convulsive-seizure reaction.

In experiments on male albino mice it has been established that upon intracerebroventricular administration in doses of 50, 100 and 300 mug per mouse GABA markedly inhibits the convulsive-seizure reactions in pentylenetetrazol and electroconvulsions and has no substantial effect on strychnine convulsions (the dose of 300 mug is toxic). Diethyldithiocarbamate (DDC) in a dose of 400 mg/kg, introduced i.p. 3 hours in advance, increases the convulsive reactivity in pentylenetetrazol and electroconvulsions. On the background of DDC the inhibitory effect of GABA is expressed only in antagonizing of the DDC effect increasing the convulsive reactivity. Alpha-methyl-paratyrosine (a-MT) in a dose of 250 mg/kg, introduced i.p. 4 hours in advance, has no substantial effect on the convulsive reactivity. On the background of alpha-MT the inhibitory effect of GABA in electroconvulsions does not change essentially, however, in pentylenetetrazol convulsions the GABA effect is practically not manifested. The results obtained show that the changes in the correlations between the catecholamines and GABA in the central nervous system result in substantial changes in the convulsive-seizure reactivity. The lower catecholamines level does not permit the marked manifestation of the GABA inhibitory effect. However, GABA counteracts to a certain extent the rise in the convulsive reactivity as a result of the drop in the brain level of the catecholamines.