Perinatal Stressors as a Factor in Impairments to Nervous System Development and Functions: Review of In Vivo Models.

The human body is faced with stress throughout ontogeny. At the stage of intrauterine development, the mother's body serves as a source of resources and most of the humoral factors supporting the development of the fetus. In normal conditions, maternal stress-related humoral signals (e.g., cortisol) regulate fetal development; however, distress (excessive pathological stress) in the perinatal period leads to serious and sometimes irreversible changes in the developing brain. The mother being in an unfavorable psychoemotional state, toxins and teratogens, environmental conditions, and severe infectious diseases are the most common risk factors for the development of perinatal nervous system pathology in the modern world. In this regard, the challenge of modeling situations in which prenatal or early postnatal stresses lead to serious impairments to brain development and functioning is extremely relevant. This review addresses the various models of perinatal pathology used in our studies (hypoxia, exposure to valproate, hyperserotoninemia, alcoholization), and assesses the commonality of the mechanisms of the resulting disorders and behavioral phenotypes forming in these models, as well as their relationship with models of perinatal pathology based on the impact of psychoemotional stressors.

Beneficial effects of xenon inhalation on behavioral changes in a valproic acid-induced model of autism in rats.

BACKGROUND: Xenon (Xe) is a noble gas that has been used for the last several decades as an anesthetic during surgery. Its antagonistic effect on glutamate subtype of NMDA (N-methyl-D-aspartate) receptors resulted in evaluation of this gas for treatment of CNS pathologies, including psychoemotional disorders. The aim of this study was to assess the behavioral effects of acute inhalation of subanesthetic concentrations of Xe and to study the outcomes of Xe exposure in valproic acid (VPA)-induced rodent model of autism. METHODS: We have conducted two series of experiments with a battery of behavioral tests aimed to evaluate locomotion, anxiety- and depression-like behavior, and social behavior in healthy, VPA-treated and Xe-exposed young rats. RESULTS: We have shown that in healthy animals Xe exposure resulted in acute and delayed decrease of exploratory motivation, partial decrease in risk-taking and depressive-like behavior as well as improved sensorimotor integration during the negative geotaxis test. Acute inhalations of Xe in VPA-exposed animals led to improvement in social behavior, decrease in exploratory motivation, and normalization of behavior in forced-swim test. CONCLUSION: Behavioral modulatory effects of Xe are probably related to its generalized action on excitatory/inhibitory balance within the CNS. Our data suggest that subanesthetic short-term exposures to Xe have beneficial effect on several behavioral modalities and deserves further investigation.

[Food-derived opioid peptides and their neurological impact].

In this review the up-to-date literature data about exorphins are analysed. Exorphins are short opioid-like food-derived peptides. Different reports about their physiological impact in animals and humans are reviewed with focus on neurotropic effects. Clinical data (case reports and clinical trials' results), on the one hand, and the results of experiments with animals of different taxons, on the other hand, are summarized. The influence of exorphins on infants' development is emphasized.

[Comparative analysis of the maternal motivation expression in WAG/Rij and Wistar rats in the place preference and open field tests].

Maternal behavior in females of WAG/Rij and Wistar rats was compared in the place preference test from 2 to 8 days after delivery, as well as in the open field test from 4 to 6 days after delivery. In females of WAG/Rij rats compared with females of Wistar rats weaker expression of maternal motivation has been revealed in both tests: they spend less time in the compartment associated with pups. Moreover, in females of WAG/Rij rats, number of approaches to pups, number of pup-carryings and time spent with pups (time of contacts) were less than in females of Wistar rats. Reduced maternal motivation in females of WAG/Rij rats in the place preference test persisted in repeated testing, while in the open field test it was detected only in the first testing, indicating higher reliability of the place preference test for revealing inter-strain differences in the expression of maternal motivation. It is supposed that weaker expression of maternal behavior and preference is due to hypo-function of the mesolimbic dopaminergic bran system in WAG/Rij rats as a genetic model of depression associated with absence epilepsy.

[Reverse learning in WAG/Rij rats with depression-like behavior].

