[Concentrations of monoamines in the brain structures and features of behavior in the two-month old WAG/Rij rats].

The first spike-wave discharges (SWDs) in WAG/Rij rats begin to appear at age of 2-3 months and are fully manifested by 5-6 months. Occurrence of SWDs in the EEG is the main indicator of absence epilepsy. Extensive absence epilepsy in 5-6 months-old WAG/Rij rats is accompanied by decreases in dopamine and its metabolites concentrations in the meso-cortico-limbic and nigro-striatal dopaminergic brain systems, resulting in the expression of depression-like behavioral symptoms. In 36 day-old WAG/Rij rats, SWDs are not manifested, deficiency of dopamine is not revealed, and symptoms of depression-like behavior are not expressed. In this study, behavior and monoamines and their metabolites concentrations were investigated in 5 brain structures (prefrontal cortex, nucleus accumbens, hypothalamus, striatum, hippocampus) in 2 month-old WAG/Rij rats in comparison with Wistar rats of the same age. Reduction of the dopamine and its metabolites concentration in 2 month-old WAG/Rij rats was found only in the prefrontal cortex, indicating rapid response of the prefrontal cortex or its high sensitivity. Rapid response of the prefrontal cortex is supposed to be a.fundamental property of this brain structure. Decreases in the dopamine and its metabolites concentration in the prefrontal cortex in 2 month-old WAG/Rij rats were associated with features of behavior which can be regarded as a state of so called pre-pathology (increased anxiety and stress reactivity) preceding the development of depression-like behavior typical for 5-6-months old rats of this strain.

[Behavior and functional state of the dopaminergic brain system in pups of depressive WAG/Rij rats].

In the present work, it has been studied for the first time behavior and functional state of the dopaminergic brain system in pups of "depressive" WAG/Rij rats. Offspring of "depressive" WAG/Rij rats at age of 6-16 days compared with offspring of "normal" (non-depressed) outbred rats of the same age exhibited reduced rate of pshychomotor development, lower body weight, attenuation in integration of coordinated reflexes and vestibular function (greater latency of righting reflex, abnormal negative geotaxis), hyper-reactivity to tactile stimulation, reduced motivation to contact with mother (reduced infant-mother attachment). Differences in a nest seeking response induced by olfactory stimuli (olfactory discrimination test) and in locomotor activity (tests "gait reflex" and "small open field") have not been revealed. Acute injection of the antagonist of D2-like dopamine receptors clebopride 20 min before testing aggravated mother-oriented behavior in 15-days-old pups of both "depressive" and "non-depressive" rats. However this effect was greater in pups of "depressive" WAG/Rij rats compared with pups of "normal" rats that may indicate reduced functional activity of the dopaminergic brain system in offspring of "depressive" rats. It is proposed that reduced attachment behavior in pups of "depressive" WAG/Rij rats might be a consequence of maternal depression and associated with it reduced maternal care. Moreover, reduced attachment behavior in pups of "depressive" rats might be an early precursor (a marker) of depressive-like pathology which become apparent later in life (approximately at age of 3 months).

[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.

[Neurochemical mechanisms of depression-like behavior in WAG/Rij rats].

Behavior in the light-dark choice, open-field, sucrose consumption/preference and forced swimming tests, monoamines and their metabolites level in 6 brain structures (prefrontal cortex, nucleus accumbens, striatum, hypothalamus, hippocampus, amygdala), and density of D2-like dopamine receptors in 21 brain regions were studied in WAG/Rij and Wistar rats. WAG/Rij rats exhibited symptoms of depression-like behavior such as increased immobility in the forced swim test and decreased sucrose consumption/preference (anhedonia). Substantial changes in behavior indicating increased anxiety in WAG/Rij rats were not revealed. Neurochemical abnormalities suggesting hypofunction of the mesolimbic dopaminergic brain system were found in "depressive" WAG/Rij rats compared with "normal" Wistar rats: decreased levels of noradrenaline, dopamine, 3,4-dihydroxyphenylacetic acid, 3-methoxytyramine in the nucleus accumbens, and increased density of D2-like dopamine receptors in the nucleus accumbens and ventral tegmental area. Reduced levels of dopamine were also observed in the prefrontal cortex and striatum. No substantial changes in the content of monoamines and their metabolites have been revealed in the hypothalamus, hippocampus and amygdala as well as in the content ofserotonin and its metabolite 5-hydroxyindolacetic acid in all studied brain structures with the exception of increased level ofserotonin in the amygdala. Results suggest that hypofunction of the mesolimbic dopaminergic brain system (nucleus accumbens) is a neurochemical mechanism of depression-like behavior in WAG/Rij rats.

[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.

[Behavioral characteristics of female Wag/Rij rats].

