Ethosuximide affects both pentylenetetrazole- and kainate-induced clonic seizures but differentiates between tonic-clonic seizures

Young (25-day-old) and adult (90-day-old) rats pretreated with ethosuximide (62.5 or 125 mg/kg i.p.) were injected with either s.c. pentylenetetrazole (100 mg/kg) or i.p. kainate (10 or 14 mg/kg). The incidences and latencies of minor (clonic) and major (tonic-clonic) seizures were registered. Ethosuximide (125 mg/kg) completely blocked clonic seizures induced by the lower dose of kainate, and slightly suppressed or delayed those induced by the higher dose of kainate or pentylenetetrazole in both age groups. The effect of ethosuximide on major kainate-induced seizures (elicited in young rats only) was insignificant (ethosuximide only partially decreased the incidence of major seizures), whereas ethosuximide abolished major pentylenetetrazole-induced seizures in both age groups. Ethosuximide also failed to affect the latencies of kainate-induced automatisms (e.g., scratching, wet dog shakes). Similarities between kainate- and pentylenetetrazole-induced clonic seizures, as well as a similar action of ethosuximide on both, suggest a common generator for the pattern of clonic seizures.     

Effects of zopiclone on blood glucose level, serum lipid concentration and clot lysis time in normoglycemic and normolipidemic rats

In normoglycemic and normolipidemic rats the i.p. injection of zopiclone induced an acceleration of fibrinolysis in a dose-dependent bell shaped manner and various changes of the blood glucose level. Total lipids, total cholesterol and triglyceride serum levels remained unaffected by doses of 1.25, 2.5 and 15.0 mg/kg, with the exception of the medium dose (5.0 mg/kg) and the next dose (10.0 mg/kg) which lowered them very significantly.     

Influence of ethosuximide and dipropylacetate on metrazol-induced electrocorticographic changes during ontogenesis in rats

Influence of ethosuximide (ESI, 125 mg/kg i.p.) and dipropylacetate (DPA, 300 mg/kg i.p.) pretreatment on electrocorticographic changes induced by pentamethylenetetrazole (PTZ, 20 mg/kg dose every 5 min) was studied in rats aged 7, 12, 18 and 90 days. PTZ alone induced isolated spikes and/or sharp waves as the first sign of its action in all age groups except in adult animals where rhythmic theta activity was elicited. The antiepileptic effect of DPA was observed in 12- and 18-day-old rats, ESI specifically inhibited rhythmic activity in adult rats. ECoG seizures induced by high doses of PTZ were inhibited by DPA in all age groups, ESI tended to be effective in adult rats only. DPA did not change the pattern of ECoG seizures, whereas ESI led to replacement of the spike-and-wave rhythm by serrated waves in adult animals. The low ability of immature brain to generalize ictal activity was further diminished by ESI.     

Does vigabatrin possess an anticonvulsant action against pentylenetetrazol-induced seizures in developing rats?

Anticonvulsant action of vigabatrin (300, 600, 900 and/or 1200 mg/kg i.p.), an inhibitor of GABA-transaminase, was studied in a model of motor sezures elicited by pentylenetetrazol. Five age groups of rats (7, 12, 18, 25 and 90 days old) received a s.c. injection of pentylenetetrazol 4, 6 and/or 24 hours after vigabatrin administration. The incidence of minimal, predominantly clonic seizures was not changed in any age group, but their latencies were prolonged in 18- and 25-day-old rats. Generalized tonic-clonic seizures were influenced in a more complex manner. Incidence of these seizures was decreased in 7-day-old rat pups 24 hours after vigabatrin administration. Higher doses of vigabatrin exhibited a similar effect in adult rats at all intervals studied. Specific suppression or at least restriction of the tonic phase was observed in all groups of immature rats, the effect was more marked 24 hours after vigabatrin than at shorter intervals. The anticonvulsant action of vigabatrin, which could be demonstrated mainly against generalized tonic-clonic seizures, varies markedly during development.     

Influence of valproate and carbamazepine on symmetrical cortical penicillin foci in the rat

Two epileptogenic foci were formed in homotopic areas of sensorimotor cortices of both hemispheres by application of penicillin. Both valproate (200 and/or 400 mg/kg i.p.) and carbamazepine (50 and/or 100 mg/kg i.p.) did not significantly alter the synchronization of interictal focal discharges. The incidence of ictal phases was suppressed by both drugs in a dose-dependent manner--higher doses (valproate--400 mg/kg; carbamazepine--100 mg/kg i.p.) fully blocked the seizures. Both drugs did not suppress the projection of focal discharges into the opposite hemisphere but were efficacious against secondary generalization.     

