Hippocampal asymmetry in serotonergic modulation of learning and memory in rats.

The modulation of learning and memory after left or right microinjections of the selective 5-HT1A receptor agonist 8-OH-DPAT and of the 5-HT1A receptor antagonist NAN190 into the hippocampal CA1 area of male Wistar rats was studied. Microinjections of 8-OH-DPAT (1 microg) into the right or left CA1 hippocampal area produced a significant decrease in the number of avoidances in a shuttle box. The impairing effect of 8-OH-DPAT was more pronounced when injected into the right hippocampus compared to the left one. Microinjections of NAN190 (1 microg) into the right or left CA1 hippocampal area produced a significant increase in the number of avoidances in a shuttle box. Right microinjections of NAN190 increased the number of avoidances more strongly than compared to left injections. These effects on learning and memory were more pronounced after injection of either of the serotonergic agents into the right CA1 hippocampal area compared to the left. The stronger memory-modulating effect after injection of 8-OH-DPAT or NAN190 into the right CA1 hippocampal area suggests a rightward bias in the rat.

CCK-8 modulates GABA-stimulated [3H]-flunitrazepam binding in vitro.

In membranes from rat cerebral cortex, cholecystokinin-8 (CCK-8) did not modulate basal [(3)H]-flunitrazepam binding at either 4 degrees C or 37 degrees C. At a concentration of 10(-6) M, CCK(-8) significantly decreased gamma-amino-butyric acid (GABA)-stimulated (10(-6) M) [(3)H]-flunitrazepam binding at 37 degrees C. Scatchard analyses suggest that the decreased GABA-stimulated binding might be due to a decrease in the affinity of benzodiazepine receptors rather than to a decrease of number of binding sites. The observed modulation of benzodiazepine receptors by CCK-8 in vitro might explain some of the functional interactions between CCK and benzodiazepine systems.

Antinociceptive effect of somatostatin microinjected into caudate putamen.

The effects of somatostatin microinjected bilaterally and unilaterally (left or right) at a dose of 10, 50 and 100 ng into the caudate putamen of male Wistar rats on nociception (analgesy-meter test) were studied. Somatostatin injected into caudate putamen resulted in analgesia. Bilateral microinjections of somatostatin significantly increased the pain threshold in a dose-dependent manner, i.e. somatostatin exerted antinociceptive effect. The pain threshold after left-side microinjections was significantly higher than that after injections into right-side. These findings suggest antinociceptive and asymmetric effects of somatostatin on pain in the caudate putamen.

Behavioral effects of somatostatin microinjected into caudate putamen.

The present study examined the behavioral responses to bilateral microinjections of somatostatin (SRIF) into caudate putamen of male Wistar rats. SRIF locally administered at doses of 10, 50 and 100 ng/side dose-dependently affected locomotor activity, as reflected in both horizontal and vertical movements. SRIF modulated locomotor activity in a biphasic manner, exerting an inhibitory and a facilitatory effect. In the elevated plus-maze experiments, SRIF at doses of 50 and 100 ng/side microinjected bilaterally into caudate putamen decreased only the total number of entries in the open and closed maze arms, confirming the suppressing effect of SRIF on locomotion at the first 5 min.

Lateralized learning and memory effects of angiotensin II microinjected into the rat CA1 hippocampal area.

The effects of angiotensin II (ANG II) microinjected unilaterally (left or right) and bilaterally (left and right) at a dose of 0.5 microg (0.5 nmol) into the CA1 hippocampal area of male Sprague Dowley rats on learning and memory (shuttle box) were studied. Bilateral microinjections of ANG II improved learning, i.e. increased the number of avoidances during the two training days as compared to the respective controls microinjected with saline. ANG II facilitated learning and memory, especially when microinjected into the left CA1 hippocampal area as compared to the respective controls microinjected with saline. Left-side microinjection of ANG II increased the number of avoidances on the first and second training day as compared to the right-side microinjection of ANG II. These findings suggest asymmetric effects of ANG II on cognitive processes in hippocampus.

Differential behavioral effects of angiotensin II microinjected unilaterally into the CA1 hippocampal area.

