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The influence of electroshock on adrenoceptor function in rat brain cerebral cortex: selectivity for the alpha-adrenoceptor site.

The present study was undertaken to examine the effect of electroshock on adrenoceptor-mediated cAMP and inositol phosphate accumulation in rat brain cerebral cortical slices. Under the conditions of these experiments, isoproterenol-induced cAMP accumulation was unaltered by electroshock, although there was a significant reduction in the norepinephrine- and isoproterenol + 6-fluoronorepinephrine-stimulated responses. No change in alpha-adrenoceptor-mediated inositol phosphate accumulation was noted. The results indicate that electroshock selectively modifies an alpha-adrenoceptor system in brain that differs from that associated with inositol phosphate accumulation.

Animals↗

Modification of electroshock and pentylenetetrazol seizure patterns in rats after precollicular transections.

Rats with precollicular transections leaving the brain stem intact were subjected to electroshock or pentylenetetrazol-induced convulsions. Animals with transections failed to display the face and forelimb clonus (with or without rearing) typically seen in sham-operated rats subjected to pentylenetetrazol- or minimal electroshock-induced convulsions elicited with corneal electrodes. Moreover, rats with transections exhibited all other components of pentylenetetrazol- and electroshock-induced seizures. These findings support the hypothesis that tonic and some types of clonic convulsions can occur independently of seizure discharge in forebrain structures, whereas clonus restricted to the face and forelimbs depends on seizure discharge emanating from structures within the forebrain for expression.

Animals↗

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 may be electroshock. The effect of electroshock on threshold may be mediated by inosine.

Animals↗

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.

Age Factors↗

Variation in threshold and pattern of electroshock-induced seizures in rats depending on site of stimulation.

Although most laboratories employ transcorneal stimulation as a means of producing electroshock seizures, transauricular stimulation is also used by many investigators. The present study shows that seizures produced with transcorneal electroshock differ from those produced by transauricular electroshock in several ways: transauricular stimulation is more effective at eliciting tonic convulsions; the threshold for clonus is lower when transcorneal electrodes are used; and the face and forelimb clonus produced by transcorneal stimulation cannot be produced with transauricular stimulation at any current. The present findings are consistent with the hypothesis that tonic seizures are more easily triggered with transauricular stimulation because they originate in the brainstem and because this brain region is preferentially activated when ear-clip electrodes are used.

Animals↗

Anticonvulsant and antiepileptogenic actions of MK-801 in the kindling and electroshock models.

The actions of MK-801, a noncompetitive antagonist at the N-methyl-d-aspartate subtype of excitatory amino acid receptor, were investigated on the development of kindling and on seizures in the electroshock and kindling models. The drug MK-801 potently and effectively suppressed the tonic hindlimb extension component of electroshock-induced seizures; it also suppressed both the electrophysiological and behavioral manifestations of the development of kindling. In contrast to its effects on electroshock-induced seizures and the development of kindling, MK-801 only partly reduced the duration of seizures in fully kindled animals and did not elevate the threshold for afterdischarge despite the use of a large dose, associated with profound untoward behavioral effects. Together with previous findings, these results support the idea that noncompetitive blockade of NMDA receptors markedly inhibits the development of kindling. The diminished effectiveness of MK-801 against kindled seizures suggests that MK-801 will not be a clinically-useful anticonvulsant against complex partial seizures.

Amygdala↗

Antiparkinsonian drugs memantine and trihexyphenidyl potentiate the anticonvulsant activity of valproate against maximal electroshock-induced seizures.

Memantine increased the threshold for electroconvulsions, when administered at 1.0-6.0 mg/kg (i.p.) and given in subthreshold doses of 0.0156, 0.0625, 0.125 and 0.5 mg/kg (i.p.) potentiated the protective efficacy of valproate, against maximal electroshock (50 mA)-induced seizures in mice, lowering the ED50 from 235 to 197, 172, 164 and 130 mg/kg, respectively. Trihexyphenidyl, applied in doses of 30 and 50 mg/kg (i.p.), did not influence the electroconvulsive threshold per se but when combined with valproate, strongly enhanced its anticonvulsant activity against maximal electroshock-induced seizures lowering the ED50 from 206 to 103 and 46 mg/kg, respectively. The chimney test and retention testing in mice revealed that administration of memantine at 0.5 mg/kg (i.p.) or trihexyphenidyl at 30 mg/kg (i.p.) together with valproate in doses of 130 or 103 mg/kg (i.p.), respectively, resulted in motor impairment and caused impairment of long-term memory, similar to the effects of valproate alone, when applied at its ED50 against maximal electroshock. Neither memantine nor trihexyphenidyl altered the total level of valproate in plasma. It may be concluded that the potentiation of the anticonvulsant activity of valproate, by memantine and trihexyphenidyl, is not associated with a pharmacokinetic interaction.

