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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.

1. The effects of Adafenoxate (Adf), meclofenoxate (Mf) and citicholine (CCh) administered at a daily dose of 100 mg/kg for 7 days on the levels of noradrenaline (NA), dopamine (DA) and serotonin (5-HT) in the frontal cerebral cortex, striatum, hippocampus and hypothalamus of rats were studied. 2. Adafenoxate increased the NA level in the striatum and decreased it in the hypothalamus; it increased the DA level in the cerebral cortex and hypothalamus and decreased it in the striatum; it increased the 5-HT level in the cerebral cortex and decreased it in the hippocampus. 3. Meclofenoxate decreased the NA level in the cerebral cortex and hypothalamus; it increased the DA level in the hippocampus and hypothalamus and the 5-HT level in the cerebral cortex, striatum, hippocampus and hypothalamus. 4. Citicholine increased the NA level in the cerebral cortex and hypothalamus; it increased the DA level in the striatum and the 5-HT level in the cerebral cortex, striatum and hippocampus. 5. An attempt is made to explain some similarities and differences in the behavioral effects of the drugs tested (and those observed in other studies) by the changes they induce in brain biogenic monoamines.

1. The effect of 7-day treatment with the benzodiazepine tranquilizer medazepam (5 mg/kg), the nootropic agent meclofenoxate (100 mg/kg) and their combination in the same doses on the binding activity of muscarinic receptors in four rat brain structures (cerebral cortex, striatum, hippocampus and hypothalamus) were studied using the antagonist [3H]-1-quinuclidinyl benzylate [( 3H]-QNB) as radio-ligand. 2. Medazepam treatment caused significant decrease of muscarinic receptor binding affinity (Kd) and of the receptor binding capacity (Bmax) in the brain structures studied. The number of muscarinic binding sites was unsignificantly decreased only in the hippocampus. 3. Meclofenoxate treatment caused an increase of muscarinic receptor affinity and a decrease of the binding capacity in the cerebral cortex and hypothalamus and an increase of the binding affinity in the striatum and hippocampus. 4. The combination of medazepam and meclofenoxate caused no significant changes of both muscarinic receptor characteristics in the hippocampus and of the receptor affinity in the striatum and hypothalamus in comparison with control rats. The Bmax values were decreased in the cerebral cortex, striatum and hypothalamus when compared with control animals. The differences observed were slighter than those determined after the comparison of medazepam treated rats with control rats. 5. The results obtained afford an opportunity to suggest that the nootropic agent meclofenoxate acts to moderate the effect of the benzodiazepine tranquilizer medazepam on the activity of rat brain muscarinic receptors.

Male Wistar rats were trained for active two-way avoidance in a shuttle-box apparatus for five consecutive days. Meclofenoxate, in doses of 100 and 300 mg/kg i.p., was applied in two separate groups of rats, 60 min before the beginning of the training. Meclofenoxate (Mf), applied in a dose of 100 mg/kg, slightly improved the avoidance training, whereas in a dose of 300 mg/kg it "deteriorated" learning during the last two training days. Retrospective analysis of the experimental results showed that Mf caused a dose-dependent increase in the percentage of rats who were "poor learners", compared with the percentage of "poor learners" among the controls. On the other hand, the Mf-treated "good learners" manifested an essentially better capacity for avoidance training, compared with the control "good learners". The data obtained suggest that Mf increases the adaptational capacities of rats trained for active avoidance possibly in two different ways: in part of the animals it causes improvement of the conditioned reflex activity, in another part of the animals it increases their resistance to the stressogenic stimuli used during such a training.

The authors administered 50 mg/body weight of centrophenoxine in white rats i.p. for five susseccive days. The content of serotonine in the cerebral cortex, brain stem and cerebellum increased statistically significant in the rats, injected with centrophenoxine. The levels of noradrenaline and dopamine in the brain stem were raised also significantly. Centrophenoxine did not alter the content of cyclic AMP and the activity of phosphodiesterase in the cerebral cortex and brain stem. These data gave foundation to the authors to suggest that in the mechanism of action of centrophenoxine a significant role is given to the changes, induced by this preparation in the content of biogenic amines in the brain stem.