Behavior of male and female WAG/Rij and Wistar rats was compared in the tests assessing the level of anxiety (light-dark choice, open field) and depression-like state (sucrose intake and preference, forced swimming). Females of WAG/Rij rats like males of the same strain exhibited symptoms of depression-like behavior: increased immobility in the forced swimming test and decreased sucrose intake and preference (anhedonia). In contrast to males, females of WAG/Rij rats displayed more distinct signs of increased anxiety as compared to Wistar rats. Both WAG/Rij and Wistar females exhibited increased locomotor and exploratory activity in the open field as compared to males.

[Does antiabsence drug ethosuximide exert antidepressant effect?].

Antiabsence drug ethosuximide (300 mg/kg/day in drinking water for 17 days) produced an antidepressant effect (a decrease in immobility time in forced swimming test) only in WAG/Rij rats genetically predisposed to absence epilepsy only at age of 5 months when spike-wave discharges well pronounced. On rats without spike-wave discharges (21-day-old WAG/Rij and Wistar rats at the age of both at 21 day and 5 months), ethosuximide didn't produce the antidepressant effect but tended to increases the immobility time and significantly decreases the number of divings (active behavior oriented to escape from stressful situation). Ethosuximide didn't substantially change the anxiety level in WAG/Rij rats but significantly enhanced anxiety in 21-day-old Wistar rats. The results suggest that ethosuximide is not possessed of antidepressant potential unrelated to its suppressive effect on spike-wave discharges.

[Remote control of the goal-directed behavior of freely moving rats by telestimulation of the rewarding brain structures].

The procedures are described that make it possible to train laboratory rats for remote control of their goal-directed behavior in open environments by telestimulation of rewarding brain structures. Rats were implanted electrodes in the lateral hypothalamus and lateral preoptic area. A week after surgery, rats were placed in an operant chamber and given electrical stimulation of increasing/decreasing intensity to each location to determine the most suitable site/hemisphere for reward delivery as well as the optimal stimulation parameters and the thresholds of behavioral reactions elicited. Then in T-maze, the animals were trained to obtain rewarding brain stimulation by running forward and turning correctly to the left or right arm of the maze in response to corresponding left- or right-turning light signal. At the last stage, rats were worn a backpack containing receiver-based remote-controlled microstimulator, connected to the implanted brain electrodes, and the animals were placed in open environments. The rewarding brain stimulation was delivered remotely using a transmitter connected to a laptop PC. Rats moved forward performing 'scanning' left-right head movements. Head movement in a desirable for the experimenter direction was reinforced. Animals remotely controlled by electrical stimulation of rewarding brain structures moved from one place of the environment to another according to any route given by an experimenter, overcame obstacles of different difficulties, not reacting to bright illumination, sounds and other external stimuli, and not exhibiting fear or curiosity, which are the typical reactions to novel surroundings. The more difficult was an obstacle the more stimulation was required to force an animal to overcome it.

[Effect of selective serotonin reuptake inhibitor fluoxetine on symptoms of depression-like behavior in WAG/Rij rats].

A possibility to correct behavioral symptoms of depression-like behasior in WAG/Rij rats with selective serotonin reuptake inhibitor antidepressant drug fluoxetine was studied. The efficacy of fluoxetine was compared with that of tricyclic antidepressant imipramine. Vehicle-treated WAG/Rij rats compared with the corresponding group of Wistar rats exhibited symptoms of depression-like behavior: a decreased level of exploratory activity and grooming reactions in the open field test, increased immobility in the forced swimming test, and decreased sucrose intake and preference (anhedonia). Differences in anxiety level in the light-dark choice test between WAG/Rij and Wistar rats were not found. Chronic injection of fluoxetine (5 mg/kg, i.p., for 15 days) didn't exert substantial influence on the anxiety level in the light-dark choice test both in WAG/Rij and Wistar rats. In the open field test, fluoxetine didn't significantly affect behavior of "depressive" WAG/Rij rats but induced anxiogenic effect in "normal" Wistar rats (a decrease in the number of center entries and an increase in the number of grooming reactions). In the forced swimming test, fluoxetine induced antidepressant effect (a decrease in immobility time and increase in the time of swimming) statistically significant in Wistar rats and at the level of tendency in WAG/Rij rats. In the sucrose consumption test, fluoxetine enhanced sucrose intake in "depressive" WAG/Rij rats and induced a tendency to a decrease in sucrose intake in "normal" Wistar rats. Fluoxetine didn't change sucrose preference (%) both in WAG/Rij and Wistar rats. In "depressive" WAG/Rij rats, selective serotonin reuptake inhibitor antidepressant fluoxetine was less effective than tricyclic antidepressant imipramine. However, a therapeutic effect of imipramine was apparent only after the cessation of chronic treatment. During treatment, worsening ofbehavioral characteristics was seen not only in "normal" Wistar rats but to an even greater degree in "depressive" WAG/Rij rats. Fluoxetine caused worsening of some behavioral characteristics only in "normal" Wistar rats. In "depressive" WAG/Rij rats, the therapeutic effect offluoxetine developed earlier than that of imipramine and was not accompanied by an adverse side effect on behavior of animals.

