Changes in Sociability and Preference for Social Novelty in Female Rats in Prolonged Social Isolation.

Chronic stress due to social isolation (SI) can lead to distress with negative consequences for both humans and animals. Numerous disorders caused by SI include disorders in the emotional-motivational domain and cognitive functions, as well as changes in social behavior. There are currently no data identifying the sequelae of SI when its duration is significantly increased. Although female rats have been shown to be highly sensitive to stress, research on them is lacking. The present study assessed sociability and preference for "social novelty" in a three-chamber social test in female Wistar rats in two series of experiments at different time points during prolonged SI, which began at adolescence and continued to ages 5.5 and 9.5 months. At two months of SI, rats showed an increased preference for a social object over a non-social object (increased sociability) simultaneously with the appearance of signs of a decrease in the preference for a new social object over an already familiar social object (signs of a decrease in the preference for social novelty). In a social interaction test, the rats also displayed increases in the durations of social contacts, including aggressive interactions; they showed a decrease in exploratory risk assessments (head dips from the open arms) in the elevated plus maze test and a decrease in exploratory activity. After SI lasting 8.5 months, the rats showed signs of social deficit and a marked decrease in the preference for social novelty. No signs of increased aggressiveness were found. Thus, the impact of SI on social behavior depended on its duration and, we believe, was accompanied by a change in coping strategies.

The Levels of Monoamines and Their Metabolites in the Brain Structures of Rats Subjected to Two- and Three-Month-Long Social Isolation.

The levels of monoamines and their metabolites in the brain structures of adult Wistar rats subjected to post-weaning social isolation for 2 and 3 months were analyzed by HPLC with electrochemical detection. We have previously shown that these rats consistently demonstrate increased aggressiveness and, as a rule, impairment of short-term habituation. Two-monthlong social isolation was accompanied by a reduction in serotonin content and its increased turnover judging from the 5-HIAA/5-HT ratio in the hippocampus; three-month-long isolation was associated with increased levels of serotonin and reduction in its turnover in the amygdala. At this term, the level of dopamine metabolite 3-methoxytyramine tended to increase in the amygdala. In the frontal cortex, a tendency to a decrease in 5-HT level was found. These findings suggest that more prolonged post-weaning social isolation is accompanied by reorganization of neural networks in the brain cortex, which can serve as the pathophysiological basis for psychoemotional disorders.

Post-Weaning Social Isolation Disturbs Gene Expression in Rat Brain Structures.

Post-weaning social isolation of male Wistar rats for 10 weeks led to an increase of their aggressiveness, sensorimotor reactivity, and cognitive deficiency, manifesting in training disorders evaluated by the acoustic startle response (amplitude of the response decreasing). Expression of gene encoding serine protease prolyl endopeptidase (EC 3.4.21.26) in the frontal cortex was higher than in control rats kept in groups, while the level of mRNA of the gene encoding dipeptidyl peptidase IV (EC 3.4.14.5) did not differ from the control in any of the brain structures. The levels of serotonin transporter gene mRNA in the striatum and hypothalamus were higher than in the control. No appreciable changes in the expression of genes encoding tryptophan hydroxylase-2 and monoaminoxidase A and B in the frontal cortex, striatum, amygdala, hypothalamus, and hippocampus were detected. The data indicated the involvement of genes associated with the serotoninergic system in the mechanisms of mental disorders induced by post-weaning social isolation and suggest the gene encoding prolyl endopeptidase as a candidate gene involved in the pathogenesis of these disorders.

Dipeptidyl Peptidase 4 Inhibitors Diprotin A and Sitagliptin Administered on Weeks 2-3 of Postnatal Development Modulate Monoamine Metabolism in the Striatum of Adult Rats.

The levels of monoamines and their metabolites in brain structures of adult (3-month-old) rats with emotional and motivational disorders induced by inhibitors of dipeptidyl peptidase 4 (DPP-4; EC 3.4.14.5) diprotin A and sitagliptin on weeks 2-3 of postnatal development (postnatal days 5-18) were studied by HPLC with electrochemical detection. A significant decrease in the level of serotonin metabolite, 5-hydroxyindoleacetic acid, and a pronounced tendency towards reduced serotonin level were detected in the striatum of rats in both study groups. In adult rats treated with diprotin A during the neonatal period, a tendency towards activation of dopamine metabolism was observed (judging from DOPAC/DA ratio). The levels of monoamines and their metabolites in the frontal cortex, hypothalamus, and amygdala remained unchanged. The findings suggest that administration of DPP-4 inhibitors during the neonatal period induces long-term dysfunction of the serotonergic and dopaminergic systems of the brain.