Animals↗

Dissociation between behavioral and electrocortical manifestations of electroshock convulsions during the action of an anticonvulsive drug.

It was shown that 5-OH-5-ethyl-5-phenyl-butyramide (formerly called 5-ethyl-5-phenyl-2-pyrrolidinone) significantly reduces convulsions induced by electroshock in rats, and by drugs in mice. We are reporting a dissociation between the effects of this drug on the behavioral manifestations of electroshock and on the electrocortical afterdischarges. At 50 mg/kg, the drug reduced greatly the duration of the tonic phase of muscular convulsions, but had little or no effect on their total duration or on the electrocortical afterdischarges. At 100-150 mg/kg, the effect on the tonic phase was only slightly larger, but the total duration of behavioral convulsions and the intensity of electrocortical afterdischarges were substantially reduced, while the duration of the latter was either slightly reduce or increased. Only 200 mg/kg, which had clear depressant effects, produced a complete disappearance of all manifestations of electroshock convulsions. It can be concluded that this drug acts more strongly on subcortical structures that transmit cortical convulsions to the muscles, than on the cortical mechanisms that generate electrocortical afterdischarges.

Animals↗

Interaction of felbamate and diazepam against maximal electroshock seizures and chemoconvulsants in mice.

The anticonvulsant effects of felbamate alone or in combination with diazepam were investigated against maximal electroshock-, pentylenetetrazol-, isoniazid- and bicuculline-induced seizures in mice. A single subprotective dose of felbamate, a dose which offers no protection to animals when combined with diazepam, enhanced the protective effects of diazepam against seizures induced by electroshock, pentylenetetrazol and isoniazid, as measured by significant reduction of ED50 values. However, felbamate failed to significantly affect the protective action of diazepam against bicuculline. Felbamate does not interact directly with the GABA-benzodiazepine-ionophore complex. Thus the enhancement of anticonvulsant activity of diazepam by felbamate against maximal electroshock and pentylenetetrazol may involve an indirect effect at benzodiazepine receptors. The anticonvulsant action of felbamate against isoniazid does not seem to involve benzodiazepine receptors and may be due to reversing the inhibitory effect of isoniazid on glutamate decarboxylase (GAD) activity. The interaction between felbamate and diazepam may also involve other mechanisms.

Animals↗

Effects of cold-restraint and swim stress on convulsions induced by pentylenetetrazol and electroshock: influence of naloxone pretreatment.

The influence of two stressogenic conditions, restraint at 4 degrees C for 30 min (cold-restraint stress; CRS) or swimming at 20 degrees C for 3 min (swim stress; SS), on nociception and on convulsions triggered by different agents was assessed in mice. In saline-pretreated mice CRS and SS caused analgesia (hot-plate test, 56 degrees C), delayed the onset of convulsions induced by pentylenetetrazol (PTZ, 100 mg/kg, IP) and aggravated convulsions elicited by maximal transcorneal electroshock (150 mA pulses at 60 Hz for 0.2 s). Pretreatment with naloxone (10 mg/kg, SC, 30 min prior to testing), which did not affect the responsiveness of nonstressed mice to the hot plate or to the convulsant treatments, attenuated the development of analgesia following CRS, but not SS, and further prolonged the latency to onset of PTZ-induced convulsions in both stressed groups. Thus the extent to which CRS and SS can each delay the onset of PTZ-triggered convulsion appears to be limited by activation of a proconvulsant opioid system. In contrast, naloxone pretreatment did not modify the effects of CRS or SS on the severity of electroshock-induced seizures. In conclusion, CRS and SS can each, simultaneously, exert anticonvulsant and proconvulsant influences on responsiveness to PTZ and electroshock, respectively. Also, both forms of stress can activate an opioid system modulating the onset of PTZ-induced seizures, which is distinct from that controlling nociception. These findings, together with those of other stress, convulsions and opioid systems, which depends on the characteristics of the stressogenic condition, species, convulsant agent and parameter considered.

Analgesia↗

Benzodiazepine receptors are not involved in the neurotoxicity and anti-electroshock activity of phenytoin in mice.