[Effects of heptapeptide selank on genetically-based and situation-provoked symptoms of depression in behavior in WAG/Rij and Wistar rats, and in BALB/c mice].

A synthetic derivative of the endogenous peptide tuftsin heptapeptide selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro) possesses an anxiolytic and psychostimulant effect, and represents a working element of a new peptide drug having completed the third phase of the clinical testing as a selective anxiolytic. The neurobiochemical spectrum of selank action combines mechanisms which are characteristics of antidepressants and psychostimulants: activation of the brain monoaminergic systems, dopamine synthesis and turnover, and modulation of the tyrosine hydroxylase activity. The aim of this study was to investigate the effect of selank in a new model of inherited (genetically-based) symptoms of depression in behavior of inbred WAG/Rij rats in comparison with its effect on situation-provoked symptoms of depression in behavior of BALB/c mice. Outbred Wistar rats constituted control group. Selank in high doses (1000-2000 microg/kg), after repeated injection counteracted symptoms of depression in behavior of WAG/Rij rats (increased immobilization in the forced swimming test and decreased sucrose intake or preference (anhedonia)). Selank in low doses (100 and 300 microg/kg) after single injection reduced the duration of immobility of BALB/c mice in the forced swimming test, but did not exert significant effect after repeated injection or after injection in high doses (600 and 900 microg/kg). Selank did not affect the level of general locomotor activity and anxiety in WAG/Rij rats, and did not exert substantial effect on the behavior of control Wistar rats. The results demonstrate the presence of antidepressant component in the spectrum of neuropsychotrophyc activity of selank and indicate the higher reliability of a new experimental model of depression (the WAG/Rij rats) as compared to the standard forced swimming test for the determination of antidepressant activity of a pharmacological drug.

[Dopamine-dependent character of depressive-like behavior in WAG/Rij rats with genetic absence epilepsy].

Placebo-treated WAG/Rij rats (as compared to normal Wistar rats without seizure pathology) exhibited depressive-like behavior similar to that of intact rats of the same strain: decreased exploratory activity in the open field test, increased immobility in the forced swimming test, decreased sucrose consumption and preference (anhedonia). Chronic injection of tricyclic antidepressant imipramine (15 mg/kg. i.p., for 15 days) exerted a therapeutic (antidepressant) effect on depressive-like behavior in WAG/Rij rats. After cessation of antidepressant therapy, the behavior of WAG/Rij rats didn't significantly differ from that of Wistar rats. Acute (single) injection of selective D2/D3 dopamine receptor antagonist raclopride (100 microg/kg, i.p., 15 min prior to behavioral testing) aggravated the symptoms of depressive-like behavior and suppressed antidepressant effect of chronic injection of imipramine in WAG/Rij rats, whereas it didn't exert a substantial effect on behavior of Wistar rats. Injection of D2/D3 dopamine receptor agonist Parlodel (bromocriptine) counteracted the depressive-like behavior in WAG/Rij rats and didn't exert substantial influence on behavior of Wistar rats with the exception of a decrease in immobility time in the forced swimming test. Injections of imipramine and raclopride didn't exert significant influences on the level of general locomotor activity and anxiety both in WAG/Rij and Wistar rats. The results demonstrate the dopamine-dependent character of depressive-like behavior in WAG/Rij rats, and indicate possible involvement of dopamine D2-like receptors in mediation of the antidepressant effect of imipramine on genetically determined depressive-like behavior in WAG/Rij rats.

[Possible mechanisms of unilateral hippocampal insult after bilateral occlusion of common carotid arteries in rats with different types of behavior].

Possible mechanisms of unilateral ischemic insults in CA1 region of hippocampus and anterior dorsal nuclei of thalamus after bilateral occlusion of common carotid arteries in rats with different types of behavior are discussed.

[Are WAG/Rij rats with genetic absence epilepsy anxious?].

Behavior of susceptible and non-susceptible to audiogenic (convulsive) seizures rats from inbred WAG/Rij strain, genetically predisposed to absence epilepsy, and outbred Wistar strain, genetically not predisposed to absence epilepsy, was compared to assess the level of anxiety (in open field, light-dark choice and elevated plus-maze tests) and the level of depressiveness (in the sucrose consumption and forced swimming tests). Increased level of anxiety was found only in susceptible to audiogenic seizures rats both from WAG/Rij and Wistar strain, but increased level of depressiveness was found only in WAG/Rij strain rats as compared with Wistar rats independently of their susceptibility to audiogenic seizures. Results suggest that increased depressiveness in WAG/Rij strain rats is associated with absence epilepsy but increased anxiety with susceptibility to audiogenic seizures.

