Adenosine-angiotensin II interactions in pentylenetetrazol seizure threshold in mice.

The effects of adenosinergic and angiotensin IIergic agents and of their combinations on the seizure threshold in mice were determined by measuring the dose of timed-intravenous (tail vein) infused pentylenetetrazol (PTZ) required to elicit clonic seizures. All drugs were administered intracerebroventricularly (i.c.v.). Angiotensin II (ANG II), its peptide analogue sarmesin, the selective adenosine A1 receptor agonists N6-cyclopentyladenosine (CPA) and 2-chloroadenosine (2-ClAdo) significantly increased the PTZ seizure threshold. The selective AT1 receptor antagonist losartan blocked the anticonvulsant effect of ANG II, sarmesin and CPA. The selective AT2 receptor antagonist PD 123319 failed to block the effect of ANG II and sarmesin on the PTZ seizure threshold but reversed the threshold-increasing effect of CPA. The selective adenosine A1 receptor antagonist 8-(p-sulfophenyl)-theophylline (8-p-SPT) alleviated the threshold-increasing effect of CPA and ANG II. Concurrent injection of 2-ClAdo and ANG II as well as of 2-ClAdo and sarmesin, at doses which had no significant effect on the PTZ seizure threshold when given alone, acted synergistically, producing greater effect on the threshold. Taken together, the findings support the possibility of specific ANG II-adenosine A1 receptor interactions in the regulation of the PTZ seizure threshold.     

The comparative effects of propofol, thiopental, and diazepam, administered intravenously, on pentylenetetrazol seizure threshold in the rabbit.

The anticonvulsant effects of propofol, thiopental, and diazepam, administered intravenously, on pentylenetetrazol (PTZ) seizure threshold were studied and compared in the rabbit. The PTZ seizure threshold determined in various rabbit groups during the control phase of conducted experiments, was found to be in the range of 10.1 +/- 2.0 to 13.5 +/- 3.7 mg/kg. Intravenous administration of comparable doses of propofol, thiopental, and diazepam resulted in marked and significant increases in PTZ seizure threshold. At all administered doses (1.25-10.0 mg/kg), propofol was found to be more effective than thiopental in increasing the PTZ threshold dose. However, the anticonvulsant effects of diazepam were more marked than those of propofol, except at a dose of 10 mg/kg where both agents exhibited equipotent activities. These data demonstrate that propofol enjoys a considerable degree of anticonvulsant activity in the rabbit. This anticonvulsant action is greater than that of thiopental at doses ranging from 2.5 to 10 mg/kg and equipotent with diazepam at the 10 mg/kg dose.     

Effect of Withania somnifera Dunal root extract against pentylenetetrazol seizure threshold in mice: possible involvement of GABAergic system

Withania somnifera (ashwagandha) is a widely used herb in the Ayurvedic system of medicine. The objective of the present study was to elucidate the effect of W. somnifera root extract (Ws) alone or in combination with exogenous gamma-amino butyric acid (GABA), a GABA receptor agonist or with diazepam, a GABA receptor modulator against pentylenetetrazol (PTZ, iv) seizure threshold in mice. Minimal dose of PTZ (iv, mg/kg) needed to induce different phases (myoclonic jerks, generalized clonus and tonic extension) of convulsions were recorded as an index of seizure threshold. Ws (100 or 200 mg/kg, po) increased the PTZ seizure threshold for the onset of tonic extension phase whereas a lower dose (50 mg/kg, po) did not show any effect on the seizure threshold. Co-administration of a sub-effective dose of Ws (50 mg/kg, po) with a sub-protective dose of either GABA (25 mg/kg, ip) or diazepam (0.5 mg/kg, ip) increased the seizure threshold. The results suggested that the anticonvulsant effect of W. somnifera against PTZ seizure threshold paradigm involved the GABAAergic modulation.     

Age-dependent increase in the threshold for pentylenetetrazole induced maximal seizure in mice

The thresholds for inducing the maximal seizure by pentylenetetrazole (PTZ) were compared for BDF1 mice of both sexes with varying ages after intraperitoneal administration of various doses of PTZ. The minimal effective PTZ concentrations (MECs) in the brain for inducing the maximal seizure were significantly higher in 24-month or older mice than in 6-month-old animals of both sexes. Some mice of 30 months did not demonstrate the maximal seizure but died within the 15-min observation period, a phenomenon never observed in mice of 24 months or younger. The relationship between plasma and brain concentrations of PTZ changed little during aging. It was concluded that the brain becomes less sensitive to PTZ with age in regard to its convulsant activity, as was previously shown for electroshock by the authors. This observation, coupled with our earlier observations on anticonvulsants, appears to support the classical hypothesis that age has a dual effect on drug sensitivity i.e. a decrease for stimulants but an increase for sedative (or depressant) drugs.     

