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.     

Depression-like changes in behavior and c-fos gene expression in dopaminergic brain structures in WAG/Rij rats

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.     

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.     

Maternal care exerts disease‐modifying effects on genetic absence epilepsy and comorbid depression

WAG/Rij rats, a genetic animal model of absence epilepsy with comorbidity of depression, exhibit behavioral depression‐like symptoms and spontaneous generalized spike‐wave discharges (SWDs) in the EEG at the age of 6 to 8 months. The aim of the present study was to test the hypothesis that maternal care is an environmental factor which, along with genetic predisposition, may contribute to the expression of absence seizures and depression‐like comorbidity later in life. To achieve this, a cross‐fostering procedure was used. EEG and behavior in the forced swimming test were analyzed in WAG/Rij and Wistar offspring reared by their own mothers (non‐cross‐fostered), foster mothers of the same strain (in‐fostered) or another strain (cross‐fostered) at the age of 7 to 8 months. Maternal care and forced swimming test behavior were assessed in the dams. WAG/Rij mothers showed depression‐like behavior and reduced maternal care irrespective of litter size and litter composition (own or foster pups) compared with Wistar dams. WAG/Rij offspring reared by Wistar dams with a high level of maternal care exhibited less and shorter SWDs and reduced depression‐like comorbidity in adulthood compared with age‐matched WAG/Rij offspring reared by their own or foster WAG/Rij mothers with a low level of maternal care. Moreover, rearing by Wistar mothers delayed the onset of absence epilepsy in WAG/Rij rats. Adoption by WAG/Rij dams did not change EEG and behavior in Wistar rats. Our study demonstrates that improvement of early care‐giving environment can be used as a disease‐modifying treatment to counteract epileptogenesis and behavioral comorbidities in genetic absence epilepsy.     

Influence of semax on the emotional state of white rats in the norm and against the background of cholecystokinin-tetrapeptide action

The effects of the adrenocorticotropic hormone (ACTH(4–10)) analog, Semax (MEHFPGP), on the level of anxiety and depression in white rats have been studied in the normal state and against the back-ground of cholecystokinin-tetrapeptide (CCK-4) action. Semax was injected intranasally in doses of 50 and 500 μg/kg 15 min before the testing. CCK-4 was administered intraperitoneally in a dose of 400 μg/kg 40 min before the testing. The level of anxiety was estimated in the elevated plus-maze test, and the degree of depression, in the forced swimming test. Semax administration did not influence the emotional state of animals in the normal state. The CCK-4 injection led to an increase in anxiety and depression in rats. Semax normalized the animal behavior disturbed by the CCK-4 administration, which attests to its anxiolytic and antidepressant effects at elevated levels of anxiety and depression.     

Piplartine, an amide alkaloid from Piper tuberculatum, presents anxiolytic and antidepressant effects in mice

In the present work, we studied the effects of piplartine (PIP), an amide alkaloid isolated from the roots of Piper tuberculatum (Piperaceae), in the elevated plus maze, open field, rota rod, pentylenetetrazole (PTZ)-induced seizures, and forced swimming tests, in mice (Swiss, male, 25 g) to assess anxiolytic, sedative, muscle relaxant, anticonvulsant and antidepressant effects, respectively. Results showed that PIP (50 and 100 mg/kg, i.p.), similarly to diazepam, significantly increased not only the number of entrances (100% and 66%, respectively) but also the time of permanence in the open arms (104% and 199%, respectively), indicating that PIP presents an anxiolytic activity. Both effects were completely blocked by the previous administration of flumazenil what suggests the involvement of benzodiazepine type receptors. In the open field test, although PIP did not alter the number of crossings, it significantly increased grooming (103% and 119%) and rearing (60% and 23%), at the doses of 50 and 100 mg/kg respectively, as compared to controls. However, in the rota rod test, PIP was devoid of effect. Although in the PTZ-induced convulsion test, PIP did not alter the latency time for the onset of the first convulsion, as compared to controls, it significantly reduced in 58% and 60%, respectively, the animal's latency time to death. Furthermore, a significant and dose-dependent decrease in the immobility time, as evaluated by the forced swimming test, was observed after PIP administration (41% and 75% decrease, at the doses of 50 and 100 mg/kg, respectively), suggesting an antidepressant effect, similarly to that observed with imipramine, a classical antidepressant drug used as standard. In conclusion, we showed that PIP presents significant anxiolytic and antidepressant activities, making this drug potentially useful in anxiety and depression.     