[Interhemispheric asymmetry of the hippocampal damage after bilateral ligation of common carotid arteries]. / Mezhpolusharnaia asimmetriia povrezhdenii gippokampa posle dvukhstoronnei pereviazki obshchikh sonnykh arterii.

Permanent bilateral occlusion of common carotid arteries in rats with different behaviour types led to non-uniform structural alterations in the hippocampus. In the majority of animals, morphological changes were diffuse (i.e. having no clear localisation in a definite region of the brain structure) and symmetrical (i.e. having no evident prevalence in one of the brain hemispheres). In 6.6% of survived animals, apart from diffuse structural changes, local and asymmetrical sites of lesions occurred in the hippocampus and mostly in the dorso-lateral thalamic nuclei of the right brain hemisphere. These local zones of strongly pronounced pathology corresponded to ischemic insults which were described earlier by other authors under transient cerebral ischemia. It is supposed that the occurrence of unilateral ischemic insults in a definite region of hippocampus and thalamus after bilateral occlusion of common carotid arteries is due to individual features of the anatomy of the vascular brain system which are found more frequently in rats with passive type of behaviour and in rats of the middle group than in rats with active type of behaviour.

[Depression-like changes in behavior and c-fos gene expression in dopaminergic brain structures in WAG/Rij rats]. / Depressivnopodobnye izmeneniia v povedenii i ékspressiia gena c-fos v dofaminergicheskikh strukturakh mozga u krys linii WAG/Rij.

In WAG/Rij rats with genetic absence epilepsy, inborn changes in behavior were observed such as decreased level of locomotion, exploratory activity, and grooming reactions in the open-field test, increased immobility in the forced-swimming test, and decreased sucrose consumption (anhedonia) as compared to Wistar rats completely lacking in seizure pathology. These behavioral alterations in WAG/Rij rats resemble the symptoms of human depression (psychomotor retardation, depressed mood, and anhedonia). No significant behavioral changes were found in the light-dark choice, social interaction, and elevated plus-maze tests. This suggests the absence of increased anxiety in WAG/Rij rats. In contrast to Wistar, WAG/Rij rats were sensitive only to chronic treatment with antidepressant imipramine like depressive patients. Behavioral "despair" induced by forced swimming led to C-fos gene expression in three brain structures (frontal cortex, nucleus accumbens, and striatum), which are, respectively, terminal regions of three dopaminergic brain systems (mesocortical, mesolimbc, and nigrostriatal). c-fos gene expression in the brain of WAG/Rij rats was substantially different from that in the brain of Wistar rats in both intensity (in WAG/Rij the c-fos gene expression was higher than in Wistar rats in all involved brain structures) and its distribution between the structures. The results suggest that WAG/Rij strain is a new experimental (genetic) model of absence epilepsy-related depression unassociated with increased anxiety.

[Possible mechanisms for forming typological features of behavior of WAG/Rij line rats]. / Vozmozhnye mekhanizmy formirovaniia tipologicheskikh osobennostei povedeniia krys linii WAG/Rij.

Typological behavior reactions of WAG/Rij rats were studied from the standpoint of divergent modulatory integration hypothesis. This rat strain has a genetically determined dominant dysfunction of the benzodiazepine system of the thalamic nuclei. This disorder provokes an epileptiform disease such as absence epilepsy. It was suggested that the dysfunction of this system would result in a modification of the modulatory systems, which support the motivation states of escape and avoidance reactions as well as of the modulatory systems, which form the emotional states. Modifications of these states are the background of typological behavioral features of WAG/Rij rats. It was shown that WAG/Rij have the lower threshold of the development of haloperidol catalepsy, higher levels of fear and depression. On the first day of training in a shuttle box, WAG/Rij rats demonstrated better avoidance performance than Wistar rats. On the second and 28th days, the amnestic effect of the epileptiform disease was observed. The amnestic effect was also observed after passive avoidance conditioning. The results are discussed in terms of the modulatory integratin hypothesis.

[Prophylactic effect of antioxidant Aekol on behavioral (psychoemotional) disturbances caused by chronic stress in rats]. / Profilakticheskoe deistvie antioksidantnogo preparata "Aekol" na povedencheskie (psikhoémotsional'nye) narusheniia, vyzyvaemye khronicheskim stressom u krys.

Antioxidant preparation "Aekol" containing vitamins A, E, and K3, was shown to possess antidepressant properties and to exert a prophylactic effect on behavioural (psychoemotional) disturbances induced by a chronic stress in rats: a depressive condition associated with an enhanced anxiety, elimination of individual differences in behaviour, weakening of the relationships among behavioural parameters recorded in the same animal in three different tests.