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Aims: Despite many antiepileptic drugs (AEDs) are available to treat epilepsy, there is still about 30% of epilepsy patients inadequately treated with these AEDs. For these patients, polytherapy with two or three AEDs to fully control their seizure attacks is recommended. Unfortunately, polytherapy is always associated with drug interactions, whose nature may be beneficial, neutral or unfavorable. To determine a type of interaction for the combination of three AEDs (i.e., phenobarbital [PB], phenytoin [PHT] and pregabalin [PGB]) at the fixed-ratio of 1:1:1, we used a model of tonic-clonic seizures in male albino Swiss mice., Materials and Method: Tonic-clonic seizures in mice were evoked by a current (sine-wave, 25 mA, 500 V, 0.2 s stimulus duration) delivered via auricular electrodes. The anticonvulsant effects of the three-drug combination (PB, PHT and PGB) in terms of suppression of tonic-clonic seizures in mice were assessed with type I isobolographic analysis. Potential acute side effects for the mixture of PB, PHT and PGB along with total brain concentrations of the AEDs were determined to confirm pharmacodynamic nature of observed interaction., Results: The three-drug combination of PB, PHT and PGB (at the fixed-ratio of 1:1:1) exerted synergistic interaction (at P < 0.01) in the mouse model of tonic-clonic seizures. The combination of PB, PHT and PGB did not produce any side effects in experimental animals, when measuring long-term memory, muscular strength and motor coordination. The measurement of total brain concentrations of PB, PHT and PGB was conducted to confirm that none of the three AEDs significantly influenced total brain concentrations (pharmacokinetic profiles) of the other co-administered AEDs in mice., Conclusions: The synergistic pharmacodynamic interaction for the combination of PB, PHT and PGB observed in this preclinical study can be translated into clinical settings and this favorable AED combination is worthy of being recommended to some patients with refractory epilepsy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Reductions in the number and size of neurons in the medial prefrontal cortex (mPFC) have been documented in many post-mortem studies of depressed patients and animals exposed to stress. Here, we examined the effect of chronic unpredictable stress (CUS) and chronic mild stress (CMS) on specific populations of neurons in the rat mPFC. Antibodies directed against parvalbumin (PV), calbindin D-28K (CB) and active caspase-3 have been used to quantify the numerical density of PV-immunoreactive (PV-ir), CB-ir and active caspase-3-ir cells, and to measure the relative optical density of neuropil. CUS decreased the density of CB-ir neurons and the optical density of CB-ir neuropil. In turn, CMS increased the densities of both CB-ir neurons and neuropil, while PV-ir neurons and PV-ir neuropil were not changed. The frequency distribution of neuronal surface areas was significantly different only for PV-ir neurons, and only between the control and CUS group. CMS reduced the density of active caspase-3-ir cells while CUS did not. We concluded that the mPFC reveals a different pattern of changes in neurons containing calcium binding proteins and active caspase-3 immunoreactivity in response to CUS and CMS.

Preclinical data indicate the antidepressant activity of zinc and the involvement of the brain-derived neurotrophic factor (BDNF) in this mechanism. The present study investigates the effect of chronic (16 days) combined treatment with zinc (15 mg/kg zinc hydroaspartate) and imipramine (5 mg/kg) in chronic unpredictable stress (CUS) on the BDNF mRNA level in the rat brain. Moreover, serum zinc concentrations were also assessed. CUS induced a significant reduction in the BDNF mRNA level in the hippocampus by 21% but had no effect in the frontal cortex. Repeated treatment with zinc induced a significant increase in the BDNF mRNA level in the hippocampus in the unstressed animals by 12% and as in the chronically stressed animals by 14%, compared to the appropriate controls. Imipramine treatment did not affect this factor. However, combined treatment of zinc and imipramine induced a 12% elevation of the BDNF mRNA level in the stressed but not in the unstressed rats. CUS induced a 19% reduction in the serum zinc concentration, whereas combined treatment of zinc and imipramine reduced this concentration by 24% in the unstressed and increased it (by 20%) in the stressed animals. These results indicate that: 1) CUS induces a reduction in the BDNF gene expression with a concomitant diminution of serum zinc concentration and 2) the CUS-induced reduction in the BDNF gene expression is antagonized by chronic treatment with zinc.