Learning and reverse learning in a complex maze, behavior in the open field test, novelty-suppressed feeding test, and forced swimming test were studies in WAG/Rij and Wistar rats. As compared with Wistar rats, WAG/Rij rats more slowly learned the spatial task, more slowly performed in the learning and reverse learning tasks, and made more errors in the complex maze (18% of WAG/Rij rats didn't reach learning criterion). Moreover, WAG/Rij rats exhibited reduced grooming reactions in the open field test, longer latency of approaching to food in the novel open field, reduced amount of food consumed in the home cage in the novelty-suppressed feeding test, and increased immobility time in the forced swimming test. The results suggest cognitive impaiment in WAG/Rij rats with depression-like behavior.

[Selective D1-receptor antagonist SCH23390 decreases maternal reactions in rats upon acute and chronic injections in postpartum period].

The influence of the D1-receptor antagonist SCH23390 on the maternal behavior of female rats has been studied. It is established that a comparatively high dose of the drug (acute injections) significantly decreases both the locomotor activity and manifestations of the parental care. Lower dosages do not affect the locomotor activity, but still suppress the maternal behavior (after both acute and chronic injections of SCH23390). The obtained results are discussed in terms of the analysis of the maternal motivation mechanisms and the development of the D1-induced postpartum depression.

Effect of single and repeated injections of selective D2-antagonist clebopride on maternal behavior of albino rats.

This study examined the effect of clebopride at low concentration that did not modify the motor activity on the parental care in female albino rats. Single injection of the drug attenuated the parental care reactions on postinjection minute 20, but not one day thereafter. The daily injection of the drug during the post partum period (1-6 days) resulted in significantly more pronounced and stable effects. The data obtained substantiated the views on the major contribution of D(2)-receptors in the development of behavioral manifestations of puerperal depression.

Behavioral effects of original tetrapeptide, an analog of N-terminal nociceptin fragment.

The study examined the effect of an analog to N-terminal nociceptin fragment AcOH×Phe-Gly-Gly-Phe-NH(2) on the behavior of albino rats. This tetrapeptide (5 µg/kg intraperitoneally) significantly enhanced motor and exploratory activity in mature rats and in 42-day pups and produced opposite effects in 21-day rat pups, which attests to the complex dynamics of maturation of nervous structures involved in the realization of nociceptin action.

[The role of dopamine and opioid systems in the regulation of maternal behavior].

This review describes in detail the different components and neuroanatomical basis of maternal behavior and also methodological approaches to investigation of parental reactions. The contributions of some endocrinal and neuromediator brain systems (in the first place, opioid and dopaminergic) to the regulation of maternal behavior are reported. The influences of ligands of opioid and dopamine receptors on the expressions of paternal reactions are analyzed especially. In concluding part the reasons of maternal depression and possibilities of this malfunction pharmacological correstion are discussed.

Role of the brain dopaminergic and opioid system in the regulation of "child's" (maternal bonding) behavior of newborn albino rats.

Administration of D(2) receptor antagonist clebopride in a dose not affecting locomotor activity was followed by a decrease in maternal bonding behavior of 10-day-old and 15-day-old albino rat pups. D(1) receptor antagonist SCH23390 had a stimulatory effect only on the behavior of 10-day-old newborns. Opioid peptide ß-casomorphin-7 abolished the effect of clebopride in rat pups of the older age group.

[Maternal behavior of WAG/Rij strain rats in normal conditions and during intervention in the activity of dopaminergic brain system].

Lactating dams of WAG/Rij and Wistar rat strains were repeatedly placed on the "open field" arena with their pups (4-9 postnatal days). In these conditions WAG/Rij rats showed significantly poorer maternal behavior and were slower in forming pup location response. These results add to the notion of disorders in the activity of the nervous system of WAG/Rij rats (as genetic models for absence epilepsy). Administration of Haloperidol in a low dose (0.1 mg/kg, i.p.) reduced the motor activity ofdams of both strains and maternal behavior under conditions of bright illumination. Under conditions of red-light illumination, haloperidol increased the number of approaches to the pups and the number of their transportations in WAG/Rij (but not Wistar) rats and reduced the latencies of the behavioral reactions. It is suggested that dopaminergic regulation of maternal behavior depends on both genetic (strain differences) and environmental (illumination conditions) factors.

[A new method of investigation of "child's" behavior (infant-mother attachment) of newborn rats].