The behavioral responses of rats to unilateral microinjections of angiotensin II (ATII) into the left or right CA1 hippocampal area were studied. Unilateral (left or right) injections of ATII at a dose of 0.5 microg decreased locomotor activity but, at a dose of 1.0 microg, ATII increased it compared to the respective controls. The effect was more pronounced when ATII was microinjected into the left CAI hippocampal area. The elevated plus-maze experiments showed that ATII microinjections into the right CA1 hippocampal area at a dose of 0.5 microg decreased the ratio of the number of entries into the open arms to the total number of entries (into the open and closed arms). These findings suggest some asymmetric effects of ATII, depending on the dose, the behavioral test and the microinjected hemisphere.

Behavorial responses to the 5-HT1A receptor antagonist NAN190 injected into rat CA1 hippocampal area.

1. Behavioral responses to unilateral and bilateral microinjections of the 5-HT1A receptor antagonist, NAN190 [1-(2-methoxyphenyl)-4-[4-(2-phthalimido) butyl]piperazine hydrobromide] (1 microgram), into the hippocampal CA1 area of male Wistar rats were studied. 2. NAN190 decreased locomotor activity (the number of horizontal and vertical movements). The effect was most pronounced with microinjections of NAN190 into the right hippocampus. 3. Microinjections of NAN190 facilitated learning and memory in shuttle-box testing. 4. Microinjections of NAN190 had an anxiogenic effect in elevated plus-maze experiments and Vogel's conflict test. 5. The different behavioral responses to left and right microinjections of NAN190 in some of the behavioral tests suggest functional asymmetry of 5-HT1A receptors in the CA1 hippocampal area.

Behavioral effects of angiotensin II microinjected into CA1 hippocampal area.

The behavioral responses of rats to bilateral microinjections of angiotensin II (ATII) at doses of 0.1, 0.5 and 1.0 microg into the hippocampal CA1 area of male Sprague-Dawley rats were studied. ATII affected locomotor activity (the number of horizontal and vertical movements) in a dose-related U-shaped manner. In the elevated plus-maze experiments, ATII at a dose of 0.1 microg microinjected bilaterally into the CA1 hippocampal area increased the number of entries into the open arms, suggesting some anxiolytic effect.

Effect of dotarizine on K(+)-stimulated [3H]-serotonin and [3H]-acetylcholine release from rat hippocampus.

1. The effect of the diphenylmethyl-piperazine derivative dotarizine on K(+)-stimulated release of [3H]serotonin ([3H]5-HT) and [3H]acethylcholine ([3H]Ach) in rat hippocampal slices was studied. 2. Dotarizine at a concentration of 10(-6) M significantly decreased the basal [3H]5-HT release and, at a concentration of 10(-5) M, it significantly decreased the K(+)-stimulated [3H]5-HT release compared to vehicle controls. 3. Dotarizine, at a concentration of 5 x 10(-7) M, significantly increased both basal and K(+)-stimulated [3H]Ach release. At higher concentrations (10(-6) and 2 x 10(-6) M), dotarizine did not change the basal release but significantly increased the K(+)-stimulated [3H]Ach release. The effect of dotarizine on K(+)-stimulated [3H]Ach release decreased with increasing dotarizine concentrations. 4. It is speculated that, in addition to its Ca2+ antagonistic activity, dotarizine exerts an antagonistic effect on the presynaptic 5-HT autoreceptors, which could account for the facilitation of [3H]Ach release.

Asymmetry in behavioral responses to cholecystokinin microinjected into rat nucleus accumbens and amygdala.

The behavioral responses of rats to uni- or bilateral microinjections of the octapeptide cholecystokinin (CCK-8) into the left and/or right or both nucleus accumbens (NA) or amygdalae were studied. There were two main findings of effects of microinjections of CCK-8 into NA. First, bilateral injections of CCK-8 into NA dose-dependently decreased the horizontal activity. The second more important finding was that CCK-8 at a specific dose (0.01 micrograms) injected into the right NA increased the number of horizontal movements 6-fold as compared to the injection into the left NA. Neither uni- nor bilateral injections of CCK-8 into NA at all doses used induced changes in the vertical movements. CCK-8 injected into left, right or both amigdalae increased locomotion at the lowest dose (0.01 microgram), while at the high doses (0.5 and 1.0 microgram) it significantly decreased it. The plus-maze test confirmed the anxiogenic effect of CCK-8 (0.01 microgram) injected into amigdalae. CCK-8 exerted a favorable effect on learning and memory (shuttle-box) when injected into the left but not into the right amygdala. Injection of CCK-8 (0.01 micrograms) into left amygdala provoked a 4-fold increase of the number of avoidances as compared to the microinjection into the right amygdala.