In this study, the neuropathological changes induced by chronic unpredictable stress (CUS) and chronic mild stress (CMS) in calbindin D-28K (CB) and parvalbumin (PV) immunoreactive neurons in the rat hippocampus were demonstrated. We used immunohistochemical techniques to quantify the numerical density and morphological changes of PV immunoreactive and CB immunoreactive neurons in the dentate gyrus (DG) and the CA1 and CA3 regions of the hippocampus. We also assessed cell proliferation (Ki-67) and apoptotic processes (active caspase-3) in the DG. We found a significant decrease (16.6% for CUS and 13.3% for CMS) in the numerical density of granule cells (GC), alterations in the CB immunoreactive cells of the GC in the DG and an impairment of mossy fiber CB immunolabelling in the CA3. These changes were not accompanied by a decrease in Ki-67 labeling or the level of caspase-3 in the DG. These data indicate a stress-induced reduction of calcium binding neuron parameters, which may be related to the behavioral paradigms exhibited in these models.

Zinc is an endogenous modulator of neuronal activity and may play an important role in the pathogenesis of depression. Recent studies have shown that zinc exhibits antidepressant-like activity in some models of depression in rodents. Our previous studies have shown that the footshock-induced fighting behavior was reduced in the rats subjected to chronic unpredictable stress (CUS). This test is used as the new experimental model of depression. Various antidepressant drugs given repeatedly prevented this kind of behavioral depression. The aim of the present study was to evaluate the effect of prolonged treatment with zinc hydroaspartate and to examine if zinc supplementation could modulate the imipramine effect in CUS model of behavioral depression in rats. The experiments were carried out on male Wistar rats. Chronic stress (persisting for 16 days) was induced by the modified method described by Katz et al. Zinc hydroaspartate at the dose of 30 mg/kg/day or 15 mg/kg/day and imipramine at the dose of 5 mg/kg/day were administered once daily for 14 days. Imipramine was given (ip) 1 h before every stress session and zinc hydroaspartate (ip) l h before the antidepressant. The footshock-induced fighting behavior test was performed 48 h after the last session of the chronic stress. It was demonstrated that in chronically stressed rats the number of fighting attacks was significantly reduced (by about 75%). Zinc hydroaspartate at the dose of 30 mg/kg/day, given alone, prevented the deficit in fighting behavior in chronically stressed rats. Neither imipramine at the dose of 5 mg/kg/day nor zinc hydroaspartate (15 mg/kg/day) administered alone changed the intensity of fighting behavior in chronically stressed rats. However, when imipramine was given at the same dose in the rats pretreated with zinc hydroaspartate (15 mg/kg/day) the deficit of fighting behavior was not observed. The present results indicate that zinc similarly to antidepressants protects the rats against the CUS-induced behavioral depression. Moreover, our findings suggest that zinc supplementation could potentiate the antidepressant effect of imipramine.

