Effects of Litoralon (gamma-L-glutamyl-taurine) and its analogues on fear-motivated behaviour of rats

The effects of a single post-trial intraperitoneal administration of the dipeptide Litoralon (gamma-L-glutamyl-taurine) and some of its analogues were tested on the passive avoidance latency of male and female Wistar rats. The avoidance latency was significantly decreased by Litoralon and gamma-aminobutyryl-ethanolamine phosphate but lengthened by DL-beta-aminoisobutyryl-ethanolamine phosphate. No differences were observed between the responses of immature male and female rats following Litoralon treatment. The observed inter-group differences in passive avoidance behaviour following dipeptide administration were also demonstrable in tests of the open-field activity of the animals examined immediately after the 24-hour retention test. The results are discussed on the basis of a central Litoralon effect on emotional arousal and the anti-conflict potencies of the dipeptide.     

L-pyroglutamyl-D-alanine amide normalizes the function of the developing brain damaged by antenatal alcoholization in rats

The effects of the synthetic dipeptide, L-pyroglutamyl-D-alaninamide (LPDA) were studied in the experiments on offspring of alcoholized during the pregnancy (5 g/kg/day) females. This dipeptide, which revealed the nootropic activity in previous experiments, was injected to the pups in dose of 1 mg/kg from 8 to 19 days of life. LPDA was shown to prevent the delayed disturbances of learning in passive avoidance test, of extrapolatory behaviour in escape test, to attenuate the emotional hyperreactivity. LPDA normalized EEG power spectrum, decreased interhemispheric asymmetry. This substance attenuated the disbalance evoked by prenatal alcoholization.     

Antifibrillatory activity of a dipeptide antagonist of the nerve growth factor

The antifibrillatoty effect of the GK-1 dipeptide was studied in anesthetized rats. This dipeptide is a fragment of the fourth loop of the nerve growth factor (NGF); it displays antagonistic activity with respect to TrkA receptor specific for NGF. It has been shown that this compound is able to significantly increase the threshold of electrical fibrillation of the heart, and its effectiveness is similar to the reference antiarrhythmics of classes I and III according to Vaughan Williams?? classification. However, unlike these reference drugs, the antifibrillatory action of the GK-1 dipeptide was delayed and occurred within 40?C60 min after its administration. The possible mechanisms underlying the antifibrillatory action of the GK-1 dipeptide are discussed. To some extent, these mechanisms may be associated with the GK-1 ability to change the reactivity of ??-adrenergic structures of the heart.     

The functional role of neurospecific protein S-100 in memory processes]

Elaboration of alimentary conditioned reflex in rats is accompanied by an increase of the level of protein S-100 in the left and right cerebral hemispheres. Amnestic factor M-cholinolytic atropine disturbs the elaborated habit and simultaneously decreases the quantity of protein S-100 up to the level of unlearned animals. The elaboration of conditioned reflex of passive avoidance does not change the content of protein S-100 in the rats brain. Intracisternal injection of antiserum to protein S-100 has an expressed amnestic action. Intracisternal injection of protein S-100 against the background of amnestic action of cholinolytic does not lead to restoration of memory. The cholinolytic and antiserum to protein S-100 mutually potentiate the amnestic effect.     

Differential effects of DGAVP on acquisition and extinction of active avoidance behavior

DGAVP facilitates consolidation and retrieval of active and passive avoidance behavior. In this study it was tested whether the long-term behavioral effects of DGAVP are the consequence of an initial increase in behavioral arousal during the learning phase. Animals that were preestimated in an open field test to be low active showed a lower number of conditioned avoidance responses (CAR's) during acquisition and extinction of a shuttle-box task than high active rats. DGAVP was administered 40 min prior to the 1st acquisition session. The immediate effect of DGAVP was a shift in the bell-shaped curve of the relation between arousal and performance (13); an increase in acquisition performance was observed with a low dose of DGAVP (0.1 microgram), while a decrease was found with a high dose of DGAVP (1 microgram). A dose-dependent inhibition of extinction was found in both low and high active animals. These results suggest an immediate effect of DGAVP on the rate of acquisition behavior, which may be a direct consequence of its arousing properties, and a long-term effect on extinction, indicating the formation of memory traces specific for vasopressin-related neuropeptides.     