The effects of the nootropic drug adafenoxate and of the cerebral vasodilator flunarizine were studied on smooth-muscle preparations isolated from rabbits (perfused central ear artery and segments of the thoracic aorta). Both drugs tested did not change the smooth muscle tone. When applied extralumenally adafenoxate decreased the noradrenaline (NA)-evoked arterial contractions. Adafenoxate (especially in high concentrations) markedly relaxed the NA-contracted arterial preparations. The arterial contractions in response to low-frequency electrical stimulation (ES) were moderately potentiated by high concentrations of extralumenal adafenoxate, but were decreased by intralumenal administration of the drug. Administered prior to or after NA adafenoxate antagonized its contractile effects on the aortic segments (this effect was much pronounced when the smooth-muscle preparations were contracted by NA). Flunarizine exerted similar but less pronounced inhibitory effects on the NA- or ES-evoked contractions of the smooth-muscle preparations. The only essential difference between the two drugs tested was that extralumenal flunarizine inhibited the arterial contractions in response to ES. It is suggested that if adafenoxate exerts an antivasoconstrictory effect not only on the peripheral arteries but also on the cerebral blood vessels, this effect might play an important role for the realization of the nootropic action of this compound.

In experiments on male rats the effects of adafenoxate (Adf), meclofenoxate (Mf), piracetam (Pc) and citicholine (CCh) on learning and memory were studied using the maze active avoidance method with punishment reinforcement. The drugs tested were administered twice daily for seven days at doses of 10 and 50 mg/kg body weight for Adf, Mf and CCh and only at a dose of 50 mg/kg body weight for Pc. The effects of these drugs on scopolamine-treated and scopolamine-untreated rats were also studied using the step-through method. Retention tests were given 24 h and 7 days after the end of the training session in the punishment-reinforcement active avoidance and 3 and 24 h after training in the passive avoidance situation. With the maze method statistically significant results about the favourable effects of the four drugs were obtained by most of the indices for learning and memory. However, the effects of the drugs tested were differently pronounced depending on the dose utilized. With the step-through method all four drugs prevented the scopolamine-induced amnesia. Comparing the present results with other data previously obtained about the effects of the drugs tested and of other nootropic drugs on brain biogenic monoamines, it is suggested that induced changes in biogenic monoamines are responsible for the similarities and the differences in the effects of nootropic drugs on learning and memory.

In experiments on male albino rats, it was found that meclofenoxate at a dose of 100 mg/kg i. p. applied 7 days before and 5 days during shuttle-box training did not influence learning but significantly facilitated retention (retention test was given 7 days after the end of training). With the step-through method for passive avoidance meclofenoxate at the same dose applied for 7 days improved learning and retention. In the staircase maze training with alimentary reinforcement and in the step-down passive avoidance situation, meclofenoxate at a single dose (50 mg/kg i. p.) applied before or immediately after training only tended to facilitate learning and retention, while applied at the same dose twice daily for 5 days, it significantly improved learning and retention. When meclofenoxate at a dose of 50 mg/kg i. p. was administered twice daily for 5 days in parallel with the staircase maze training, learning reached its maximum on the 5th day and remained at this level till the 10th training day even after withdrawal of meclofenoxate. In the control animals the improvement of learning progressively increased till the 10th training day. The present results suggest that the learning- and memory-facilitating effect of meclofenoxate is influenced by the training method, motivation, dose used and treatment duration.

In training for passive avoidance using a device of the step-down type, the nootropic agents piracetam (60 mg/kg orally) and centrophenoxine (100 mg/kg, i. p.) do not facilitate learning, while the ergot alkaloid elymoclavine (1 mg/kg, i. p.) tends to have a positive effect on learning and memory. The muscarine cholinergic receptor blocker scopolamine (2 mg/kg, i. p.) substantially deteriorates short-term memory in passive avoidance training. Piracetam in a dose of 600 mg/kg does not change the negative effect of scopolamine on the memory, while centrophenoxine (100 mg/kg) and elymoclavine (1 mg/kg) eliminate it in view of the fact that the impairment of the short-term memory in the reported experiments was induced by the cholinolytic agent scopolamine, it should be assumed that the observed effects of piracetam, centrophenoxine and elymoclavine are due to definite interactions between the cerebral cholinergic and monoaminergic mechanisms.

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.