Severe and prolonged stress but also long-term treatment with glucocorticoids (GCs) have been described to cause brain damage (especially hippocampal and striatal neurons) in humans as well as in animals. GCs potentiate stress or ischemia-induced accumulation of excitatory amino acids (EAA) in the extracellular space of the hippocampus. It was shown that EAA play a major role in various neurologic disorders with cognitive dysfunction. Many authors suggested the neuroprotective effect of N-methyl-D-aspartate (NMDA) glutamate receptor antagonists in some acute or chronic neurodegenerative diseases. On the other hand, many NMDAreceptor antagonists produce highly undesirable side-effects at the doses within their putative therapeutic range. The aim of the present study was to evaluate the behavioral effects (memory performance, motor coordination, lethality and body weight) of MK-801 or memantine (MEMAN, non-competitive NMDAreceptor antagonists) (at the doses of 25 and 50 microg/kg/day or 2.5 and 5.0 mg/kg/day, respectively) on neurotoxicity induced by dexamethasone (DEX) administered chronically at the doses of 40 or 80 mg/kg/day in mice. It was shown that prolonged treatment (for 10 days) with DEX at the dose of 80 mg/kg/day (but not at 40 mg/kg/day) significantly decreased the retention time in the memory task in mice and impaired the motor coordination in "chimney" test. Neither MK-801 nor MEMAN (at the both doses used) were able to counteract the behavioral impairment induced by DEX administration. Moreover, the potentiation of the body weight reduction and lethality induced by DEX were noted in mice co-treated with MK-801 or MEMAN. The above findings suggest that MK-801 or MEMAN at the doses used have no neuroprotective effect. On the contrary, both NMDA receptor antagonists potentiate the toxicity of DEX given chronically.

Glucocorticoids are expressed in the central nervous system. Radioligand binding studies have shown their presence in the neurons of the limbic system, a structure involved in mood control and subtle regulation of hypothalamic-pituitary-adrenal (HPA) axis. Structures of the limbic system are also rich in dopaminergic innervation. It has been hypothesized that glucocorticoids may be important in causing and perpetuating depression. Our previous study has demonstrated that dexamethasone decreases the locomotor activity of mice and counteracts the hyperactivity induced by agonists of dopamine receptors. The aim of the present study was to find the possible mechanism responsible for these behavioral effects of dexamethasone. So we sought to examine the influence of chronic dexamethasone treatment on selective radioligand binding to dopamine D(1) ([(3)H]SCH 23390) and D(2) ([(3)H]spiperone) receptors in the brain of mice. The male Albino Swiss mice received dexamethasone (4, 8 or 16 mg/kg/day) for 14 days. The striatum and limbic system structures were isolated and the binding procedure was performed 3.5 or 48 h after the last injection. It was shown that 3.5 h after the last dose of dexamethasone (4 mg/kg/day), specific D(2) receptor binding was statistically significantly increased (by 64%) in the limbic system. On the contrary, the tendency to the reduction of specific D(2) receptor binding was observed in the striatum. Dexamethasone treatment did not influence the specific binding to D(1) receptors in any structure of the brain.

Chronic unpredictable stress (CUS) is one of the behavioral models resembling in some respects (loss of normal aggresiveness) human depression. In the present study, consistent with the ethical principles for scientific experiments on animals, we have decided to modify the CUS procedure. In this new modified model named chronic unpredictable mild stress (CUMS), we have introduced mild stressor (14 h period of 45 degrees cage tilt) instead of one severe stressor (20 s exposure to electric footshock). The purpose of the present study was to determine whether this new procedure CUMS, similarly to CUS, affected the footshock-induced fighting behavior. We have also investigated the effect of antidepressant drugs with different pharmacological profiles (imipramine, mianserin, fluoxetine, moclobemide, tianeptine) and anxiolytic drug (oxazepam) on fighting behavior in rats submitted to CUMS. It was found that in rats subjected to CUMS procedure the number of fighting attacks was significantly reduced (by about 80%). Prolonged treatment (once daily, for 14 days) with imipramine (10 mg/kg/day), tianeptine (12.5 mg/kg/day), mianserin (10 mg/kg/day), moclobemide (50 mg/kg/day), fluoxetine (10 mg/kg/day), but not oxazepam (5 mg/kg/day) prevented the deficit in fighting behavior in rats subjected to CUMS. In conclusion, the results of the present study indicate that CUMS, similarly to CUS procedure, induced behavioral deficit in rats which was normalized by antidepressants with a different pharmacological profile.