Involvement of serotoninergic brain structures in the mechanisms of neurotensin effect on passive avoidance in rats

The purpose of the research was to reveal the features of neurotensin (administered in substantia nigra or dorsal raphe nucleus) effect on recall of passive avoidance reactions in rats. It was shown that the effect of neurotensin injected into the substantia nigra was characterized by a sharp reduction of passive avoidance reactions. On the contrary, injection of the substance in the dorsal raphe nucleus led to an intensification of these reactions and delay of their extinction. The effects of microinjections of serotonin 1A receptor agonist, 8-hydroxy-dipropylaminotetralin (8-OH-DPAT), into the mentioned brain structures was similar to that of neurotensin. Changes in the content of serotonin and its metabolite 5- hydroxyindoleacetic acid (5-HIAA) in the caudate nucleus corresponded to various behavioral effects. The conclusion was made that neurotensin effect on the passive avoidance behavior is related to regulation of emotional state of animals mediated by its action on the function of the serotoninergic brain structures.     

Effects of oxytocin and vasopressin on retrieval of passive avoidance response in melatonin-treated and/or pinealectomized male rats

The role of the pineal gland and its hormone-melatonin-as to the impact of vasopressin (VP) and/or oxytocin (OT) on the regulation of behavior was studied, the passive avoidance task being chosen as an experimental model. The results showed that VP facilitated the avoidance latency during the first retention trial; after pinealectomy, however, VP was ineffective in this regard. Intraperitoneal application of OT was ineffective in modifying the passive avoidance latency when compared with respective saline-treated animals. Melatonin alone, when injected to shamoperated animals 30 min before behavioral experiment, did not affect the passive avoidance response in SA- or OT-treated rats, but blocked the VP-induced lengthening of the passive avoidance latency in the first retention trial. In pinealectomized and OT-treated animals the passive avoidance latency during the second retention trial was severely diminished by melatonin when compared to respective control. We conclude that: a) VP needs a regulated pineal function for developing short-term effects on the passive avoidance response and b) the effect of OT on the avoidance latency in pinealectomized rats develops after melatonin treatment as a long-term effect.     

Memory effect of caerulein and its analogs in active and passive avoidance responses in the rat

The memory effects of caerulein (CER) and its analogs ([des-Gln2]-CER and [Leu5,Nle8]-CER) were compared with that of cholecystokinin octapeptide (CCK-8) using active and passive avoidance responses in rats. In the active avoidance test, single subcutaneous (SC) injection of CER and its analogs immediately after the learning trials at doses of 10 and 100 ng/kg prevented extinction of learned task for 10 days, and at a dose of 1000 ng/kg for at least 15 days, but the effect of CCK-8 was somewhat weaker. In the saline control group, the number of responses decreased after 5 days. In the passive avoidance response, electroconvulsive shock (ECS)-induced amnesia was partially prevented by CCK-8 at doses of 100 and 1000 ng/kg SC, while CER and its analogs at doses of more than 100 ng/kg totally prevented the ECS-induced amnesia. Intraperitoneal administration of scopolamine caused complete amnesia which was also partially prevented by CCK-8, while CER could totally prevent the amnesia following SC injection of 2 micrograms/kg. These results indicate that CER and its analogs are more effective than CCK-8 for preventing experimental amnesia.     

Newly revealed range of action in the preparation derinat: Mnemotropic effect

Mnemotropic effect has been revealed in the action of Derinat, a biologically active compound of natural origin, on the formation of conditioned reflexes of active and passive avoidance. Derinat accelerates the elaboration of conditioned reflexes. This effect manifests itself already at initial stages of the elaboration, which resembles the effect produced by nootropics.     

The ACTH-(4-9) analog ORG 2766 and desglycinamide9-(Arg8)-vasopressin reverse the retrograde amnesia induced by disrupting circadian rhythms in rats

Disrupting circadian organization by exposing rats to a shifted illumination schedule after training for passive avoidance and shuttle box avoidance behavior resulted in retrograde amnesia as evidenced by impaired performance during retention and extinction testing respectively. A single treatment with either the ACTH-(4-9) analog ORG 2766 or desglycinamide9-(Arg8)-vasopressin (DGAVP) 1 hour prior to the retention of passive avoidance or extinction of shuttle box avoidance behavior restored the behavioral impairment. It is suggested that these peptides may be useful to relieve memory deficits induced by disturbances in circadian organization.     

Angiotensin II--derived peptides devoid of phenylalanine in position 8 have full psychotropic activity of the parent hormone.

In this work we compared in rats the influence of heptapeptide 1-7-angiotensin II, hexapeptide 2-7-angiotensin II, pentapeptide 3-7-angiotensin II and angiotensin II on motility, stereotypy, learning of conditioned avoidance responses and recall of passive avoidance behaviour allowing to avoid aversive stimulation. The 4 peptides administered 15 min before the experiment, tended to increase the number of crossings, rearings and bar approaches in open field, significantly accelerated acquisition of conditioned avoidance responses and improved recall of the passive avoidance. All the peptides applied immediately before the experiment intensified stereotypy evoked by apomorphine in the dose 1 mg/kg and amphetamine in the dose 6.5 mg/kg given intraperitoneally. These results show full psychotropic activity of the examined fragments of angiotensin II, comparable with the activity of the parent octapeptide. Our previous hypothesis that the Val-Tyr-Ile-His-Pro fragment of angiotensin II is responsible for the psychotropic activity evoked by angiotensins in rats is thus confirmed.     