The maze method for active avoidance with punishment reinforcement and the step-through method for passive avoidance with negative reinforcement were used to study the processes of learning and memory in 22-month-old rats, as well as the effects of meclofenoxate (Mf) and citicholine (CCh) on these processes. Meclofenoxate, administered in a dose of 50 mg/kg twice daily for 7 days using the maze-training method, increased the number of responses to the conditioned stimulus, when retention tests were made 24 hours and 7 days after training, whereas citicholine, applied in the same way in a dose of 10 mg/kg, shortened the latency of the responses with reinforcement during the training and increased the number of correct responses to the conditioned stimulus in retention tests 7 days after the training. With the same pattern of administration, both Mf and CCh strongly prolonged the time spent by the animals in the light chamber (i.e., improved retention) in tests using the step-through method 24 hours and 7 days after the training. Both drugs prevented the occurrence of scopolamine-induced (2 mg/kg i.p.) amnesia. A comparison of the results obtained for 22-month-old rats with the results obtained in earlier experiments on 5-month-old rats under fully identical experimental conditions showed that the age-dependent differences in the memory process and in the effects on it of the psychotropic agents meclofenoxate and citicholine were not unidirectional in character.

The effects of centrophenoxine on the release of acetylcholine and on the changes in the bioelectrical activity are determined in experiments on non-anaesthesized cats subjected to perfusion of the anterior horn of the lateral cerebral ventricle and simultaneous recording of the bioelectrical activity of cortical and subcortical structures. Centrophenoxine is tested in doses of 25, 50 and 100 mg/kg intravenously. Most characteristic changes are found to occur after the dose of 50 mg/kg, when centrophenoxine markedly increases the amount of the released acetylcholine and changes the bioelectrical activity (synchronous changes in the cortex and hypothalamus). The parallelism between the increase release of acetylcholine and the bioelectrical changes continued until the time of the peak effect of centrophenoxine (45 min), followed by dissociation between them (the level of the released acetylcholine gradually approached the initial level, while the changed bioelectrical activity persisted for a longer time.

The effect of the nootropic agents meclofenoxate (Mf) and adafenoxate (Adf) on the content of biogenic monoamines in the frontal cerebral cortex, striatum, hypothalamus, and hippocampus of 22-month-old rats was studied. Mf and Adf were administered orally for seven days twice daily in a dose of 50 mg/kg weight. Both agents tested increased the content of serotonin (5-HT) in the cortex and striatum. Adf also raised the noradrenaline (NA) content in the cortex and hippocampus, lowering the dopamine (DA) level in the striatum. Comparison of the results obtained in the present study with the finding of earlier experiments of ours on 4-5-month-old rats revealed the following: 1. Biogenic monoamines (BMA) in the brain tend to decrease with ageing. 2. In addition to the unidirectional effects of Mf and Adf on the BMA content in the brain of both young and old rats, but in some cases there were also differences. 3. The comparison of the effects of Mf and Adf on the BMA content in the different brain regions with the changes in this content, characteristic of certain diseases, reveals prospects for selectivity in the application of these nootropic agents, which are generally rather similar in pharmacological characteristics.

The effect of adafenoxate (Af), meclofenoxate (Mf) and citicholine on the brain muscarinic receptors was studied in groups of ten male Wistar rats. The compounds were administered in doses of 50 mg/kg body weight twice daily for 7 days. One hour after the last treatment the animals were killed and the frontal cerebral cortex striatum, the hypothalamus and the hippocampus were removed immediately. Af and Mf were found to diminish significantly and to an analogous extent the density (Bmax) of the muscarinic receptors in the cerebral cortex, striatum and the hippocampus. At the same time, however, the greater decrease of Kd induced by these two nootropic agents, i.e. the increased affinity of the muscarinic binding sites, exceeded considerably the decreased number of the binding sites. These differences in the effects on Bmax and Kd suggest that the functional capacity of the cerebral cholinergic system increases under the action of Mf and Af. The surprising increase in the number of muscarinic receptors in the striatum, observed in citicholine-treated animals, is assumed to be due to the great increase of the dopamine content in this structure, induced by this acetylcholine precursor, observed in other experiments. This increase would result in reduced acetylcholine production by the inhibited cholinergic neurones, with a subsequent increase in the number of the muscarinic receptors.