The aim of the research was histological assessment of the influence of MK-801 (NMDA receptor antagonist) and dexamethasone on the kidney. The experiment was carried out on adult Albino-Swiss mouse males. MK-801 was administered in the dose of 0.3 mg/kg/24 h for 8 days, dexamethasone--in the toxic dose of 120 mg/kg/24 h. Kidney slices stained with hematoxylin and eosin and with PAS method were examined with light microscope. The performed experiments revealed that MK-801 causes morphological changes in the shape of slight narrowing of the urinary spaces in renal corpuscles and narrowing of the lumen of the proximal convoluted tubules and dexamethasone administered in toxic doses causes dilatation of these spaces with kidney's hyperemia. MK-801 intensifies morphological changes of the kidney induced by toxic doses of dexamethasone.

Several animal models of "depression" have been examined. One of them is chronic unpredictable stress (CUS)-induced deficit of fighting behavior in rats. In the present study, we compared the effects of two antidepressants (fluoxetine or fluvoxamine) and three anxiolytics (buspirone, lorazepam or oxazepam) on the electric footshock-induced fighting behavior in the pairs of male Wistar rats exposed to CUS procedure (16-day application of various unpredictable stressors). It was found that, in chronically stressed rats, the number of fighting attacks was significantly reduced (by about 70%). Prolonged (for 14 days) treatment of rats with fluoxetine or fluvoxamine (both at the dose of 10 mg/kg/day) counteracted the deficit of aggression induced by the chronic stress. On the contrary, the anxiolytics: lorazepam (0.5 mg/kg/day), oxazepam (5 mg/kg/day) or buspirone (0.2 mg/kg/day) administered for 14 days, did not modify the deficit of fighting induced by CUS procedure. It must be underlined that prolonged treatment with all used drugs did not change the intensity of fighting in normal (unstressed) rats. In conclusion, prolonged treatment with antidepressant drugs prevents the CUS-induced deficit of fighting behavior, whereas no beneficial effect of anxiolytic agents was found.

Chronic unpredictable stress (CUS) model of depression is one of the well validated animal models of depression. In this paper, we report the results of investigations into dopaminergic D-1 and serotonergic 5-HT-2A receptors in the brain of rats subjected to CUS procedure and treated chronically with imipramine. We have examined the dopaminergic D-1 ([3H-SCH 23390) in the limbic area and serotonergic 5-HT-2A ([3H-ketanserin) receptors in the cerebral cortex by a saturation radioligand binding method in rats subjected to CUS paradigm, imipramine, both CUS and imipramine and control animals. CUS procedure resulted in a significant 36% increase in the D-1 receptor density in the limbic system, which was attenuated by chronic imipramine treatment. Also a 21% increase in the density of 5-HT-2A receptors in the cerebral cortex induced by CUS was reduced by chronic imipramine treatment. The present data indicate that the increases in the density of brain D-1 and 5-HT-2A receptors of rats subjected to CUS, which are "normalized" by imipramine, might be involved in the pathophysiology of "animal depression" (and, thus, in pathophysiology of human depression) and in the mechanism of antidepressant therapy.

Studies showing the presence of glucocorticoids, and their binding sites in the central nervous system indicate that these hormones may affect central neurotransmission. Both, dopaminergic brain system and glucocorticoids are considered to be involved in certain psychopathological conditions in humans, including depression, addiction or schizophrenia. The present study aimed to investigate the influence of glucocorticoids on dopamine agonists-induced stereotyped behavior and locomotor hyperactivity in rats. The results of the experiment demonstrate that prior to administration of prednisolone (4, 6, 10 or 20 mg/kg) or dexamethasone (4 or 8 mg/kg) intensified and prolonged the stereotypy induced by apomorphine (1 mg/kg sc) or amphetamine (2 mg/kg ip). The effect of dexamethasone was more potent. Amphetamine (0.4 mg/kg)- or amantadine (50 mg/kg)-induced locomotor hyperactivity was significantly reduced in rats pretreated with dexamethasone at a dose of 8 mg/kg or 4 mg/kg. Our observations suggest that exogenous glucocorticoids may enhance the activity of the dopaminergic agonists in the striatum but reduce it in the mesolimbic system of rats.