MIF-1 potentiates the action of tricyclic antidepressants in an animal model of depression.

In the present paper, the effect of simultaneous treatment of rats with low doses of MIF-1 and tricyclic antidepressants on rat behavior in the forced swim test was studied. It was found that MIF-1 stimulated in a dose-dependent manner "active" behavior of animals in this paradigm. The effect of MIF-1 appeared to be independent of changes in rats' locomotion in the open field test. The combined treatment of rats with MIF-1 (0.01 mg/kg IP) and amitriptyline (5 mg/kg IP) or desipramine (1.25 mg/kg) IP) significantly stimulated active behavior in the forced swim test above the level obtained with each of the drugs given separately. The present data suggest the potential clinical efficacy of a combined therapy of depressive patients with MIF-1 and small doses of tricyclic antidepressants.     

Evidence for sedative effects of low doses of morphine in mice involving receptors insensitive to naloxone

Low doses of morphine (0.30–2.5 mg/kg) decrease in a dose-dependent manner spontaneous climbing behaviour in mice. This effect is not modified by administration of naloxone at doses up to 1.25 mg/kg. These morphine doses do not modify the locomotor activity but, when they are associated with naloxone (0.5 mg/kg), an obvious inhibition occurs. In rats, a hyperactivity follows the akinesia produced by a morphine administration (10 mg/kg). This hyperactivity is changed into a significant hypokinesia when the animals are treated with naloxone (0.05 mg/kg). These results might reveal a dual effect of low doses of morphine, the excitatory effect of morphine being antagonized by naloxone whereas no action on the sedative effect is observed.     

Antiepileptic effects of ghrelin on pentylenetetrazole-induced seizures in rats

It is well known that neuropeptide Y (NPY) and gamma-aminobutyric acid (GABA) exert antiepileptic effects in animal models. It has recently been shown that ghrelin neurons increase the activities of GABA and NPY in the brain. Therefore it can be said that ghrelin is an antiepileptic agent. In this study we aimed to investigate the antiepileptic effect of ghrelin in an acute experimental epilepsy model in pentylenetetrazole (PTZ) injected rats. Adult male Wistar albino rats were divided into a control group and four experimental groups with seven rats in each group. In order to generate epileptic seizures, PTZ (50mg/kg) was injected intraperitoneally. The experimental groups received intraperitoneal injections of ghrelin at doses of 20, 40, 60 and 80microg/kg 30min before PTZ injection. After PTZ injection, the latencies were separated into three components: first myoclonic jerk, generalized clonic seizures and tonic generalized extension. The injection of 50mg/kg PTZ-induced epileptic seizures in the control group. The onset times of the three characteristic behavioral changes were significantly delayed and the duration of tonic generalized extension was diminished by dose-dependent ghrelin administration. Our results demonstrated that ghrelin suppresses the onset time of PTZ-induced seizures. In the light of our current knowledge, it seems that ghrelin may be considered as an antiepileptic drug.     

Modulation of benzodiazepine by lysine and pipecolic acid on pentylenetetrazol-induced seizures

L-lysine, an essential amino acid for man and animals, and its metabolite pipecolic acid (PA) have been studied for their effects on pentylenetetrazol (PTZ)-induced seizures in mice. L-Lysine or L-PA i.p. significantly increased clonic and tonic latencies in a dose-dependent manner against 90 mg/kg PTZ-induced seizures. L-Lysine but not L-PA enhanced the anticonvulsant effect of diazepam (DZ) (0.2 mg/kg). L-PA (0.1 mmol/kg) i.c.v. showed a slight decrease in clonic latency; it did not enhance the antiseizure activity of DZ; it caused seizures at 0.6 mmol/kg. D-PA (0.1 mmol/kg) i.c.v. displayed an opposite effect compared to its L-isomer. The anticonvulsant effect of L-lysine in terms of increase in seizure latency and survival was even more amplified when tested with a submaximal PTZ concentration (65 mg/kg). L-Lysine showed an enhancement of specific 3H-flunitrazepam (FZ) binding to mouse brain membranes both in vitro and in vivo. The possibility of L-lysine acting as a modulator for the GABA/benzodiazepine receptors was demonstrated. Since L-PA showed enhancement of 3H-FZ binding only in vitro but not in vivo, the anticonvulsant effect of L-PA may not be linked to the GABA/benzodiazepine receptor.     