Hippocampal asymmetry in the behavioral responses to the 5-HT1A receptor agonist 8-OH-DPAT.

The present study examined the behavioral responses of rats to unilateral and bilateral injections of the selective serotonin 1A (5-HT1A)-receptor agonist 8-hydroxydipropylaminotetralin hydrobromide (8-OH-DPAT) 1 microgram into the hippocampal CA1 area of male Wistar rats. 8-OH-DPAT increased locomotor activity, which was most pronounced with injections into the left hippocampus. The agonist impaired learning and memory (shuttle-box), especially when injected into the right hippocampus. The elevated plus-maze experiments showed that neither left nor right nor bilateral hippocampal injections of 8-OH-DPAT produced any anxiogenic effect. However, with Vogel's conflict test, right injections of 8-OH-DPAT produced anxiety. The present study has revealed hippocampal asymmetry in the behavioral responses to the 5-HT1A-receptor agonist 8-OH-DPAT.

Hemispheric asymmetry in behavioral response to D1 and D2 receptor agonists in the nucleus accumbens.

The present study examined the locomotor response of rats to unilateral injections of the mixed D1/D2 agonist apomorphine, the D2 agonist quinpirole, and the D1 agonist SKF 38393 into the left or right nucleus accumbens (NA) of male Sprague-Dawley rats. There were 2 main findings. First, unilateral (left or right) injections of apomorphine, quinpirole, or SKF 38393 all provoked locomotor hyperactivity. The second and more important finding was that, at specific dosages, apomorphine and SKF 38393 injections into the right NA produced significantly more locomotor hyperactivity than identical injections into the left NA. These findings suggest the presence of asymmetries in the NA which may involve quantitative differences in the distribution of D1 and D2 receptors.

Effect of N-aminomethylpiperazine-3,3-diethyl-2,4-pyridinedione on the aggressive behaviour and avoidance training of rats with isolation syndrome.

The article investigates the effect of N-aminomethylpiperazine-3,3-diethyl-2,4-pyridinedione (DKMP), a newly-synthesized compound with a clearly manifested anticonvulsant action, on the aggressive behaviour and on the training for active two-way avoidance by using a shuttle-box. The effects of DKMP were compared with the effects of Diazepam on mouse killing behaviour and avoidance training both of isolated aggressive rats and of rats reared in groups. It was found that DKMP (100 mg/kg, subcutaneously) inhibited the aggressiveness in 88 per cent of the aggressive rats, whereas Diazepam (1 mg/kg, i. p.)--in 75 per cent for 4 hours. DKMP manifested a more substantial positive effect on learning (higher number of avoidances) in the aggressive rats, whereas Diazepam had a better effect on the group-reared rats. Both compounds shortened the latencies of the avoidances of aggressive rats, inducing no changes in the grouped rats. The results obtained show that with respect to the effects studied there is similarity in the pharmacological activities of DKMP and Diazepam, indicating only some not very essential quantitative differences.

Epileptogenic effect of intracortically applied kainic acid in cats.

The effect of two doses (5 micrograms/microliters) of kainic acid (KA) injected intracortically into the posterior lateral gyrus of cats was investigated. KA in a dose of 5 micrograms/microliters provoked cortical epileptogenic focus 8-12 min after its application, developing later into a focal seizure. Administration of 10 micrograms/microliters KA resulted after 15-20 sec in paroxysmal discharges of spikes and sharp-slow waves at the site of the application, which propagated ipsilaterally. Thereafter the paroxysmal activity spread contralaterally, became generalized and developed into an epileptic state. The effect of KA was considered to be a dose-dependent one. N-Aminomethylpiperazine-3, 3-diethyl-2, 4-pyridinedione (DKMP) in a dose of 100 mg/kg injected i.v. on the background of developed epileptic state exerted a rapid inhibitory effect of 60-100 min duration on the paroxysmal activity. employed as a model of secondary generalized focal epilepsy.