In the present study we investigated the effect of two monoamine oxidase (MAO) inhibitors: moclobemide (selective, reversible inhibitor of MAO-type A) or selegiline (selective irreversible inhibitor of MAO-type B) on electric footshock-induced fighting behavior in normal (unstressed) and chronically stressed (14 various stressors over 16 days) rats. In rats exposed to chronic stress the number of fighting attacks was reduced by about 75%. Prolonged (once a day, for 14 days) treatment with moclobemide (50 mg/kg/day) or selegiline (2 mg/kg/day) counteracted the deficit in aggression induced by chronic stress. The findings of the present study demonstrate that the selective MAO inhibitors, moclobemide and selegiline, protect against "behavioral depression" induced by the chronic stress similarly to other classes of antidepressant drugs.

Chronic severe stress (CSS) and chronic mild stress (CMS) affect the properties of [3H]5,7-dichlorokynurenic acid (5,7-DCKA) binding to strychnine-insensitive glycine/NMDA sites in the rat cerebral cortex. Specifically, CSS decreases, while CMS increases, the potency of glycine to displace [3H]5,7-DCKA binding to glycine/NMDA sites. Moreover, in both models, a reduction of the specific [3H]5,7-DCKA binding was observed. The present results demonstrate the involvement of the cortical NMDA receptor complex in the animal models of depression.

Excitatory amino acids participate in the generation of seizure activity. Consequently, the effects of GYKI 52466 [1-(4-aminophenyl)-4-methoxy-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride], an antagonist of glutamate-mediated events, on the protective activity of conventional antiepileptic drugs against pentetrazol were studied. GYKI 52466 (up to 10 mg/kg, i.p.) did not affect the clonic phase of pentetrazol (injected s.c. at its CD97 of 90 mg/kg) convulsions. Only the antipentetrazol activity of valproate (100 mg/kg) was enhanced by GYKI 52466 (10 mg/kg)--the percentage of mice protected was significantly increased from 20 to 90%. The anticonvulsive activity of clonazepam (at 0.01), ethosuximide (at 50), and phenobarbital (at 2.5 mg/kg) was not modified by GYKI 52466 (up to 10 mg/kg). The combination of valproate (100 mg/kg) with GYKI 52466 (10 mg/kg) did not affect the performance of mice evaluated in the chimney test. However, this combination resulted in significant memory deficits, measured in the passive avoidance task. In no case did GYKI 52466 (10 mg/kg) affect either total or free plasma levels of antiepileptic drugs (as measured by immunofluorescence), so a pharmacokinetic interaction is not probable. Finally, the interaction of the non-NMDA receptor antagonist with antiepileptic drugs does not seem promising in the pentetrazol test, recognized as a model of human myoclonic epilepsy.

Chronic stress-induced behavioral disturbances have been used as experimental models of depression. One of them is the deficit of fighting behavior induced by 16-day application of various unpredictable stressors. In the present study we investigated the effect of beta-adrenoceptor antagonists (propranolol, pindolol, nadolol and acebutolol) on electric footshock-induced fighting behavior in chronically stressed (14 various stressors over 16 days) male Wistar rats. It was found that the number of fighting attacks was reduced by about 50-80% in the rats submitted to chronic stress. Prolonged, 14-day, but not acute, treatment with propranolol, pindolol or nadolol (but not acebutolol) counteracted the deficit of aggression induced by chronic stress. It is suggested that beta-adrenoceptor antagonists which penetrate the blood-brain barrier may prevent the behavioral changes induced by chronic stress.

