[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.

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.

[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 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.

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.

Effect of a prolyl endopeptidase inhibitor benzyloxycarbonyl-alanyl-proline on the development of experimental depressive syndrome in rats.

The effects of a competitive prolyl endopeptidase inhibitor benzyloxycarbonyl-alanyl-proline were studied in rats with experimental dopamine deficiency-dependent depressive syndrome due to systemic administration of a proneurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine for 14 days. The inhibitor was injected intraperitoneally 30 min before treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (2nd week of the study). This substance contributed to rapid disappearance of depressive symptoms during the recovery of behavioral activity. Our results indicate that benzyloxycarbonyl-alanyl-proline has the antidepressant properties.

Involvement of brain dopaminergic systems in the development of an MPTP-induced depressive state in rats.

A depressive state was induced in Wistar rats by repeated i.p. injections of the proneurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which induces the death of dopaminergic neurons in the brain. Signs of the development of the experimental depressive state were a reduction in body weight and an increase in the proportion of REM sleep during daytime sleep. The rearrangement of the spectral characteristics of electrical activity during the development of experimental depressive syndrome in rats was shown to occur in target structures of the nigrostriatal, mesocortical, and mesolimbic dopaminergic systems of the brain, as well as in the amygdala and hippocampus. The most marked changes were seen in the terminal field of the nigrostriatal dopaminergic system and hippocampus. Spectral rearrangements of electrical activity in the theta-1 and theta-2 ranges in the hippocampus and dopaminergic structures suggest the involvement of the hippocampus in mediating changes in the emotional status of the experimental animals during the development of the MPTP-induced depressive state.

[Involvement of the brain dopaminergic systems in the development of the MPTP-induced depressive state in rats].

Depressive state was produced in Wistar rats by repeated intraperitoneal administration of proneurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) inducing death of brain dopaminergic neurons. Weight loss and increase in REM-sleep rate during diurnal sleep were considered to be signs of the development of an experimental depressive state. During the development of the depressive state of rats, the MPTP-induced reorganization of the spectral power of electrical activity was observed in the terminal fields of the nigrostriatal, mesocortical, and mesolimbic dopaminergic systems, amygdala, and hippocampus. The most pronounced changes were revealed in the terminal field of the nigrostriatal system and hippocampus. The reorganization of the spectral power in the thetal and theta2 bands in the hippocampus and dopaminergic structures suggests the involvement of the hippocampus in producing changes in the emotional state during development of the MPTP-induced depressive syndrome.

Activities of prolyl endopeptidase and dipeptidyl peptidase IV in brain structures of rats with dopamine deficiency-dependent MPTP-induced depressive syndrome.

The development of MPTP-induced depressive syndrome in rats was accompanied by activation of prolyl endopeptidase and dipeptidyl peptidase IV in the brain frontal cortex. Prolyl endopeptidase activity in the striatum also increased under these conditions. Our results indicate that proline-specific peptidases in the target structures of the brain dopaminergic system are involved in the pathogenesis of dopamine deficiency-dependent depressive states.

Experimental depressive-pain syndrome in rats with initial various anxiety-phobic levels: a behavioral study.

Modeling of neurogenic pain syndrome by sciatic nerve transection in rats with pronounced dopamine-deficiency-dependent 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine-induced experimental depressive syndrome forms a stable state of combined pain and depression, which can be considered as a model of the pain-depressive syndrome. The neurogenic pain syndrome prolongs the state of behavioral depression in rats irrespective of their initial anxiety level. The depressive symptoms can potentiate the severity of pain syndrome. By a number of indices, more pronounced behavioral changes during the development of pain-depressive syndrome occur in initially nonanxious rats.

[Alteration in the brain electrical activity, diurnal sleep structure, and the rat behavior after immunization with bovine serum albumin conjugated with dopamine]. / Izmeneniia élektricheskoi aktivnosti mozga, struktury dnevnogo sna i povedeniia krys posle immunizatsii zhivotnykh kon''iugatom dofamina s bych'im syvorotochnym al'buminom.