A role for the autonomic nervous system in modulating the immune response during mild emotional stimuli

The role of the autonomic nervous system in the modulation of the immune response to emotional stimuli, was established in rats subjected to the passive avoidance test. An increase in splenic primary antibody response directed against SRBC was found after exposure of rats to the passive avoidance apparatus (novelty). Both local surgical denervation of the spleen and beta-receptor blockade (timolol, 1 mg/kg i.p. 1 h prior to testing) prevented the increase in primary antibody response.     

MSH/ACTH4-10: a tool to differentiate between the role of vasopressin in memory consolidation or retrieval processes

MSH/ACTH4-10 induces a dose dependent increase of latency scores during retention of a passive avoidance response, when injected SC prior to retention but not when administered immediately after the learning trial. Intracerebroventricular administration of anti-vasopressin serum immediately after the learning trial or 1 hr prior to retention induces marked deficits in passive avoidance behavior as indicated by low latencies during retention. SC injection of MSH/ACTH4-10 increased latency scores in animals which received anti-vasopressin serum prior to retention, but did not alter latencies in animals, which received anti-vasopressin serum after the learning trial. These results suggest that MSH/ACTH4-10 is involved in retrieval processes and is able to differentiate between the effects of vasopressin on memory consolidation and on retrieval.     

Bioassay-guided isolation of an alkaloid with antiangiogenic and antitumor activities from the extract of Fissistigma cavaleriei root

Fissistigma cavaleriei (Levl) Rehd (Annonaceae) is used as a folklore medicine for treatment of inflammation, arthritis, and tuberculosis by Miao people in China. In the present study, the antiangiogenic activity of F. cavaleriei was investigated. The chorioallantoic membrane of the fertilized hen's egg (CAM assay) was used to determine antiangiogenic activity of the plant extract. Compound (1), a compound with antiangiogenic activity, was isolated by bioassay-guided fractionation from F. cavaleriei for the first time. The structure of compound (1) was elucidated on the basis of spectroscopic methods. Colorimetric COX (ovine) inhibitor screening assay was used to determine its inhibitory effect on COX-1 and COX-2. MTT and Sulforhodamine B assays were used to investigate its cytotoxic effects on tumor cell lines. As a result, compound (1) showed a selectively inhibiting effect on COX-2 and could inhibit the growth of tumor cells in vitro. The antitumor activity of compound (1) was further confirmed by the observation that compound (1) administration significantly inhibited the growth of S-180 cells in mice. Moreover, compound (1) was able to enhance the antitumor activity of doxorubicin in the mice bearing with S-180 cells while combined with doxorubicin. In conclusion, compound (1) is a multi-target molecule and further experimental investigations are needed to determine whether it can be used as a lead molecule for tumor treatment.     

Photoaffinity inhibition of dipeptide transport in Escherichia coli.

A dipeptide containing a nitrene precursor, glycyl-4-azido-2-nitro-L-phenylalanine, has been synthesized. This compound is a photoaffinity inhibitor of dipeptide transport in E. coli. In the dark, the dipeptide is a reversible inhibitor of glycylglycine uptake by live E. coli W cells. The 14C-labeled compound is a substrate for the transport system, with a Km of 7 micrometer and V max of 5 x 10(3) molecules cell-1 s-1 (compare 9 micrometer and 1 x 10(4) molecules cell-1 s-1, respectively, for the transport of glycylglycine under the same conditions). When intact E. coli cells are photolyzed at approximately 350 nm in the presence of the photolabile dipeptide, their ability to transport either glycylglycine or unphotolyzed glycyl-4-azido-2-nitro-L-phenylalanine is irreversibly inhibited, but their ability to transport arginine is unaffected. The presence of glycylglycine in the medium during photolysis protects the cells against the light-dependent inactivation of dipeptide transport.     