Evidence exists that the 4-10 or 4-9 fragments of adrenocorticotropic hormone (ACTH) produce some behavioral effects in animals and in humans. The present study was designed to investigate whether ACTH 4-9 interferes with the effects of antidepressants: fluoxetine (FLU), fluvoxamine (FOX), selegiline (SEL) or dopamine agonists: piribedil (PRB) or quinpirol (QPR) in forced swimming test and in open field in rats. ACTH 4-9 was given in a single dose (25, 50 or 100 micrograms/kg) or for 7 days (50 micrograms/kg/day), alone or together with antidepressants or dopamine agonists. It was shown that ACTH 4-9 alone did not influence the behavior of rats. However, when given in a single dose, ACTH 4-9 potentiated the antiimmobility effect of all antidepressants and dopamine agonists. ACTH 4-9 given for 7 days, facilitated only the effect of selegiline. The results suggest a functional interaction of ACTH 4-9 with serotonergic and dopaminergic brain mechanisms of drugs action.

In the present study we investigated the effect of two non-competitive antagonists of N-methyl-D-aspartate (NMDA) subtype of glutamate receptor: memantine (2.5 mg/kg) or MK-801 (0.1 mg/kg) on electric footshock-induced fighting behavior in normal (unstressed) and chronically (14 various stressors over 16 days) stressed rats. In rats submitted to chronic stress the number of fighting attacks was reduced by about 60%. Prolonged treatment with memantine or MK-801 counteracted the deficit of aggression induced by chronic stress (the same effect was observed after a single dose of MK-801 but not of memantine). The findings of our study demonstrate, that the non-competitive NMDA antagonists can reduce the behavioral deficits produced by chronic stress, the effect of which is similar to those of antidepressant drugs.

The effect of dopamine (DA) agonists (apomorphine, quinpirole) and three antidepressants (selegiline, nomifensine, imipramine), given in a single dose, on the electric footshock-induced fighting behavior was investigated in the control and chronically stressed rats. It was found that 48 h after the last session of chronic stress (various stressors applied for 16 days) the number of shock-induced fighting attacks was reduced by 50-70% in comparison with the control value. The drugs (except for imipramine), given in a single dose, 48 h after the last session of chronic stress, increased the number of fighting attacks and restored it to the control or above the control value. The same drugs at doses used, changed neither the intensity of fighting in the control (unstressed) rats nor the exploratory activity in both groups of animals. It is concluded that the short-lasting dopaminergic activation facilitates the aggressiveness reduced by chronic stress and that this effect does not depend on the locomotor activity level.

The influence of some calcium channel antagonists (CaChaA): nifedipine (NIF), nimodipine (NIM), nitrendipine (NITR), cinnarizine (CIN), and flunarizine (FLU) on electric footshock-induced aggressive behavior was investigated in chronically stressed rats. It was found that chronic stress (various stressors over 16 days) reduced the number of fighting attacks (by about 50%) without changing the pain reactivity of rats. The CaChaA given in a single dose (5 mg/kg ip) did not influence the intensity of fighting. However, when the same drugs were administered chronically (5 mg/kg/day) for 14 days they counteracted the reduction of fighting attacks induced by chronic stress. Neither chronic stress nor CaChaA in doses used change the exploratory activity of rats in open field. The obtained results indicate the similarity of CaChaA effects to those of antidepressant drugs in the recovery of aggressiveness reduced by chronic stress.