Male Wistar rats (380-430 g) were immunized with bovine serum albumin conjugated with dopamine (2 mg/kg, 0.25 ml) mixed with Freund's adjuvant complete (0.25 ml) or with bovine serum albumin mixed with Freund's adjuvant complete in the same doses. One week after the immunization with bovine serum albumin conjugated with dopamine, irregular spike activity and high-amplitude spindles associated with the state of awake immobility were recorded in the rat neocortex and caudate putamen, the relative power of the electrical activity in the caudate putamen was decreased in the alpha band, while the relative power of the beta 1 in the cortical EEG was increased. In the structure of 4-hour diurnal sleep, a decrease in the mean duration of sleep episodes and a reduction in the REM sleep content were observed. The parameters of the electrical activity and diurnal sleep structure returned to normal during the following 4 weeks. The open-field behavior 2 weeks after the second immunization (without Freund's adjuvant complete) did not differ from that of the control rats immunized only with bovine serum albumin. Titres of antibodies to dopamine after the second antigen injection were 1:32-1:64 in the electrophysiological series and 1:128-1:256 in behavioral experiments.

[Sensorimotor reactivity (acoustic startle response) in rats with experimental depressive syndrome]. / Sensomotornaia reaktivnost' (po akusticheskomu startl-otvetu) u krys s éksperimental'nym depressivnym sindromom.

Alterations of the sensorimotor responses in Wistar rats with experimental dopamine deficit-dependent depressive syndrome induced by neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine were measured by acoustic startle. In rats with innate high level of anxiety the development of behavioral depression was accompanied by the decrease in startle amplitude. In rats with innate low level of anxiety the decrease in startle amplitude did not reach the statistical significance. Correlation between the anxiety-phobic level and the expression of behavioral depression was not revealed. Independently of the initial anxiety-phobic level, in rats with depressive syndrome at the stage of behavioral rehabilitation after the neurotoxin withdrawal the prepulse inhibition of the acoustic startle was decreased as compared to control animals. It is suggested that the decrease in startle amplitude and, to a greater extent, the decrease in prepulse inhibition may characterize the development of dopamine deficit-dependent states.

[The effect of active immunization with a conjugate of dopamine and bovine serum albumin on the development of an experimental MPTP-induced depressive syndrome and on the monoamine metabolism in the brain of rats]. / Vliianie aktivnoi immunizatsii kon''iugatom dofamina s bych'im syvorotochnym al'buminom na razvitie éksperimental'nogo MFTP-indutsirovannogo depressivnogo sindroma i obmen monoaminov v golovnom mozge u krys.

Active immunization with dopamine conjugated with bovine serum albumin (DA-BSA) or BSA with complete Freund's adjuvant (CFA) partly suppressed the development of the MPTP-induced depressive syndrome in rats preventing the appearance of "behavioral despair" symptoms: increase in immobility time and higher index of depression in forced-swim test. In DA-BSA-immunized rats the content of DOPA, DA, HVA, NA, and 5-HN in caudate putamen and that of NA in the frontal cortex was increased, while in BSA-immunized rats the content of 5-HT in both brain areas and that of DOPAC in the frontal cortex was decreased both in rats with reduced depressive syndrome and in saline control as compared with intact animals a day after the last drug injection. In DA-BSA-immunized rats with reduced depressive syndrome the increase in DA and 5-HT content in caudate putamen was less expressed and DOPAC content was lower than in saline control. In BSA-immunized depressive rats DA content in the frontal cortex was also reduced as compared to control.

Count and phagocytic activity of leukocytes in rats with experimental depressive syndrome caused by systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Leukocyte count decreased, relative content of neutrophils and monocytes increased, and their phagocytic activity was suppressed in rats with 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine-induced depressive syndrome at the stage of acute behavioral depression. The severity of behavioral depression inversely correlated with changes in the absolute neutrophil and monocyte counts.

[The method of the integral evaluation of the behavioral depression in rats]. / Metod integral'noi otsenki vyrazhennosti depressii povedeniia u krys.

A new method of the evaluation of behavioral depression was developed based on a ranged scale of changes in a number of depressive symptoms in behavior and general state of animals. The method makes it possible to evaluate the individual expression of depressive symptoms in rats and can be used for revealing a correlation between the decrease in motivation level in depressive animals and alterations of some pathophysiological parameters.