Antipentylenetetrazol action of clobazam in developing rats

Clobazam (0.5 to 7.5 mg/kg i.p.) was tested against motor seizures elicited by pentylenetetrazol in rats 7, 12, 18, 25 and 90 days old. Minimal, predominantly clonic seizures with preserved righting ability were reliably induced by pentylenetetrazol and suppressed by clobazam in rats aged 18 days or more. The incidence of minimal seizures after clobazam pretreatment was not increased in 7- and 12-day-old rat pups. Generalized tonic-clonic seizures were markedly suppressed by clobazam in all age groups. In 18-day-old and older animals clobazam doses suppressing generalized seizures were always lower than those necessary for exerting an effect on minimal seizures. The differences in clobazam action appearing at various levels of maturation are only quantitative.     

Action of two neuroactive steroids against motor seizures induced by pentetrazol in rats during ontogeny

The anticonvulsant action of two neuroactive steroids, 3alpha-hydroxy-5beta-pregnan-20-one (pregnanolone) and triethylammonium 3 alpha-hydroxy-20-oxo-5 alpha-pregnan-21-yl hydrogensuccinate (THDOC-conjugate), was tested against motor seizures induced by pentetrazol in immature rats. Five age groups (7, 12, 18 and 25 days old and adult rats) were pretreated with the steroids in doses from 2.5 to 40 mg/kg i.p. Twenty minutes later pentetrazol (100 mg/kg s.c.) was administered. Minimal seizures (clonic seizures of head and forelimb muscles with preserved righting ability) could be induced in the three older age groups. They were suppressed by pregnanolone in all these tested groups (this effect was best expressed in 18-day-old rats and decreased with age), whereas significant changes in THDOC-conjugate-pretreated animals appeared only in 18-day-old rats. Generalized tonic-clonic seizures were suppressed by both neuroactive steroids in all age groups, this effect being more marked with pregnanolone and again decreased with age. The 7- and 12-day-old rats exhibited higher sensitivity of the tonic phase so that generalized clonic seizures were observed. Duration of the effect was studied in 12- and 25-day-old animals; it was substantially shorter in the older rats than in 12-day-old animals. Both drugs exhibited an anticonvulsant action in developing rats but, unfortunately, their effect was only shortlasting.     

Anti-metrazol action of R 57720 during postnatal development in rats

The effects of an experimental antiepileptic drug R 57720 (Janssen Pharmaceutica) on metrazol-induced seizures were studied in rats aged 7, 12, 18, 25 and 90 days. R 57720 exhibited a marked dose-dependent anticonvulsant effect against major, generalized tonic-clonic seizures in all the age groups studied. Similar action on minimal metrazol seizures (mMS) was present in rats aged 18 days and more. In the two youngest groups where metrazol did not induce mMS under control conditions, the combination of the 5- and 10-mg/kg doses of R 57720 and metrazol led to the appearance of mMS, whereas mMS failed to appear after the highest dose of R 57720 used (20 mg/kg).     

Monoamine Oxidase-Inhibiting Properties of SR 95191, a New Pyridazine Derivative, in the Rat: Evidence for Selective and Reversible Inhibition of Monoamine Oxidase Type A In Vivo but Not In Vitro

In rodents, SR 95191 [3-(2-morpholinoethylamino)-4-cyano-6-phenylpyridazine] has been shown to be active in animal models of depression. The profile of activity of SR 95191 suggests that the compound is a selective and short-acting type A monoamine oxidase (MAO) inhibitor (MAOI) in vivo. In the present study, the interaction of SR 95191 with MAO-A and MAO-B activity was further examined in vivo and in vitro. In brain, liver, and duodenum of pretreated rats, SR 95191 selectively inhibited MAO-A (ED50 = 3-5 mg/kg, p.o.), whereas MAO-B was only weakly inhibited for doses as high as 300 mg/kg, p.o. In vivo, SR 95191 (1-100 mg/kg, p.o.) antagonized, in a dose-dependent fashion, the irreversible inhibition of brain and liver MAO-A induced by phenelzine. Finally, dopamine and 5-hydroxytryptamine depleted from their striatal stores by tetrabenazine were able to displace SR 95191 from the active site of MAO-A. However, ex vivo, kinetic studies showed that the inhibitory effect of SR 95191 (1-10 mg/kg) towards MAO-A was noncompetitive and was unchanged after dilution or dialysis. In vitro, the inhibition of brain MAO-A, but not MAO-B, by SR 95191 was time dependent, with a 19-fold decrease in the IC50 values being observed over a 30-min incubation period (140 to 7.5 microM). At this time, the SR 95191-induced inhibition of MAO-A was not removed by repeated washings. When the reaction was started by adding the homogenate without prior preincubation with SR 95191, the inhibition of brain MAO-A was fully competitive (Ki = 68 microM).(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of ontogenetic development on the anticonvulsant activity of midazolam.