The influence of dopamine (DA) receptor blockers (haloperidol, sulpiride) on electric footshock-induced fighting behavior and on the effect of antidepressants (imipramine, clomipramine, nomifensine, mianserine) was investigated in chronically stressed male Wistar rats. Exploratory activity in an open field was measured in the same groups of animals. The effect of chronic stress and antidepressants on DA utilization in the brain was also investigated. It was shown that 48 h after the last session of repeated stress (various unpredictable stressors over 16 days) the number of fighting attacks was significantly reduced. However in stressed rats treated chronically (for 14 days) with antidepressants the intensity of fighting was restored to control value. On the contrary, when the stressed rats, receiving antidepressants chronically, were pretreated with DA receptor blockers: haloperidol (0.5 mg/kg) or sulpiride (50 mg/kg) but also alpha 1-adrenergic receptor blocker - prazosin (3 mg/kg) the effect of antidepressants was abolished. Exploratory activity was not significantly reduced under influence of stress. Neither antidepressants nor sulpiride modified exploratory activity of stressed rats. Haloperidol and prazosin but not sulpiride decreased this activity of normal, stressed and antidepressant-treated rats. It is concluded that prolonged treatment with antidepressants counteracts the decrease in aggression induced by chronic stress and that DA mechanism participate in this effect of antidepressant drugs.

The effect of chronic stress (14 various unpredictable stressors over 16 days) on electric footshock-induced fighting behavior of pairs of male Wistar rats was studied. The influence of antidepressant drugs (imipramine, desmethylimipramine, nomifensine, clomipramine, mianserine and doxepine) administered chronically (1 h before the stressor) on the aggressive behavior was also investigated in control and in stressed rats. Moreover, the effect of chronic stress on noradrenaline (NA) utilization in the brain was estimated in control and in antidepressant-treated rats. It was demonstrated that, in rats submitted to repeated unpredictable stress, the fighting behavior was significantly reduced 48 and 72 h after the last stressor. NA utilization in the brain was decreased 72 h after the stress termination. Prolonged treatment with antidepressant drugs restored the intensity of fighting behavior in stressed rats to control value as well as normalized NA utilization in the brain. It is suggested that antidepressant drugs may counteract the affective aggression deficit induced by chronic stress.

Cobalt alloys produced in Poland and meant for orthopedic implants were morphologically and toxicologically evaluated. They were implanted subcutaneously in the para-osseous region of rats' heads. The results of the experimental tests strongly suggest the advisability of a clinical research project (study) on the examined cobalt alloys: Medpol-1 and Medpol-2.

A single electroconvulsive shock (ECS) has no influence on seizures induced by picrotoxin and bicuculline, although it decreases the level of GABA in the cortex. A repeated ECS (once daily for 7 days) does not change the level of GABA in the cortex, brain stem, and cerebellum, but depresses seizures induced by both compounds. It prolongs the time of their occurrence and decreases their intensity. This effect is stronger in the case of bicuculline. It manifests itself in the increase of the number of animals protected from seizures and decrease of their lethality. Baclofen does not change ECS action on seizures induced by picrotoxin and bicuculline whereas it enhances catalepsy caused by ECS. Bicuculline does not change the time-course of catalepsy. The obtained results suggest that repeated ECS reduces the seizures induced by GABA antagonists probably y increasing GABA-ergic transmission or/and by increasing dopaminergic and serotoninergic transmission which significantly modify the activity of GABA-ergic neurons.

Daily administration of insulin, 2 U/kg/day for 9 days, leads to a marked increase in the activity of central dopaminergic structures, reflected by an increase in the apomorphine or amphetamine-induced stereotypy and a decrease in fluphenazine-induced catalepsy. These changes are accompanied by a depression of cerebral dopamine and noradrenaline levels and a depression of noradrenaline utilization in the brain.

The effect of 10 mg/kg per day desipramine for 7 days on performance in the forced swimming test was studied in rats given various treatments aimed at reducing central noradrenergic transmission. 6-Hydroxydopamine-induced destruction of noradrenaline-containing neurons originating in the locus coeruleus or ascending in the ventral bundle had no effect on the anti-immobility activity of desipramine. Likewise, no changes in the effect of desipramine were seen with an intraperitoneal injection of DSP-4 (50 mg/kg) which destroyed brain noradrenergic neurons, particularly those of the dorsal bundle ascending to the forebrain. The results argue against a role of noradrenaline in the mechanism by which repeated treatment with desipramine reduces the immobility of rats in the forced swimming test.