Possible mechanisms for forming typological features of behavior of WAG/Rij line rats

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.     

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.     

Rearing by foster Wistar mother with high level of maternal care counteracts the development of genetic absence epilepsy and comorbid depression in WAG/Rij rats

It has been shown for the first time that rearing by a foster Wistar mother with high level of maternal care (MC) counteracts the expression of genetic absence epilepsy (AE) and comorbid depression – reduces the number, duration and index of spike-wave discharges (SWDs) and immobility time in the forced swimming test, as well as exerts substantial effects on morphology and time-frequency dynamics of SWDs in WAG/Rij rats. It is supposed that increases in MC early in development might be used to counteract epileptogenesis and comorbid depression in people genetically predisposed to AE.     

Low dose of disulfiram and l-dopa evoked synergistic modification in behavior of Wistar and WAG/Rij rats

Comparative analysis of behaviors of two rat strains, Wistar and WAG/Rij, was performed. No behavioral differences between Wistar and WAG/Rij were found in the emotional resonance test. Disulfiram injection produced similar effects in both rat strains. Animals of the first group (with slow acquisition of emotional resonance reaction) transformed into the animals of the second group (with fast acquisition). Passive avoidance conditioning was successfully reproduced in Wistar and was significantly impaired in WAG/Rij. A low dose of disulfiram injected before or immediately after conditioning substantially improved the reproduction to a greater extent in WAG/Rij than Wistar strains thus eliminating in interstrain differences. Active avoidance conditioning was more successful in WAG/Rij than in Wistar rats However, on the next day conditioning in WAG/Rij was substantially impaired. Administration of the low dose of disulfiram or L-DOPA prior to conditioning impaired the acquisition but improved the reproduction on the following day in both strains, but disulfiram injection after conditioning improved conditioning in WAG/Rij to a greater extent than in Wistar. Thus, the pharmacologic enhancement of the reward system substantially changed animal behavior and improved memory consolidation.     

Anxiety and behavior in WAG/Rij strain rats with genetically induced absence attacks

Behavior of nonlinear rats and animals from Wistar and WAG/Rij (with inborn generalized absence epilepsy) strains was examined in the elevated plus-maze and the hole board. WAG/Rij rats demonstrated low exploratory behavior in both tests. In the elevated plus-maze, WAG/Rij rats were more balanced and more anxious than Wistar and nonlinear rats. Administration of ethosuximide completely eliminated spike-wave discharges but did not change behavioral interstrain differences. Since the spike-wave patterns develop in WAG/Rij at the age of 3 months, the behavior of young (2-moth-old) pups from different strains was compared and significant differences were revealed. Correlation between the genetically defined features (spike-wave discharges) and behavioral peculiarities in WAG/Rij rats is supposed.     

Antidepressant- and anxiolytic-like activities of an oil extract of propolis in rats

PurposePropolis biological effects are mainly attributed to its polyphenolic constituents such as flavonoids and phenolic acids that were recently described in the chemical composition of an extract of propolis obtained with edible vegetal oil (OEP) by our group. The aim of this study was to evaluate the effect of OEP on the behavior of rats.Materials and methodsAn in vivo open field (OF), elevated Plus-maze (EPM), and forced swimming (FS) tests were performed to evaluate locomotor activity, anxiolytic- and antidepressant effects of the extract. Besides, oxidative stress levels were measured in rat blood samples after the behavioral assays by evaluation of the Trolox equivalent antioxidant capacity (TEAC) and nitric oxide levels.ResultsOEP increased locomotion in the OF test (50 mg/kg) and central locomotion and open arm entries in the OF and EPM tests (10–50 mg/kg) and decreased the immobility time in the FS test (10–50 mg/kg). Moreover, OEP reduced nitric oxide levels in response to swim stress induced in rats.ConclusionOEP exerted stimulant, anxiolytic and antidepressant effects on the Central Nervous System and antioxidant activity in rats, highlighting propolis as a potential therapeutic compound for behavior impairment of anxiety and depression.     