Omega-3 polyunsaturated fatty acids when administered to lactating rats modify the development of experimental anxiety-depressive state in the rat pups exposed to the dipeptidyl peptidase-IV inhibitor diprotin A on the second - third weeks after the birth.

Omega-3 polyunsaturated fatty acids (PUFAs) belong to the hypolipidemic drugs, exhibit antioxidant properties and are used in the clinic for secondary prevention of several diseases. The effects of omega-3 PUFAs on the course of the stress-induced and endogenous depression are under investigation. We have previously demonstrated that synthetic inhibitors of prolyl endopeptidase (PEP; EC 3.4.21.26) exhibit antidepressant-like properties in different experimental models of emotional and motivational disorders. It is known that omega-3 PUFAs show PEP inhibitory activity. The purpose of this work was to study the effects of the drug Omacor (Abbot, Germany) containing omega-3 PUFAs, when administered to the lactating Wistar rats, on the emotional and motivational behavior of the offspring with the experimental anxiety-depressive disorder caused by the inhibitor of dipeptidyl peptidase IV (DPP- IV; CD 26; EC 3.4.14.5) diprotin A on postnatal day (PND) 5-18 (second - third weeks of postnatal development). Methods: We used conventional methods of assessing the emotional and motivational behavior and sensorimotor reactivity in animals. Omega-3 PUFAs were administered to lactating rats at a dose 0.3 g / kg, per os, for 28 days starting from the next day after the birthing. Diprotin A was administered systemically at a dose of 2 mg/kg. Results: Omega-3 PUFAs when administered to the lactating females, prevented the development of depressive-like behavior in adolescent rats neonatally exposed to DPP-IV inhibitor diprotin A, and contributed to the formation of antidepressive phenotype in control rats. However, under these circumstances, the omega-3 PUFAs increased anxiety and did not prevent an increase in aggression in rats with the experimental anxiety-depressive disorder and increased anxiety and stress-provoked aggression in the controls. Conclusion: The results support the hypothesis on the involvement of proline-specific peptidases DPP-IV and PEP in the mechanisms of emotional and motivational disturbances and expand the spectrum of omega-3 PUFAs action.

[Emotional Motivational Disorders in Rats as a Result of Diprotin A and Sitagliptin Administration in the First Postnatal Week].

The inhibitors of proline specific peptidase dipeptidyl peptidase-IV (DPP-IV, CD 26; EC 3.4.14.5) diprotin A (2 mg/kg) and sitagliptin (4 mg/kg) upon daily systemic exposure in rat pups on postnatal days 1-7 induced emotional and motivational disorders in one- and two-month-old rats. In adolescent rats, both the inhibitors produced a decreased locomotion in the automated open field test and an in- creased depression-like behavior in the Forced Swimming Test. At the same time, diprotin A increased sucrose consumption (a percent of the body weight) while sitagliptin decreased anxiety in the Elevated Plus Maze (EPM). In adult rats, diprotin A caused an increase in anxiety according to the reduced pref- erence for open arms of the maze and both the inhibitors decreased the percentage of rats entering open. arms in the EPM. Adult diprotin A-treated animals demonstrated increased aggression in social contact test. as compared to sitagliptin-treated rats. The one-and two-month-old animals in both experimental groups exhibited a decreased weight as compared to the controls. The results of the study show that diprotin A compared with sitagliptin negatively affects emotional and motivational behavior in adolescent and adult rats by increased number of indices increasing depression, anxiety, and aggression, while the main result of sitagliptin is increased depression when the animals were treated with the DPP-IV inhibitors in the first postnatal week. The findings support the hypothesis that DPPIV is involved in the genesis of emotional-motivational disorders.

[Modification of the Rat Ethogram by Contagion Behavior].