A new method of studying "child's" (maternal bonding) behavior of newborn rats was developed. The efficiency of the method was proved in estimation of dopaminergic control of the infant-mother attachment. Selective D2-antagonist clebopride applied in subthreshold for motor activity doses caused a decrease in aspiration of pups to be in contact with a dam. On the basis of features analyzed (latent periods and expression of various behavioral components), the integrated criterion for the estimation of "child's" reactions was suggested. Application of this criterion made it possible to neutralize high individual variability of the behavior typical of newborns.

[Effects of several exorphins and endorphins on the escape reaction of the cockroach Periplaneta americana under elevated temperature conditions].

The ability of several alimentary opioid peptides (exorphin C, rubiscolin-5, cytochrophi-4) and endorphins (met-enkephalin, dynotphin A(1-10), beta-neoendorphin) to change the escape reaction of the cockroaches Periplaneta americana at their placement into a hot chamber was studied. The ED50 values increasing twice the insect stay time in the hot chamber as well as duration and dynamics of the effects were determined. It has been shown that ED5 decreases statistically significantly with increase of the length of the peptide molecule and its affinity of duration of the effects and to an increase of their affinity to delta-receptors - to prolongation of the reaction (more than150 min). In the group of alimentary peptides (exorphins) the most active was a fragment of D-ribulose-1,5-biphosphate carboxylase/oxigenase rubiscolin-5 (ED5 = 386 nM per individual). This might indicate a specific ability of some plant proteins to regulate (decrease) the insect protective behavior.

[Delayed effect of exorphins on learning of albino rat pups].

The delayed effect of food-derived opioid peptides (exorphins) after chronic administration on postnatal days 1-14 on the learning of albino rat pups has been studied. Heptapeptide YPFPGPI (beta-casomorphin-7), pentapeptide YPLDL (rubiscolin-5) and pentapeptide YPISL (exorphin C) improved the development of the conditioned foraging reflex in a complex maze. Hexapeptide PFPGPI lacking the N-terminal tyrosine proved inefficient. Only beta-casomorphin-7 had an effect (negative) on passive avoidance conditioning. The obtained data confirm that exorphins (particularly, milk-derived beta-casomorphins) can have significant and long-term effects on the environmental adaptation of young mammals.

Activation of maternal behavior of albino rats after combined treatment with dopamine and opioid receptor antagonists in low doses.

We studied the effect of D1/D2 antagonist haloperidol on maternal motivation in nursing albino rats. Haloperidol in a dose of 0.2 mg/kg significantly attenuated parental reactions and motor and exploratory activities. In a lower dose (0.1 mg/kg) the drug produced the same effect on maternal behavior (number of approaches to newborns) without reducing motor activity. The effect of low-dose haloperidol was different after naloxone treatment (0.2 mg/kg intranasally): the number of pup transfers increased significantly. The detected phenomenon indicates good prospects of combined treatment with agents modifying the cerebral dopaminergic and opioid systems as the method for correction of disorders in maternal behavior.

Effect of opioid antagonist naloxone on maternal motivation in albino rats.

We studied the effect of nonselective antagonist of opioid receptor naloxone on the behavior of albino female rats on days 4-6 after delivery. Intraperitoneal injection of naloxone (5 mg/kg) significantly stimulated maternal reactions (increased the number of approaches to pups, decreased the latency of their transfer into new location). Intranasal naloxone (1 mg/kg) produced similar changes. Naloxone in intraperitoneal dose of 1 mg/kg and intranasal dose of 0.2 mg/kg virtually did not modify maternal behavior.

[Influence of acute and chronic administrations of beta-casomorphins on the maternal motivation in albino rats].

The influence of food-derived opioid peptides beta-casomorphines on the manifestation of nursing albino rats maternal behavior was investigated. It was shown that both acute and chronic (during the postnatal period) administration of beta-casomorphin-7 (Tyr-Pro-Phe-Pro-Gly-Pro), the typical representative of this group of peptides, decreases the level of the parental motivation. The effects of beta-casomorphin-7 were naloxone-dependent; N-terminal-reduced analogues had a significantly lesser activity. The obtained results testify in favor of the probable role of casein opioid fragments which were formed in mammary glands of a nursing female, in the development of maternal behavior abnormalities. At the same time, beta-casomorphins could be considered as the limiting factors to the excessive manifestation of the parental motivation.