Effect of inferior olive lesion on seizure threshold in the rat

Cerebellar stimulation has been associated with anticonvulsant activity in several experimental seizure models. We examined the effect of destruction of cerebellar climbing fibers, by systemic administration of 3-acetylpyridine (3AP) or electrothermic lesion of the inferior olive, on seizures produced by various chemical convulsants in rats. We found that inferior olive lesioned rats had lower threshold to seizures induced by strychnine and brucine, both glycine antagonists. The dose response curve for strychnine seizure was shifted 2.5 times to the left in 3AP lesioned rats. No difference in seizure threshold was seen when picrotoxin, bicuculline or pentylenetetrazole PTZ) were used to produce seizures. Abnormal motor behavior (AMB) including myoclonus, backward movement and hyperextension, produced by all of the convulsants tested, was significantly aggravated in 3AP pretreated rats. The inferior olive-climbing fiber projection to the cerebellum appears to modulate seizures induced by inhibition of glycinergic neurotransmission.     

Gastric mucosal damage induced by arecoline seizure in rats

In an attempt to know the relation of seizure and gastric mucosal damage, we challenged arecoline (ACL) centrally to induce seizure and investigated gastric hemorrhagic injury in acid-irrigated stomachs of rats. The protective effects of several drugs also were evaluated. After deprivation of food for 24 h, rats were received laparotomy under diethylether-anesthesia. Both pylorus sphincters and carotid esophagus were ligated. The forestomach was equipped with a cannula for gastric irrigation. After recovery from anesthesia (approximately 1 h), the stomach was irrigated for 2 h with an acid solution containing 100 mM HCl and 54 mM NaCl or the same volume of normal saline. Intracerebroventricular (i.c.v.) ACL (0, 1, 3 or 10 mg/kg dissolved in 10 microl of CSF) was challenged to rats immediately after gastric irrigation. The seizure in rats was produced by ACL in a dose-related manner. The ulcerogenic parameters such as decrease of gastric mucosal glutathione levels and increase of histamine concentrations and lipid peroxide generations as well as the raise of luminal hemoglobin contents and exacerbated mucosal lesions were obtained depending on the doses of ACL challenged. These ulcerogenic parameters produced in ACL (10 mg/kg, i.c.v.) seizure rats were markedly ameliorated by gastric vagotomy or central anticholinergics. Intraperitoneal ketotifen, zinc sulfate, diphenhydramine or cimetidine also produced significant (p<0.05) inhibitions of these ulcerogenic parameters in ACL seizure rats. In conclusion, central ACL seizure may produce gastric oxidative stress and hemorrhagic lesions via vagal nervous activation and histamine release in acid-irrigated stomachs of rats.     

Effect of tryptophol on pentylenetetrazol and picrotoxin induced convulsion in mice.

The effect of treatment of mice with tryptophol (TOL), a neutral metabolite of tryptophan, on drug-induced convulsion was studied. TOL effectively suppressed both pentylenetetrazol and picrotoxin induced convulsion. Diphenylhydantoin (DPH), a potent inhibitor of brain aldehyde reductase, significantly reduced the anticonvulsant effect of TOL, however, TOL level in brain of DPH-treated mice was rather higher than that of control one. These results strongly suggest that the manifestation of the anticonvulsant effect of TOL requires the conversion of TOL to its active metabolite, indoleacetaldehyde.     

Cyclosporine lowers seizure threshold in an experimental model of electroshock-induced seizures in Munich-Wistar rats

We have developed a model of cyclosporin A (CsA) central nervous system toxicity in the Munich-Wistar rat in which CsA, 20 mg/kg/day i.p., produces significant EEG abnormalities and mortality. In the present study we used cohorts of Munich-Wistar rats to assess effects of CsA on the threshold for tonic-clonic electroshock-induced seizures. Rat cohorts were begun on cremephore, CsA-10 mg/kg/day, or CsA-20 mg/kg/day. On day 7 and day 14 of the dosing protocol, cohorts of animals were exposed to maximal electroshock (MES) using a minimal staircase method within each cohort. Multiple logistic regression models were used to determine differences between groups on the relative odds of producing a MES-induced seizure while controlling for other variables. Seizure threshold was significantly affected by shock amperage and body weight, but not by SUN, creatinine, bilirubin, sodium, potassium, weight loss or day the shock was delivered. The odds ratios of seizure induction in the CsA-treated groups versus placebo group were 1.91 for CsA-10 mg/kg/day and 3.63 for CsA 20-mg/kg/d, both statistically significant. These results suggest that cyclosporine lowers seizure threshold and probably increases susceptibility to seizures, the etiology of which may be multifactorial clinically.     