The study was performed on a contagious behavior model based on drinking, behavior in rats. In the presence of familiar drink-motivated conspecific showing drinking behavior (rat-demonstrator), drink-unmotivated rat-viewer begins to demonstrate behavioral signs ofdrinking motivation that is the signs of behavioral contagion. In this paper; the changes in the ethogram of rats-viewers with behavioral contagion were studied by analyzing atransition probabilities matrix. Those animals showed a decrease in the frequency of aggression and defensive behavior patterns simultaneously with an increase in the frequency of exploratory activity, drinking and exploratory approaches to bottles as compared with the ethogram of rats-viewers with no signs of behavioral contagion when tested in the presence of familiar drink-unmotivated con specific-demonstrator.

Differences in Active Avoidance Conditioning in Male and Female Rats with Experimental Anxiety-Depressive Disorder.

Using rat model of experimental anxiety-depressive disorder caused by postnatal administration of methionyl-2(S)-cyanopyrrolidine, an inhibitor of dipeptidyl peptidase IV, we compared conditioned active avoidance response and memory retention in males and females. In experimental males and females, conditioning was impaired in comparison with the control. In experimental groups, females were worse learners than males, while in control groups, females were better learners than males. Memory retention in experimental animals did not differ from that in controls 24 h after learning. Two months after learning, control females demonstrated better retention than control males.

[Early social isolation increases aggression and impairs a short-term habituation in acoustic startle reflex in rats].

Prolonged social isolation in early ontogeny leads to various changes in behavior and cognitive dysfunction in adult rats; however, data on the disorders are contradictory. In the present work, we studied the effects of early social isolation in Wistar rats by indices of psychomotor activity, aggression, anxiety, depression-like behavior, sensorimotor reactivity and short-term habituation of acoustic startle reflex. On the 24th postnatal day, rats were weaned from the dams and housed in individual cages for nine consecutive weeks. Animal behavior was evaluated at the age of one, two and three months. Immediately after weaning from the dam rats in the experimental group did not differ from the control on any of the indices. After four weeks of social isolation, rats showed an increased aggression in the social contact test. In rats isolated for an 8-weeks period, the increase in active non-aggressive contacts with a slight increase in motor activity in the elevated plus maze (E PM) accompanied increased aggression. At any terms of examination, isolated rats did not differ from the control in the anxiety in EPM, in the anxiety-phobic score, which is evaluated in a battery of tests, and in the duration of immobility which characterizes depression in the forced swimming test. Rats isolated for an 8-weeks period increased daily liquid intake by increasing the consumption of sucrose. After nine weeks of isolation, basal startle amplitude and prepulse inhibition that is, the characteristics of sensorimotor gating did not differ from the control, but there was a lack of short-term habituation of the acoustic startle reflex. Based on the data obtained, Wistar rats subjected to prolonged social isolation can be seen as a model of increased aggression with signs of cognitive deficits by indices of non-associative learning in the acoustic startle reflex.

[The contagious behavior model on the basis of rat drinking behavior].

In work, the attempt of contagious behavior modeling on the basis of rat drinking behavior was made. Rats' behavior was observed in home cage with two bottles. The rat without drinking motivation (viewer) was placed in the cage for adaptation. The rat-demonstrator was placed into the same cage 3 minutes later. If the viewer was tested with drink-motivated demonstrator, it had less latency of approach to bottles, higher frequency of approaches and increased drinking behavior time than the rat tested with unmotivated demonstrator or the rat tested without demonstrator. The intragastric infusion of coffee increased frequency of approaches to demonstrated bottle. Phenazepam intragastric injection decreased frequency of approaches and drinking behavior time at demonstrated bottle. The results suggest that drugs may affect rat contagious behavior based on drinking behavior.

[Effect of course intake of bio-active flavonoids-containing plant preparation Extralife on the level of anxiety and sensorimotor reactivity in rats].