The anticonvulsant effects and duration of protective action of midazolam against Metrazol induced seizures were studied in 528 rats aged 7,12,18,25 and 90 days. The doses of 0.025, 0.05, 0.25, 0.5 and 1.0 mg/kg were administered immediately before Metrazol (100 mg/kg in all but 18-day-old animals where 90 mg/kg were given) for detection of antimetrazol activity at all age groups. The doses of 0.05, 0.25, and/or 0.5 mg/kg were used to study the time course of the protective action of midazolam. Each experimental group consisted of eight animals. Dose-dependent antimetrazol effects of midazolam till now described only in adult animals were demonstrated at all developmental stages studied. There were no qualitative differences in these effects among age groups studied. Midazolam action was better expressed against major Metrazol seizures than against minimal Metrazol seizures. Duration of the protective action depended on the dose tested at all developmental stages, as a rule, lasted longer in young animals than in adult rats. Only quantitative changes of action were found.     

Carbetapentane attenuates kainate-induced seizures via sigma-1 receptor modulation

We examined the effects of a non-opioid antitussive, carbetapentane (CB) on kainic acid (KA)-induced neurotoxicity in rats. KA administration (10 mg/kg, i.p.) produced robust behavioral convulsions lasting 4 to 5 h. CB (12.5 and 25 mg/kg. i.p.) pretreatment consistently and in a dose-dependent manner reduced the KA-induced seizures, mortality, and marked loss of cells in regions CA1 and CA3 of the hippocampus. Consistently, CB pretreatment also significantly attenuated the KA-induced increase in Fos-related antigen immunoreactivity in the hippocampus. In contrast, pretreatment with the sigma-1 receptor antagonist BD1047 (1 and 2 mg/kg, i.p.) blocked, in a dose-related manner, the neuroprotection afforded by CB. These results suggest that CB provides neuroprotection against KA insult via sigma-1 receptor modulation.     

Involvement of GABAergic and glutamatergic systems in the anticonvulsant activity of 3-alkynyl selenophene in 21?day-old rats

In this study, we investigated the role of GABAergic and glutamatergic systems in the anticonvulsant action of 3-alkynyl selenophene (3-ASP) in a pilocarpine (PC) model of seizures. To this purpose, 21 day-old rats were administered with an anticonvulsant dose of 3-ASP (50 mg/kg, per oral, p.o.), and [(3)H]γ-aminobutyric acid (GABA) and [(3)H]glutamate uptakes were carried out in slices of cerebral cortex and hippocampus. [(3)H]GABA uptake was decreased in cerebral cortex (64%) and hippocampus (58%) slices of 21 day-old rats treated with 3-ASP. In contrast, no alteration was observed in [(3)H]glutamate uptake in cerebral cortex and hippocampus slices of 21 day-old rats that received 3-ASP. Considering the drugs that increase synaptic GABA levels, by inhibiting its uptake or catabolism, are effective anticonvulsants, we further investigated the possible interaction between sub-effective doses of 3-ASP and GABA uptake or GABA transaminase (GABA-T) inhibitors in PC-induced seizures in 21 day-old rats. For this end, sub-effective doses of 3-ASP (10 mg/kg, p.o.) and DL-2,4-diamino-n-butyric acid hydrochloride (DABA, an inhibitor of GABA uptake--2 mg/kg, intraperitoneally; i.p.) or aminooxyacetic acid hemihydrochloride (AOAA; a GABA-T inhibitor--10 mg/kg, i.p.) were co-administrated to 21 day-old rats before PC (400 mg/kg; i.p.) treatment, and the appearance of seizures was recorded. Results demonstrated that treatment with AOAA and 3-ASP or DABA and 3-ASP significantly abolished the number of convulsing animals induced by PC. The present study indicates that 3-ASP reduced [(3)H]GABA uptake, suggesting that its anticonvulsant action is related to an increase in inhibitory tonus.     

