[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.

[Effect of apomorphine injection into the nucleus accumbens on the limb preference in manipulation movements in rats].

The concentration of dophamine and its derivates is known to correlate with the degree of handedness in manipulative movements in rodents. In this work we studied a possibility to changing handedness in rats by injection of a dopamine agonist into the nucleus accumbens. Retrieving food from a horizontal tube was used to determine the limb preference (10 food retrievals by the preferred limb). Then apomorphine was injected into the n. accumbens ipsilateral to the preferred limb in the course of 7 days. The same volume of buffer solution was injected into the contralateral n. accumbens. Just after the last injection the limb preference was tested. It was shown that the chronic injection of the non-specific agonist of dophamine receptors significantly changed the limb preference.

[Asymmetry in the dopamine content in the nucleus accumbens and the motor preference in rats].

A number of published studies reported a correlation between the paw preference in mice and asymmetry of tissue concentrations of dopamine (DA) and DA metabolites measured in the nucleus accumbens (NAcb) the DA concentration being higher in the nucleus ipsylateral to a preferred paw. This study aimed to investigate whether such asymmetry existed in rats. The paw preference was defined by reaching into a small horizontal tube for a food pellet. Tissue concentration of DA was measured by high-performance liquid chromatography with electrochemical detection. It was shown that the DA concentration in the left NAcb was significantly higher in "left-handed" rats than in "right-handed" animals. Within the group of "right-handers", the DA concentration was significantly higher in the right NAcb than in the left NAcb. The results confirm in part the experimental data obtained in mice and support the hypothesis that the paw preference is paralleled by elevated tissue DA in the ipsylateral NAcb of rodents.

[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.

Depressive-like behavioral alterations and c-fos expression in the dopaminergic brain regions in WAG/Rij rats with genetic absence epilepsy.

Wistar derived inbred line, the WAG/Rij rats, genetically absence epilepsy prone and their normal counterparts, outbred Wistar rats, were compared in respect to differences in behavior, in acute and chronic antidepressant imipramine treatment and in the immediate early gene c-fos expression in the brain regions induced by forced swimming test procedure. The WAG/Rij rats as compared with Wistar rats were found to exhibit decreased activity in the open field test, increased immobility in the forced swimming test and decreased sucrose intake (anhedonia). Interline differences indicating increased anxiety in the WAG/Rij rats were not revealed in the light-dark choice, social interaction and elevated plus-maze tests. The WAG/Rij rats in contrast to Wistar rats responded only to chronic antidepressant imipramine treatment with a reduction in their enhanced immobility in the forced swimming test. "Behavioral despair" induced by forced swimming led to c-fos expression in frontal cortex, nucleus accumbens and striatum, terminal regions of three dopaminergic brain systems (mesocortical, mesolimbic, nigrostriatal). The c-fos expression in the brain of WAG/Rij rats was substantially higher than that of Wistar rats. Moreover, the strains differed in the distribution of c-fos expression between brain regions. Results suggest that WAG/Rij rats are prone to adopt passive strategies of behavior in stressful situations, and so in this certain aspect this strain might be regarded as new experimental (genetic) model of depressive-like (passive) behavior accompanying absence epilepsy. Further testing this hypothesis is proceeding. This putative model could be used for the investigation of neurobiological basis and mechanisms of such "double pathology" and for the examination of new concepts of its therapy.

[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.

Electrophysiological and pharmacological characteristics of two types of spike-wave discharges in WAG/Rij rats.

Rats of the WAG/Rij strain are commonly seen as a genetic model for generalised absence epilepsy in man. Interestingly, generalised absence epilepsy shows, in addition to the fully generalised spike-wave discharges, a second type of spike-wave discharge, which lasts for a shorter time, has a lower frequency, and a lower incidence. The originally described distinction between the two types of spike-wave discharges was mainly based on the shape, polarity and duration of the discharges. In the present study other characteristics such as the spatial and temporal distribution of the spike and wave components of the two discharges and frequency spectra were found to differ between the two types. In addition, a reciprocal regulation of the two types of spike-wave discharges by drugs affecting the dopaminergic system (haloperidol and apomorphine) was observed. The results convincingly demonstrate the difference between the two phenomena and warrant the search for neurobiological mechanisms underlying both types of spike-wave discharges.

[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.

[Two types of "spike-wave" discharges in the electrocorticogram of WAG/Rij rats, the genetic model of absence epilepsy]. / Dva tipa razriadov "pik-volna" na elektrokortikogramme krys linii WAG/Rij, geneticheskoi modeli absence-épilepsii.

WAG/Rij rats were injected with apomorphine (0.5 mg/kg, i.p.), an agonist of D2 receptors. Two types of spike-wave discharges (generalized and local) were found in the baseline ECoG of the intact and injected rats. Injections of apomorphine led to a suppression of the generalized (type 1) for about 30 minutes and a 8-10-fold increase in the local spike-wave discharges (type 2) within 4-6 minutes. Since it has been shown earlier that haloperidol, which acts on dopamine receptors oppositely to apomorphine, enhance the generalized spike-wave activity and suppress the local discharges. Thus, the different pharmacological characteristics of the two types of spike-wave activity suggest the controlling role of the dopaminergic system in the processes of spike-wave generation.

[Haloperidol induces changes in the electrocorticogram of rats with genetic petit mal epilepsy]. / Galoperidol vyzyvaet izmeneniia élektrokortikogrammy krys s geneticheskoi maloi épilepsiei.

The WAG/Rij rats, a genetic animal model of human absence epilepsy, were injected with D2 autoreceptor antagonist haloperidol. Increase in the amount of spike-wave discharges and the prevalence of short spike-wave discharges was observed. The pattern of spike-wave discharge sequence changed in a characteristic way. The findings may testify to participation of dopaminergic system both in the processes of generation and cessation of the spike-wave complex absence epilepsy.