Effect of combined treatment with imipramine and metyrapone on the immobility time, the activity of hypothalamo-pituitary-adrenocortical axis and immunological parameters in the forced swimming test in the rat.

Major depression is frequently associated with the hyperactivity of the hypothalamic-pituitary-adrenocortical axis, and glucocorticoid synthesis inhibitors have been shown to exert antidepressant action. The aim of the present study was to examine the effect of joint administration of metyrapone (50 mg/kg) and imipramine (5 and/or 10 mg/kg) on immobility time, plasma corticosterone concentration, the weight of spleens and thymuses and the proliferative activity of splenocytes in rats subjected to the forced swimming test--an animal model of depression. Metyrapone alone (50 mg/kg) reduced the immobility time of rats in the forced swimming test and decreased plasma corticosterone level, but did not change immunological parameters. Joint administration of metyrapone and imipramine (5 and 10 mg/kg) produced a more pronounced antidepressant-like effect than either of the drugs given alone. The forced swimming procedure significantly increased the proliferative activity of splenocytes, that parameter being reduced only by co-administration of metyrapone and imipramine. Joint administration of metyrapone and imipramine inhibited to a similar extend the corticosterone level as did treatment with metyrapone alone (about twofold); however, the plasma corticosterone level in animals treated with metyrapone and the higher dose of imipramine did not differ from the concentration of this steroid in control, not-stressed rats. The obtained results indicate that metyrapone potentiates the antidepressant-like activity of imipramine and exerts a beneficial effect on the stress-induced increase in plasma corticosterone concentration and the proliferative activity of splenocytes. These finding suggest that a combination of metyrapone and an antidepressant drug may be useful for the treatment drug-resistant depression and/or depression associated with a high cortisol level.     

Extracts of Valeriana officinalis L. s.l. show anxiolytic and antidepressant effects but neither sedative nor myorelaxant properties.

Extracts of Valeriana officinalis L. s.l. are used for treating mild sleep disorders and nervous tension. Despite intensive research efforts, the pharmacological actions accounting for the clinical efficacy of valerian remain unclear. Thus, it was the aim of this study to evaluate CNS-related effects of different valerian extracts using behavioral paradigms (mice and rats). Following oral administration two commercially available preparations (extraction solvents: 45% methanol m/m and 70% ethanol v/v), a 35% ethanolic v/v extract and a refined extract derived from it (patented special extract phytofin Valerian 368) were tested for sedative (locomotor activity, ether-induced anaesthesia) and anxiolytic (elevated plus maze) activity. Using the forced swimming and the horizontal wire test the latter two extracts were additionally tested for antidepressant and myorelaxant properties. Up to maximum dosages of 500 or 1000 mg/kg bw none of the valerian extracts displayed sedative effects. Neither spontaneous activity was reduced nor the duration of ether-induced narcosis was prolonged. In contrast, results obtained in the elevated plus maze test revealed a pronounced anxiolytic effect of the 45% methanolic and 35% ethanolic extract as well as of phyotofin Valerian 368 in a dose range of 100-500 mg/kg bw. Additionally and different from its primary extract (35% ethanolic extract) phytofin Valerian 368 showed antidepressant activity in the forced swimming test after subacute treatment. Myorelaxant effects were not observed in dosages up to 1000 mg/kg bw. Due to these findings it is proposed that not sedative but anxiolytic and antidepressant activity, which was elaborated particularly in the special extract phytofin Valerian 368, considerably contribute to the sleep-enhancing properties of valerian.     