The present study was undertaken to investigate whether benzodiazepine receptors are involved in either the anticonvulsant activity of phenytoin against supramaximal seizures or maximal threshold seizures induced by electroshock or the neurotoxicity of phenytoin. Ro 15-1788, a benzodiazepine receptor antagonist, reversed the anticonvulsant activity of clonazepam against both supramaximal and maximal threshold seizures induced by electroshock but not that of phenytoin. Moreover, Ro 15-1788 did not decrease the neurotoxicity of phenytoin. These results suggest that benzodiazepine receptors are not involved in either the anticonvulsant action of phenytoin against seizures induced by electroshock or the neurotoxicity of phenytoin.

Animals↗

Anticonvulsant role of nigrotectal projection in the maximal electroshock model of epilepsy--I. Mapping of dorsal midbrain with bicuculline.

Previous work has indicated that the anticonvulsant effect of nigral inactivation on the maximal electroshock model of generalized seizures is mediated by the projection from substantia nigra to superior colliculus. In accordance with this idea, and with the GABAergic nature of the nigrotectal pathway, microinjections of the GABAA antagonist bicuculline methiodide into the superior colliculus have been reported to block tonic hindlimb extension induced by maximal electroshock. To characterize the relevant circuitry more precisely, the present study sought to determine which region of the superior colliculus was important for the anticonvulsant effect of bicuculline by systematic mapping in the rat. Bilateral injections of bicuculline methiodide (50 pmol in 400 nl/side) were most effective in the caudal deep layers of the superior colliculus and adjoining midbrain reticular formation. These results suggest that the well-known projection from substantia nigra pars reticulata to the superior colliculus may not be involved in the anticonvulsant effect of nigral inactivation in the electroshock model, because this pathway terminates primarily in the intermediate layers of the superior colliculus throughout its rostrocaudal extent. Instead, some other pathway from ventral midbrain to a dorsal midbrain anticonvulsant zone appears to be part of the brain's anticonvulsant circuitry. The following paper [Redgrave et al. (1991) Neuroscience 46, 391-406] describes an anatomical study to characterize this pathway.

Animals↗

Chinese herb constituent beta-eudesmol alleviated the electroshock seizures in mice and electrographic seizures in rat hippocampal slices.

We have found that beta-eudesmol, a sesquiterpenol constituent of Chinese herb antagonized organophosphate-induced lethal toxicity by reversing the neuromuscular failure and reducing the occurrence of convulsions. Its possible antiepileptic action was further explored in electroshock seizure mice in vivo and in high potassium treated rat hippocampal slices in vitro. At a dose with little effect on the motor activity, beta-eudesmol prevented the convulsions and lethality induced by maximal electroshock but not those by pentylenetetrazol or picrotoxin. At subeffective doses, beta-eudesmol and phenytoin showed additive effect in preventing electroshock seizures. Extracellular recording of field potentials in CA1 pyramidal layer of hippocampal slices showed that beta-eudesmol reduced the high potassium (8.5 microM)-induced electrographic seizure activity. The potential of beta-eudesmol to serve as an antiepileptic or a conjuvant in phenytoin therapy is suggested.

Animals↗

Kindling-like effect induced by repeated corneal electroshock in mice.

The present study demonstrates that with the use of corneal electrodes mice can be kindled to minimal convulsions by repeated 60-Hz electroshocks. The efficacy of kindling was found to be dependent upon several stimulus parameters, including duration and intensity as well as the intertrial interval. Because the complexity and generalization of the minimal convulsions increased with the number of electroshock treatments, it was apparent that such kindling had quantitative as well as qualitative characteristics. Moreover, the fact that 50% of the mice remained completely kindled to minimal convulsions 8 weeks after cessation of repeated stimulation indicated that the phenomenon is relatively long-lived. Finally, the increase in CNS excitability associated with kindling extended to some, but not all, chemo- and electroshock tests of excitability. Altogether, the results show that mice kindled by corneal electrode stimulation have many features in common with animals kindled by stimulation of discrete brain areas. Because the procedure can readily and rapidly yield large numbers of kindled animals, an important application for the method will be in the evaluation of drug effects on kindled animals.

Animals↗

Competitive NMDA-receptor antagonists, LY 235959 and LY 233053, enhance the protective efficacy of various antiepileptic drugs against maximal electroshock-induced seizures in mice.