Generalized epilepsy induced by kainic acid and anticonvulsant effect of N-aminomethylpiperazine-3,3-diethyl-2,4-pyridinedione.

Systemic administration of kainic acid in rats (30 mg/kg s.c.) and cats (5 mg/kg i.p.) produced after a definite period (30 to 60 min) secondary generalized seizures occurring first in the limbic structures (amygdala and hippocampus). The effect of N-aminomethylpiperazine-3,3-diethyl-2,4-pyridinedione (DKMP) at a dose of 100 mg/kg i.v. was evaluated on the background of developed kainic epilepsy. In rats, DKMP inhibited kainic clonic and tonic seizures and 100% of the animals survived. The drug was ineffective against limbic seizures. In cats, DKMP strongly suppressed the cortical EEG paroxysmal activity and slightly influenced the limbic one. The present data contribute to the knowledge of the anticonvulsive activity of DKMP, showing it to be a promising antiepileptic drug with mainly cortical action.

Comparative study of the anticonvulsive activity of N-aminomethylpiperazine-3,3-diethyl 2,4-pyridinedione with the activity of known antiepileptic agents.

N-aminomethylpiperazine-3,3-diethyl-2,4-pyridinedione (DKMP) is a newly synthesized compound with a marked anticonvulsive effect in various epileptic models. The aim of the present work is to compare its anticonvulsive effect in corazol convulsions (100 mg/kg corazol, s.c.) with known anticonvulsants applied in clinical practice. The compounds tested were applied subcutaneously in equitoxic doses (1/20 and 1/30 of their respective LD50). Some undesirable side effects of the antiepileptic agents tested were also studied. With the experimental model used, DKMP was found to have a better anticonvulsive effect compared with diphenylhydantoin, depakin, suxilep and phenobarbital. Diazepam completely inhibited the convulsions, but it has an undesirable strong myorelaxing effect. In a subchronical experiment it was found that no tolerance developed toward DKMP, while the anticonvulsant effect of diazepam significantly decreased on the 15th day, compared with a single administration. Using the rota-rod test it was found that the agents studied had a stronger neurotoxic action compared with DKMP. These results outline DKMP as a promising compound with good antiepileptic activity, comparable to that of the known anticonvulsants.

Toxicological studies on the acute and subchronic toxicity of two new derivatives of 3,3-diethyl-2,4-pyridinedione.

The acute and subchronic toxicity (30 days) of N-aminomethylmorpholine-3,3-diethyl-2,4-pyridinedione (DKMM) and N-aminomethyl-piperazine-3,3-diethyl-2,4-pyridinedione (DKMP) was studied. The two compounds were found to have low acute toxicity. No changes are found in the haematological, urological and biochemical parameters, as well as in the histological tests of liver and parts of the cerebrum, after subchronic treatment with doses 150 there is an increase in GOT, GPT and the acid phosphatase. These results also correlate with the histological studies of the liver. The results of the acute toxicity show that DKMM and DKMP are weakly toxic substances (LD50 above 1500 mg/kg). Under conditions of the subchronic experiment the substances were tolerated very well by the animals, without causing lethality and essential toxicological changes in the organs studied.

Neuropharmacological activity of newly-synthesized derivatives of 3,3-diethyl-2,4-pyridinedione. V. Relation between chemical structure and pharmacological activity.

On the basis of neuropharmacological screening of newly-synthesized derivatives of 3,3-diethyl-2,4-pyridinedione ( Pyrithyldion ) some regularities are pointed out, related to the link between the chemical structure and the pharmacological activity of the pyridinedione derivatives. The following groups of compounds were studied: N-acyl, N-alkyl, N-amino-methyl, 5- acyloxymethyl and 5-aminomethyl. The derivatives tested were found to be biologically active substances with central depressant action differing from that of pyridinedione. Most generally, it may be stated that substitution of the pyridinedione nucleus with N-alkyl and 5-aminomethyl radicals results in compounds with analgesic action without soporific effect, while substitution with N-aminomethyl radicals leads to compounds with marked anticonvulsive activity and manifestation of soporific effect in high doses (1/2 of the lethal doses).