Clinical and epidemiological data evidence the need to search for new substances for treatment and prevention of increased anxiety associated with emotional and neurotic breakdown and worsening clinical prognosis of psychosomatic diseases. Of particular interest are the drugs of plant origin, which are generally well tolerated under prolonged use, and treat- ment is cheaper as compared with modem anxiolytics. The purpose of this study was to investigate the effects of course taking a flavonoid-containing plant preparation Extralife (water-soluble extract Pentaphylloides fruticosa, 40 mg/kg per day for 1 month) in <> and <> inbred albino rats sampled in the population using a multi-parameter method for evaluating anxiety-phobic states. This method was also used for evaluating the severity of anxiety (state anxiety) in rats in the dynamics of the survey. Sensorimotor reactivity (emotionality) was assessed by the parameters of the acoustic startle response. Extralife did not prevent the increase in state anxiety in <> rats and did not change the level of anxiety in the <> animals. However, the drug reduced the amplitude of the acoustic startle response in the <> animals and increased startle response latency in both <> and <> rats, that is reduced the symptoms of anxiety caused by alarm sound stimuli in terms of sensorimotor reactivity. The data testify to the anxiolytic and sedative effects of Extralife more pronounced in the <> animals. In a course intake of Extralife <> rats demonstrated transient decrease in the pre-pulse inhibition of the acoustic startle response, probably associated with the occurrence of transient disturbances in the psycho-emotional sphere. The findings suggest that Extralife in a course taking may have negative side effects on the emotionality of animals that determines the need to incorporate the features of mental and emotional status of the individual in the development of therapeutic approaches to the correction of high anxiety with the inclusion of the drug.

Effect of prolyl endopeptidase inhibitor benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine on activity of proline-specific peptidases in brain structures of rats with experimental MPTP-induced depressive syndrome.

A noncompetitive synthetic inhibitor of prolyl endopeptidase benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine (1.0 mg/kg intraperitoneally for 2 weeks) prevented the increase in activity of prolyl endopeptidase in the frontal cortex, striatum, and hypothalamus and activation of dipeptidyl peptidase IV in the frontal cortex of rats with experimental dopamine deficiency-dependent depressive syndrome caused by administration of proneurotoxin MPTP (2 weeks). Our results suggest that the antidepressive effect of prolyl endopeptidase inhibitor is at least partly related to prevention of enzyme activation in the frontal cortex. The antistress effect of this substance can be associated with prevention of enzyme activation in the hypothalamus.

Effect of prolyl endopeptidase inhibitor benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine on the course of experimental depressive syndrome in rats.

The effects of noncompetitive prolyl endopeptidase inhibitor benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine were studied in rats with the experimental dopamine deficiency-dependent depressive syndrome induced by systemic injections of a pre-neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin for 14 days. The inhibitor (3.0 mg/kg, i.p., 30 min before pre-neurotoxin injection on days 8-14) alleviated depression symptoms and promoted normalization of behavioral activity after drug withdrawal. The obtained data reflected therapeutic antidepressant properties of inhibitor for prolyl endopeptidase benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine.

Benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine, a prolyl endopeptidase inhibitor, modulates depression-like behavior of rats in forced swimming test and activities of proline-specific peptidases in the brain structures.

High activities of prolyl endopeptidase and dipeptidylpeptidase IV in the striatum and of prolyl endopeptidase in the frontal cortex were recorded in rats with stress-induced depression-like state (behavioral despair) developed in the Porsolt forced swimming test. Acute injection of benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine (prolyl endopeptidase noncompetitive synthetic inhibitor) in a dose of 1 mg/kg prevented the development of behavioral despair and the increase of prolyl endopeptidase and dipeptidylpeptidase IV activities in the brain structures. In a dose of 2 mg/kg prolyl endopeptidase inhibitor did not modify the development of behavioral despair, but prevented the increase of prolyl endopeptidase and dipeptidylpeptidase IV activities in the striatum.

[Blood serum corticosterone level in modeling depression-like states in rats].

In two models of depression-like state--"behavioral despair" and experimental dopamine deficit-dependent MPTP-induced depression-like syndrome--as well as in a model of anxiety-depression-like state induced by dipeptidyl peptidase IV inhibitor methionyl-2(s)-cyanopyrrolidine administered in early postnatal period, the symptoms of behavioral depression in rats in the forced swim test were accompanied by the increase of corticosterone level in blood serum. In every model non-competitive prolyl endopeptidase (PEP) inhibitor benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine showed antidepressant-like properties preventing the development of depressive-like behavior. PEP Inhibitor also prevented the increase of serum corticosterone level in the models of "behavioral despair" and anxiety-depressive state, but not in the model of MPTP-induced depression-like syndrome. These findings testify for the involvement of hypothalamic-pituitary-adrenal system in the implementation of depression-like behavior in the specified models of depression-like state.