Vasopressin deficiency and blood glucose interactions on passive avoidance behavior

The performance of a passive avoidance task (measured for two trials based upon number of complete step-downs and latency to respond) and blood glucose levels were examined in five groups of animals. The groups included vasopressin-deficient (DI) and vasopressin-containing (LE) rats under ad lib (AL) and food-restricted (FR) conditions, as well as DI-FR animals provided with access to an 8% sucrose solution (SUC). In the AL condition, no significant differences were found between DI and LE animals in either step-down occurrences or blood glucose levels. However, the DI animals were significantly slower in latency to respond in trial 1. With FR, the LE animals resembled the LE-AL animals in both passive avoidance behavior and blood glucose levels. The DI-FR animals that were not provided with SUC showed an impairment in passive avoidance behavior and low blood glucose levels, whereas DI-FR animals provided with SUC showed an amelioration of passive avoidance deficiencies and had blood glucose levels comparable to AL animals and LE-FR animals. On trial 2, a significant negative correlation was found between number of step-down occurrences and blood glucose levels, and a significant positive correlation was found between latency to respond and blood glucose levels. The experiment demonstrates that: 1) because DI rats have a different responsiveness in novel situations, caution must be exercised in using response latency as a measure of passive avoidance performance in the AL condition; 2) AL and FR conditions produce different responses in DI, but not LE, animals; 3) deficiencies in passive avoidance behavior in DI-FR rats can be ameliorated by the consumption of exogenous carbohydrate; and 4) there is a significant correlation between blood glucose levels and passive avoidance behavior.     

Naltrexone-sensitive behavioral actions of the ACTH 4-9 analog (Org 2766)

The effects of the ACTH 4-9 analog (Org 2766) and the COOH-terminal tripeptide of Org 2766 (Phe-D-Lys-Phe; PDLP) on retrieval of one-trial learning passive avoidance behavior were compared with those of beta-endorphin, [Met5]-enkephalin, [D-Ala2,Met5]-enkephalin, des-Tyr1-[Met5]-enkephalin and des-enkephalin-gamma-endorphin (DE gamma E). Amounts of intracerebroventricularly administered Org 2766, PDLP, [Met5]-enkephalin, [D-Ala2,Met5]-enkephalin and DE gamma E, which induced a comparable attenuation of passive avoidance behavior were determined. Pretreatment with the opiate antagonist naltrexone prevented the attenuating effect of these peptides on passive avoidance behavior except that of DE gamma E. The attenuating effect of Org 2766 and of [Met5]-enkephalin was reversed to facilitation of passive avoidance behavior in the presence of naltrexone. Subcutaneous treatment with Org 2766 and [D-Phe7]-ACTH 4-10 decreased electrical self-stimulation behavior elicited from the medial septal area. Naltrexone prevented the inhibitory effect of Org 2766 on this behavior, but not that of [D-Phe7]-ACTH 4-10. Although the attenuating effect of PDLP on passive avoidance behavior was not reduced by pretreatment with [Met5]-enkephalin- or beta-endorphin-antiserum, and PDLP induced neither analgesia nor excessive grooming, the data suggest that the inhibitory effect of Org 2766 and PDLP on passive avoidance behavior and electrical self-stimulation are mediated by endorphin systems in the brain.     

Effect of drugs of the nootropic class on rat behavior after deprivation of the paradoxical stage of sleep

Pharmacological analysis was used for studying the influence of 24-hour deprivation of paradoxical sleep by Jouvet method on retention of conditioned reaction of passive avoidance in rats. Psychotropic substances of different action were used for the analysis: nootropes as anti-amnestic--pyracetam (400 mg/kg), kleregil (100 mg/kg), centrofenoxin (50 mg/kg) and watersoluble salt of 3-oxypiridin derivative (3-OP) (50 mg/kg) and tranquilizer of bensodiazepine series phenazepam (1 mg/kg) as antistress and antiphobic. It was established that 24-hour deprivation disturbed the elaborated reaction but did not change the rate of emotionality and orienting-investigating behaviour of rats in the open field. Nootropes effectively restored the conditioned passive avoidance reaction while phenazepam had no effect. This allows to suggest that Jouvet method of paradoxical sleep deprivation elicits amnesia and its cause is not only stress but deficit of paradoxical sleep.     

Comparative effects of prenatal and postnatal undernutrition on learning and memory in rats.

Effects of pre- and post-natal undernutrition on learning and memory parameters were studied in albino rats. Prenatal undernutrition was induced in rat pups by restricting the mother's diet by 50% during the entire gestation period, whereas postnatal undernutrition was induced in rat pups by restriction of their diet by rotating them between lactating and non-lactating maternalised females for 12 hr each day during suckling period from 2nd day to 18th day after birth. At 2.5 to 3 months of age all the rat offsprings were subjected to (i) original and reversal discrimination learning, (ii) passive avoidance, and (iii) active avoidance and its retention tests. The results indicate that both pre- and post-natal undernutrition in rat pups caused significant deficits in original and reversal discrimination learning, retention of passive avoidance after one week retention interval, and retention of active of avoidance learning. However, both pre- and post-natal undernutrition did not show significant effect on acquisition of active avoidance and retention of passive avoidance after 24 hr retention interval.