Stress, glucocorticoids and absences in a genetic epilepsy model

Although stress can alter the susceptibility of patients and animal models to convulsive epilepsy, little is known about the role of stress and glucocorticoid hormones in absence epilepsy. We measured the basal and acute stress-induced (foot-shocks: FS) concentrations of corticosterone in WAG/Rij rats, non-epileptic inbred ACI rats and outbred Wistar rats. The WAG/Rij strain is a genetic model for absence epilepsy and comorbidity for depression, which originates from the population of Wistar rats and, therefore, shares their genetic background. In a separate experiment, WAG/Rij rats were exposed to FS on three consecutive days. Electroencephalograms (EEGs) were recorded before and after FS, and the number of absence seizures (spike-wave-discharges, SWDs) was quantified. Both WAG/Rij rats and ACI rats exhibited elevated basal levels of corticosterone and a rapid corticosterone increase in response to acute stress. The WAG/Rij rats also displayed the most rapid normalization of corticosterone during the recovery phase compared to that of ACI and Wistar rats. FS had a biphasic effect on SWDs; an initial suppression was followed by an aggravation of the SWDs. By the third day, this aggravation of seizures was present in the hour preceding FS. This increase in SWDs may arise from anticipatory stress about the upcoming FS. Together, these results suggest that the distinct secretion profile of corticosterone found in WAG/Rij rats may contribute to the severity of the epileptic phenotype. Although the acute stressor results in an initial suppression of SWDs followed by an increase in SWDs, stress prior to a predictable negative event aggravates absences.     

Antidepressant-type effect of the NK3 tachykinin receptor agonist aminosenktide in mouse lines differing in endogenous opioid system activity.

The influence of the tachykinin NK3 receptor agonist, aminosenktide on the immobility in the forced swimming test was studied in mouse lines selectively bred for divergent magnitudes of stress-induced analgesia. The high analgesia (HA) line is known to display enhanced, and the low analgesia (LA) line displays reduced activity of the opioid system. Aminosenktide at doses of 125 microg/kg or 250 microg/kg intraperitoneally (IP) reduced, in naltrexone-reversible manner, the immobility more of opioid receptor-dense HA than of unselected mice, but was ineffective in the opioid receptor-deficient LA line. The effect of aminosenktide was quite similar to the antiimmobility action of desipramine (10 mg/kg IP), a prototypic antidepressant agent. None of the compounds increased animals' locomotion as found with an open field test; therefore their antiimmobility effect cannot be attributed to a change in general motility. The results claim that aminosenktide causes an antidepressant effect, and endogenous opioids are involved in this process.     

The induction and abolition of specific immunosuppression of heart allografts in rats by use of donor blood and cyclophosphamide.

Intravenous pretreatment of WAG/Rij rats with BN blood 14 days before transplantation leads to permanent survival of BN heart allografts. Pretreatment with donor blood in the reverse donor-host combination gives rise to accelerated rejection of WAG/Rij hearts. Addition of 100 mg/kg Cy to the pretreatment with donor blood in the WAG/Rij to BN model resulted in permanent graft acceptance, presumably due to the phenomenon of immunologic enhancement. This effect could be observed only if the interval between drug administration and antigen pretreatment was short. The use of Cy had a more profound and long-lasting effect on humoral than on cellular immunity. Addition of 100 mg/kg Cy to the active enhancement protocol in the "easy" BN to WAG/Rij combination produced permanent graft survival in an immunologic setting reminiscent of immunologic tolerance. The combined pretreatment with donor blood and 50 mg/kg Cy in this donor-host combination abolished the operation of immunologic enhancement, which could be induced if donor blood was given alone.     

Characteristics of the combined action of melatonin and imizin on the structure of forced swimming and the circadian rhythm

Acute administration of melatonin (10 mg/kg) produced a depressed effect on the mice behavior. But it's injection after chronic imipramine (10 mg/kg/day, 2 weeks) potentiated antidepressant ability and shortened the duration of immobility in the structure of swimming. In rats, which had a high amplitude of circadian rest-activity rhythm, melatonin produced imipramine effect on circadian mobility, but potentiated antidepressant action in animals with low initial level of locomotor activity.     

Antidepressant activity of standardized extract of Bacopa monniera in experimental models of depression in rats.

Bacopa monniera Wettst. (syn. Herpestis monniera L.; Scrophulariaceae) is a commonly used Ayurvedic drug for mental disorders. The standardized extract was reported earlier to have significant anti-oxidant effect, anxiolytic activity and improve memory retention in Alzheimer's disease. Presently, the standardized methanolic extract of Bacopa monniera (bacoside A - 38.0+/-0.9) was investigated for potential antidepressant activity in rodent models of depression. The effect was compared with the standard antidepressant drug imipramine (15 mg/kg, ip). The extract when given in the dose of 20 and 40 mg/kg, orally once daily for 5 days was found to have significant antidepressant activity in forced swim and learned helplessness models of depression and was comparable to that of imipramine.