The level and turnover of biogenic monoamines in some rat brain structures were determined after treatment with meclofenoxate at a dose of 50 mg/kg administered i.p. two times a day (9 a.m. and 5 p.m.) for 5 days. Meclofenoxate decreased dopamine (DA) turnover in the frontal cortex and striatum and highly increased it in the hypothalamus. The DA level significantly declined in the striatum, tended to decline in the cortex and significantly rose in the hypothalamus. The noradrenaline (NA) turnover and level in the cortex and striatum were decreased. Meclofenoxate decreased serotonin (5-HT) turnover in the cortex, striatum and hypothalamus and increased it in the pons. At the same time, the 5-HT level rose in the cortex, striatum and pons and declined in the hypothalamus. These results suggest the neurochemical basis of the psychotropic and neuroendocrine effects of meclofenoxate.

The effects of adafenoxate (Adf), meclofenoxate (Mf), piracetam (Pc), and citicholine (CCh) on scopolamine (Scop)--impaired memory and exploratory behavior (experiments on rats) and on physical capabilities (experiments on mice) were studied. In the experiments with scopolamine (2 mg/kg i.p.) we used the step-through passive avoidance method to determine the memory changes. In the case of single treatment with the drugs tested scopolamine was injected immediately after training and Adf, Mf, and CCh at doses of 20 and 100 mg/kg and Pc at a dose of 100 mg/kg were administered immediately after scopolamine. In the case of multiple administration the drugs were applied at the same doses for 7 days before training. Scopolamine was injected immediately after training. Retention tests were given 3 and 24 hours later. All the four drugs tested prevented to a large extent or completely the scopolamine-induced retrograde amnesia. However, significant quantitative differences in the antiamnestic effects of the drugs tested were observed. The effects of the four drugs on exploratory behavior were tested in the Opto Varimex apparatus. After 7-day treatment with the drugs at the doses utilized, the behavior of experimental animals was observed for 10 min, checking out the changes in the frequency of rearing, ambulation, and rotation. Only Adf at a dose of 50 mg/kg significantly decreased rearing and ambulation frequencies; this effect was considered to be an expression of accelerated habituation. The physical capabilities of mice were studied, using the method of treadmill (revolving drum activity cage) training. Before the experiment the mice received orally Adf, Mf, and Pc at a dose of 100 mg/kg or were injected intraperitoneally with CCh at doses of 50 and 100 mg/kg once daily for 7 days. The number of revolutions of the drum cages was counted for 4 hours. Only Pc significantly increased the physical capabilities of mice and much delayed the occurrence of fatigue.

The effect of phentolamine (alpha-adrenoceptor antagonist) and propranolol (beta-adrenoceptor antagonist) on the increased brain acetylcholine-releasing effect of centrophenoxine were studied in unanaesthetized cats in which perfusion of the anterior horn of a lateral cerebral ventricle was performed. Phentolamine alone decreased the amount of spontaneously released acetylcholine and did not change the effect of centrophenoxine. Propranolol alone did not change the amount of spontaneously released acetylcholine and reversed the centrophenoxine effect. The effects of centrophenoxine on acetylcholine release are attributed to its action on the presynaptic adrenoceptors (alpha and beta) situated in the cholinergic terminals of structures lying the anterior horn of a lateral cerebral ventricle.

The effects of a single and 5-day treatment of male albino rats with meclofenoxate in a dose of 100 mg/kg on the clonic-tonic convulsions during the kindling phenomenon, induced by multiple injection of a subconvulsive dose (40 mg/kg) pentylenetetrazol (PTZ) were tested. Its effects on convulsions, induced by a single convulsive dose of 100 mg/kg, were investigated for the sake of comparison. Meclofenoxate, introduced in a single dose of 100 mg/kg, lowered the intensity of the convulsions in PTZ-kindled rats. Meclofenoxate treatment for 5 days had an even more pronounced inhibitory effect on PTZ kindling. As regards the convulsions induced by a single injection of a convulsive PTZ dose, meclofenoxate only tends to decrease the percentage of rats with tonic convulsion and the lethality. On the basis of the results of earlier studies, the role of the serotoninergic neurotransmitter system for the observed inhibitory effect of meclofenoxate on PTZ kindling in albino rats is discussed.