Electroshock raises pentylenetetrazol threshold: Possible role of inosine

A series of 15 single electroshocks administered through electrodes applied to the scalp of mice raised the threshold to pentylenetetrazol-induced seizures as determined by a tail vein infusion method. The same stimulus increased brain inosine and hypoxanthine. Phenytoin, which blocks the increase in inosine produced by this stimulus, reversed the elevation in threshold by electroshock. The effect of electroshock on threshold may be mediated by inosine.     

Effect of bacterial lypopolysaccharide on penicillin-induced seizure activity in rats

In experiments on Wistar rats, we found that, within an early period (2 to 4 h) after injection of bacterial lypopolysaccharide, LPS (0.1 mg/kg, i.p.), the latency of generalized seizures induced by injection of benzylpenicillin (sodium salt; 3.0 million IU/kg, i.p.) became significantly shorter, while the severity of seizure manifestations was higher than in the control group. Within this period, the power of oscillations of the delta and alpha-frequency ranges increased in the frontal cortex and hippocampal structures; fast ECoG components (beta and gamma rhythms) were suppressed, and the power of the theta activity decreased. In the hippocampal structures, these changes were more clearly pronounced, as compared with the neocortex. Within a later period of the action of LPS (12 to 18 h from the moment of injection), the latency of penicillin-induced seizures significantly exceeded the control value, and the severity of such seizures was lower. Under such conditions, we observed a smaller power of the synchronized activity of delta and alpha frequencies combined with intensification of the theta activity (most clearly pronounced in the hippocampal structures), and also an increase in the power of “desynchronized” rhythms (beta and gamma oscillations) in the cortex and hippocampus. Neirofiziologiya/Neurophysiology, Vol. 40, No. 3, pp. 236–241, May–June, 2008.     

A possible role for spinal noradrenaline in the mechanisms of 6-hydroxydopamine against pentylenetetrazol induced convulsions in rats

The threshold of the generalized clonic convulsions induced by intravenous infusion of pentylenetetrazol (PTZ) was significantly increased by the intraperitoneal administration of noradrenaline (NA) neurotoxin, 6-hydroxydopamine, which produced no changes in the levels of catecholamines in discrete areas of rat brain, but the effect was accompanied by spinal depletion of NA. Moreover, the anticonvulsant effects of phenobarbitone (PB) and diphenylhydantoin (DPH) against PTZ convulsions were also significantly increased in the animals pretreated with 6-OHDA. These results suggest that the observed elevation of PTZ convulsive threshold and the potentiation of anticonvulsant activity of PB and DPH in 6-OHDA treated rats were possibly mediated through spinal cord depletion of NA.     

Intensity threshold for 60-Hz magnetically induced behavioral changes in rats

Experiments were conducted to further investigate the effect of 60-Hz cyclotron-resonance exposures on rats performing on a multiple FR-DRL schedule. The previously reported temporary loss of DRL baseline response, when measured as a function of A.C. magnetic intensity, was found to have a threshold. Utilizing the component of A.C. magnetic intensity parallel to the D.C. field, we report this threshold as (0.27 +/- 0.10) x 10(-4) Trms.     

Endorphin mediated increase in pain threshold induced by long-lasting exercise in rats

Rats were trained to run spontaneously, without stress, in running wheels. The running activity increased gradually and could reach a plateau of 7 km/night after 3–4 weeks. During the first hour of running in the dark phase the squeak threshold increased significantly and remained high in the morning. The degree of increased threshold was correlated to the amount of running activity. The squeak threshold declined during the following 6 hours of inactivity. A rapid decrease in threshold occurred after naloxone (1–2 mg/kg i.p.). It is suggested that long-lasting muscle exercise (e.g. jogging), acupuncture, and low frequency electrical stimulation of afferent nerve fibres produce discharges in muscle afferents which influence central endorphin mechanics giving analgetic effects.     