PURPOSE: The objective of this study was to evaluate an interaction of two competitive N-methyl-D-aspartate (NMDA)-receptor antagonists, LY 235959 l(-)-3R,4aS,6R,8aR-6-(phosphonomethyl)-decahydroiso-qu inoline-3-carboxylic acid; < or = 0.5 mg/kg] or LY 233053 cis-(+/-)-4-[(2H-tetrazol-5-yl) methyl]piperidine-2-carboxylic acid; < or = 5 mg/kg] with carbamazepine, diphenylhydantoin, phenobarbital, or valproate magnesium against maximal electroshock-induced convulsions in mice. METHODS: Electroconvulsions were produced by means of an alternating current (ear-clip electrodes, 0.2-s stimulus duration, tonic hindlimb extension taken as the end point) delivered by a Hugo-Sachs stimulator (Type 221, reiburg, FRG). Adverse effects were evaluated in the chimney test (motor performance) and passive-avoidance ask (long-term memory). Plasma levels of antiepileptic rugs were measured by immunofluorescence. RESULTS: Both LY 235959 and LY 233053 ( < or = 0.5 and 5 mg/kg, respectively) did not influence the electroconvulsive threshold but potentiated the anticonvulsant action of all antiepileptics studied. The combined treatment of LY 233053 (5 mg/kg) with carbamazepine, diphenylhydantoin, or phenobarbital (providing a 50% protection against maximal electroshock) resulted in the impairment of long-term memory. No adverse effects were observed with combinations of LY 235959 with these antiepileptics. The combined treatment of valproate with either LY 235959 or LY 233053 was superior to valproate alone, as regards motor impairment, but not the impairment of long-term memory. Neither NMDA-receptor antagonist elevated the total plasma levels of antiepileptic drugs studied. CONCLUSIONS: It may be concluded that NMDA-receptor blockade leads to the enhanced anticonvulsive action of conventional antiepileptics against maximal electroshock-induced seizures. A pharmacokinetic interaction does not seem probable.

Animals↗

Comparison of the effects of propofol and thiopental on the pattern of maximal electroshock seizures in the rat.

The anticonvulsant effects of propofol and thiopental (thiopentone) were determined by measuring the durations of the various phases of maximal electroshock seizures in the rat. Five min. after intraperitoneal administration of subanaesthetic (6.25, 12.5 and 25 mg/kg) and 50 mg/kg doses of propofol, the 2 highest doses abolished both tonic hindlimb extensor phases (full and partial extension) in all rats and decreased the duration of the total tonic phases of the seizure. Although the lowest dose produced no effect, the 12.5 mg/kg dose decreased the duration of both the full and partial tonic extensor phases and increased the duration of tonic flexion, showing that even this low dose had anticonvulsant activity. Subanesthetic doses of thiopental (5, 10 and 20 mg/kg) produced similar changes in the maximal electroshock seizures except that even the lowest dose also significantly decreased the duration of total extension and total tonus. Postseizure depression was prolonged only by the highest dose of propofol. Thus, even low doses of either propofol or thiopental, that produced only minimal behavioural effects, had marked anticonvulsant effects against electrically induced convulsions in the rat. No evidence of enhanced convulsant maximal electroshock seizures patterns was observed at any dose.

Animals↗

Brain areas involved in the catecholamine mediated regulation of electroshock seizure intensity.

Selective treatments which alter the catecholamine content of discrete areas of the brain were tested for their effect on electroshock seizure intensity in the rat. The data indicate that depletion of noradrenaline and dopamine in near ventricular areas by the intracerebroventricular administration of the benzoquinolizine, Ro 4-1284, enhances electroshock seizure intensity. The enhancement of seizure produced by systemic Ro 4-1284 was antagonized by the intracerebroventricular injection of noradrenaline or dopamine which do not appear to penetrate more than 1 mm into the brain. Further, pretreatment with systemic iproniazid and L-dopa completely antagonized the increased seizure intensity produced by intracerebroventricular Ro 4-1284 and repleted brain catecholamines in both near and far ventricular areas. Thus, the effects of both noradrenaline and dopamine in attenuating electroshock seizure intensity appear to be exerted principally through periventricular structures.

2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-↗

Electroshock effects on brain protein synthesis: relation to brain seizures and retrograde amnesia.

The effects of electroshock on brain seizure activity and brain protein synthesis were studied in male mice. A significant but short-lasting inhibition of brain protein synthesis and an increase in the amount of free leucine were produced by electroshock at intensities above the brain seizure threshold. Electroshock at intensities below the brain seizure threshold did not affect brain protein synthesis.

Amnesia↗