Effect of imipramine and prolyl endopeptidase inhibitor benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine on activity of proline-specific peptidases in the brain of rats with experimental anxious-depressive syndrome.

Activities of prolyl endopeptidase and dipeptidyl peptidase IV in the frontal cortex, hypothalamus, nucleus accumbens, striatum, and hippocampus were measured in rats with the experimental anxious-depressive syndrome induced by treatment with a dipeptidyl peptidase IV inhibitor during the early postnatal period (days 5-18). Prolyl endopeptidase activity was elevated in the frontal cortex, hypothalamus, and nucleus accumbens. Increased activity of dipeptidyl peptidase IV was observed in the hypothalamus and striatum. Norepinephrine/serotonin reuptake inhibitor, imipramine, and noncompetitive prolyl endopeptidase inhibitor, benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine, were shown to abolish depression-like behavior of animals in the forced swimming test. These compounds had a normalizing effect on activities of prolyl endopeptidase and dipeptidyl peptidase IV in brain structures of rats.

[The search of small molecules with antipsychotic activity on the background of neurotensin].

Tridecapeptide neurotensin (NT) is known to exert the neuroleptic-like effects in case of its intracerebral administration. The group of systemically active dipeptides , acylprolyltyrosines, was constructed on the background of NT. Methyl ester of N-caproyl-L-prolyl-L-tyrosine (Dilept) was chosen for further development. The paper is dealing with main principles of Dilept'design and with analysis of the experimental data concerning its effect on the "translational" model of schizophrenia--the deficit of prepulse inhibition of the acoustic startle-reaction caused by either dopamine-mimetic, apomorphine, or by the uncompetitive NMDA-blocker, ketamine. Dilept was shown to attenuate these deficits both in case ofintraperitoneal and peroral administration. Dilept is considered as a potential antipsychotic.

Activities of proline-specific peptidases in brain structures of rats with experimental anxiety-depressive state caused by administration of dipeptidyl peptidase IV inhibitor in the early postnatal period.

We studied the dynamics of activity of dipeptidyl peptidase IV (DP-IV) and prolyl endopeptidase (PEP) in the frontal cortex, hypothalamus, striatum, nucleus accumbens, and hippocampus of rats with experimental anxiety-depression state induced by administration of methionyl-2(s)-cyano-pyrrolidine, an inhibitor of DPP-IV, in the early postnatal period. In 1-month-old experimental males, PEP and DP-IV activities increased in the frontal cortex and hypothalamus, while in 1-month-old experimental females PEP activity increased in the hippocampus and DP-IV activity increased in all studied brain structures. At the age of 3 months, increased PEP activity in the hypothalamus and nucleus accumbens was detected in males and decreased DP-IV activity in the nucleus accumbens and decreased PEP activity in the hippocampus were detected in females. At the age of 7 months, PEP activity increased in the frontal cortex and striatum and DP-IV activity increased in all studied brain structures in males; in 7-months-old females, activity of both enzymes increased in the striatum.

[Peptidergic mechanisms in the regulation of emotional and motivational behavior].

The involvement of regulatory peptides of different groups in emotional and motivational behavior is analyzed comparing experimental and clinical data. Existing contradictions are underlined. The putative role of peptidases in emotional and motivational behavor is discussed. Changes in peptidases' activity are suggested to play regulatory and even trigger role in the organization of emotional and motivational behavior.

Experimental model of combined pain and depression status in rats.

Combined pain and depression status in rats was created by inducing experimental depressive syndrome (by subchronic injection of MPTP proneurotoxin) in animals with manifest and developing neurogenic pain syndrome induced by preliminary crossing of the sciatic nerve in the hind limb. The neurogenic pain syndrome augmented by some parameters the depressive symptoms and provoked manifestation of signs of depressive behavior in animals treated with saline.