Cardiovascular effects of delta 9- and delta 9(11)-tetrahydrocannabinol and their interaction with epinephrine

The administration of delta-9-tetrahydrocannabinol (delta 9-THC, 0.078-5.0 mg/kg, i.v.) to rats anesthetized with pentobarbital caused as much as a 50% decrease in mean arterial blood pressure, heart rate and respiratory rate in a dose-dependent manner. Delta-9(11)-tetrahydrocannabinol (delta 9(11)-THC) was approximately 8-fold less potent than delta 9-THC in its hypotensive effect and had smaller effects on heart and respiratory rates that were not dose-related at doses below 5 mg/kg. Alternate injections of epinephrine (2 micrograms/kg) with vehicle and increasing cannabinoid doses (1.25-5.0 mg/kg) indicated a potentiation of both the duration of the pressor effect and the magnitude of the reflex bradycardic effect of epinephrine by both delta 9- and delta 9(11)-THC. Epinephrine also produced arrhythmias in rats receiving cannabinoids, but not in rats receiving alternate injections of vehicle. It is concluded that both cannabinoids have adverse effects on the cardiovascular system and adverse interactions with epinephrine in rats anesthetized with pentobarbital.     

Effects of the cannabinoid receptor agonist CP 55,940 and the cannabinoid receptor antagonist SR 141716 on intracranial self-stimulation in Lewis rats.

Lewis rats were trained to self-stimulate the medial forebrain bundle (MFB) using a rate-frequency paradigm. They were then tested for the effects of the cannabinoid receptor agonist CP 55,940, the selective cannabinoid receptor antagonist SR 141716 and the dopamine D1 receptor antagonist SCH 23390. CP 55,940 (0, 10, 25 and 50 microg/kg i.p.) had no effect on MFB self-stimulation behaviour as assessed by the M50, the stimulation frequency at which half-maximal response rates were obtained. With SR 141716, only a very high dose (20 mg/kg i.p.) caused a significant inhibition of the rewarding efficacy of the stimulation. This was seen as an increase in the M50. All other doses of SR 141716 (0, 1, 3, 10 mg/kg i.p.) were ineffective in modulating the M50. By comparison, a relatively low dose (0.06 mg/kg i.p.) of SCH 23390 caused a large increase in M50. These results indicate a relatively modest influence, if any at all, of exogenous or endogenous cannabinoids on reward-relevant neurotransmission.     

The cardioprotective effect of different doses of vasopressin (AVP) against ischemia-reperfusion injuries in the anesthetized rat heart

The aim of the present study was to investigate the protective effect of various doses of exogenous vasopressin (AVP) against ischemia–reperfusion injury in anesthetized rat heart. Anesthetized rats were randomly divided into seven groups (n = 4–13) and all of them subjected to prolonged 30 min regional ischemia and 120 min reperfusion. Group I served as saline control with ischemia, in treatment groups II, III, IV and V, respectively different doses of AVP (0.015, 0.03, 0.06 and 1.2 μg/rat) were infused within 10 min prior to ischemia, in group VI, an AVP-selective V1 receptor antagonist (SR49059, 1 mg/kg, i.v.) was administrated prior to effective dose of AVP injection and in group VII, SR49059 (1 mg/kg, i.v.) was only administrated prior to ischemia. Various doses of AVP significantly prevented the decrease in heart rate (HR) at the end of reperfusion compared to their baseline and decreased infarct size, biochemical parameters [LDH (lactate dehydrogenase), CK-MB (creatine kinase-MB) and MDA (malondialdehyde) plasma levels], severity and incidence of ventricular arrhythmia, episodes and duration of ventricular tachycardia (VT) as compared to control group. Blockade of V1 receptors by SR49059 attenuated the cardioprotective effect of AVP on ventricular arrhythmias and biochemical parameters, but partially returned infarct size to control. AVP 0.03 μg/rat was known as effective dose. Our results showed that AVP owns a cardioprotective effect probably via V1 receptors on cardiac myocyte against ischemia/reperfusion injury in rat heart in vivo.