Increase of seizure threshold and resistance to stress in rats after immunization against fragment of diazepam-binding inhibitor]

White rats were immunized against fragment of diazepam-binding inhibitor octadecaneuropeptide (ODN) with conjugate ODN bovine serum albumin. This rats have reduced reactions of fear and anxiety in stress model of "open field" and in conflict Vogel test; their pain sensitivity ("tail flick" test) was lowered. The number and intensity of generalized seizure reactions after injection of pentylenetetrazole were decreased. The results show that active immunization to endogenous ODN has stress--protective and anti-seizure effects.     

The pentylenetetrazol model of anxiety detects withdrawal from diazepam in rats

This experiment tested whether benzodiazepine withdrawal could be detected in an animal model of anxiety. Rats were trained in operant chambers using food reward to press one lever after pentylenetetrazol (PTZ), 20 mg/kg, injection and the other lever after saline injection. Previously, the PTZ cue has been shown to be simulated by anxiogenic drugs and blocked by anxiolytic drugs. After rats reliably performed this discrimination, they were injected with diazepam, 20 mg/kg, from 1 to 4 times a day for six days. For one group of subjects, on the third, fourth and sixth days, they were also injected with 40 mg/kg of RO 15-1788, a benzodiazepine receptor antagonist, and tested for lever selection: 50–80% of the subjects selected the PTZ lever; these results are in contrast to those obtained prior to chronic diazepam treatment in which RO 15-1788 did not generalize to PTZ. A second group of subjects was also injected for six days with diazepam and then allowed to withdraw spontaneously for eight days: PTZ lever selection over this period varied from 20 to 60% of rats. These data indicate that animals trained to discriminate a PTZ cue: 1) generalize the benzodiazepine withdrawal state to the PTZ cue, and 2) discriminate the withdrawal state for long periods of time, agreeing with clinical observations of long-lasting anxiety signs during benzodiazepine withdrawal.     

Anaerobic threshold in rats

• 1.1. The aim of this study was to find out whether the anaerobic threshold (AT) can be estimated in rats running at increasing speed and if so what is the reproducibility of the measurements.
• 2.2. Lactate (LA) concentrations in blood taken from 11 rats were determined during a discontinued, multistage treadmill exercise test repeated four times in each animal.
• 3.3. It was found that blood LA changes vs speed have an exponential pattern with a distinct, rapid rise at the speed above 25 m/min which corresponds to blood LA of approx. 4 mmol/1.
• 4.4. The variation coefficient of the speed at which AT occurred in individual animals ranged between 10 and 20%.
• 5.5. These results offer a potential application of AT determination in the animal studies concerning mechanisms controlling exercise metabolism.

     

Effect of paleocerebellar cortex electrical stimulation on generalized penicillin-induced seizure activity in rats

It was shown that low-frequency electrical stimulation (ES) (10-12 Hz, 0.5 ms) of paleocerebellar cortex (nodulus, uvula) is followed by activation of spike discharges which were induced via i.p. administration of sodium benzilpenicillin salt to alert Wistar rats (300,000 IU/kg). The facilitation of ictal discharges generation was also seen in the course of such an ES. High-frequency (100-300 Hz, 0.25 ms) ES of the same structure was followed by suppression of spike discharges and prevented the ictal discharges precipitation. Antiseizure action was obvious under condition of relatively low level of epileptic activity generation. In the course of such ES the decreasing frequency and amplitude of spike discharges were noted during interstimuli periods. Besides, the life-span of seizure activity was shortened as well. The repeated paleocerebellar ES made after electrocoagulation of irritated tissue did not cause modulations of seizure activity.     

Age related increased threshold for electroshock seizure in BDF1 mice

The thresholds for inducing the minimal and maximal electroshock seizures were examined in relation to age in BDF1 mice of both sexes. The 50 percent effective intensities for the maximal electroshock seizure (tonic hindlimb extensor component) were lowest in the youngest age groups (6-month-old) for both male (10.68 mA) and female (9.18 mA) animals. The threshold increased with age and became significantly higher at 24 months (14.00 mA, 12.70 mA for male and female mice respectively). There was also a further increase in threshold at 30 months for both sexes. Similarly, the threshold for inducing the minimal seizure also increased with age but the differences in mean threshold levels between the youngest and oldest groups were much smaller in comparison to the maximal seizure. It was concluded that the threshold for inducing electroshock seizures significantly increases with age in mice of both sexes.