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This study evaluated the anticonvulsant activity of D-cycloserine against maximal electroshock seizures in rats. Systematically administered D-cycloserine (i.p.) inhibited maximal electroshock-induced tonic hindlimb extension in a dose-dependent manner with an ED50 of 153 mg/kg. No neurological deficit was detected at any dose of D-cycloserine. In contrast, L-cycloserine had no effect on the maximal electroshock seizures. Administration of the strychnine-insensitive glycine receptor antagonist 7-chlorokynurenic acid (100 nmol, i.c.v.) significantly antagonized the anticonvulsant activity induced by D-cycloserine. Centrally administered D-cycloserine (i.c.v.) induced significant anticonvulsant activity 1-2 h after administration with an approximate ED50 of 5 mumol. 7-Chlorokynurenic acid (100 nmol, i.c.v.) significantly antagonized the anticonvulsant activity of centrally administered D-cycloserine. L-Cycloserine (i.c.v., 2 h) induced no significant anticonvulsant activity. These results provide evidence that the anticonvulsant activity of D-cycloserine in maximal electroshock seizures may be mediated by strychnine-insensitive glycine receptors.
The effect of electrically induced seizures on the permeability of the rat blood-brain barrier was investigated. The small radioactive tracers sodium (24Na+), chloride (36Cl-) carbon labelled thiourea (14C-thiourea) and glucose (14C-D-glucose) were studied in indicator dilution experiments with indium labelled diethylenetriaminepenta-acetic acid (113mIn-DTPA) as reference substance. This method allows a quantitative estimate of the transcapillary loss of solutes, the extraction (E), during a single passage through the brain. Passage of macromolecules was studied using as marker substance Evans Blue which binds to plasma albumin. In the resting state ENa, ECl, Ethiourea and Eglucose were 2.9, 4.8, 9.3 and 12.5%, respectively. During seizures and during shortlasting hypercapnia E glucose decreased while E for the other tracers was unchanged. As cerebral blood flow increased, there must be an increased transfer of test substances into the brain. This finding is in agreement with recent human studies [15]. When Evans Blue was injected intravenously prior to electroshock, there was no staining of brain tissue after one electroshock but following repeated electroshocks some staining was observed. In an attempt quantify this transcapillary loss of albumin by means of indicator dilution, 51Cr-labelled erythrocytes were used as intravascular reference substance against 113mIn-DTPA (a plasma tracer). However, the albumin loss (by pinocytosis or otherwise) occurring after ten electroshocks could not be detected during a single passage through the brain.
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.
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.
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.
Modification of electroshock (60 Hz; a.c.) convulsive responses and thresholds by monoamine-reducing drugs was investigated in developing rats. Throughout postnatal development, tetrabenazine (TBZ) reduced brain monoamines and increased the severity of motor responses to electroshock. The predominant maximal response in control pups progressed from hyperkinesia (day 1) to clonic convulsions (day 3) and tonic forelimb (day 7) and hindlimb (day 19) extension. The pattern in TBZ-treated pups progressed from tonic forelimb extension (day 1) to tonic hindlimb extension (day 7). On day 7, TBZ reduced the thresholds for clonic (CT) and tonic convulsions (TT) to 41 and 24% of control, respectively. Reserpine (1.25 mg/kg, 24 hours) decreased the TT but not the CT; TBZ, 4 hours before reserpine, prevented this decrease. A higher dose of reserpine (2.5 mg/kg) decreased both the CT and TT. On day 8, TBZ (25 mg/kg, 4 hours) decreased the TT (46% control); L-dihydroxyphenylalanine, but not 5-hydroxytryptophan prevented this decrease. Intracisternal 6-hydroxydopamine reduced the TT on day 8, while intracisternal 5,7-dihydroxytryptamine had no effect despite a 46% reduction in serotonin. The results indicate that in the neonatal rat brain, monoaminergic systems are sufficiently mature to attenuate electroshock convulsive responses, perhaps by limiting propagation of seizure discharge.
Intraovular pressure was measured in 20 patients undergoing anesthesia for electroshock therapy. Compared to control values, determined on the day before electroshock therapy, statistically significant elevations of intraocular pressure followed the post-electroshock therapy convulsions and were still significant 5 minutes later, but not of sufficient magnitude or duration to cause concern.
Since the introduction of medicamental therapies in psychiatry, the electroshock technique has been put aside. After having noticed the fact "figures in hand", the speaker: --Reminds the practical conditions of electroshock, its principal indications during depressions and schizophrenia. --Compares the various convulsive techniques and especially the unilateral electroshock as well as those based on the use of pharmacological agents. --Proposes applicable therapeutical rules divided into six points and meant for "resistant" depressions.
Losigamone (AO-33) is a recemate of a tetronic acid derivative. The effects of losigamone and its three isomers (AO-242, AO-294 and AO-23) were compared on maximal electroshock (MES) induced convulsions in mice and on different patterns of extracellularly recorded, low Mg2+ induced epileptiform activity in slices of the rat temporal cortex. Lowering Mg2+ induced recurrent short discharges in areas CA3 and CA1 while ictaform events that lasted for many seconds were induced in the entorhinal cortex. In the hippocampus the activity stayed stable over a number of hours. In contrast, the ictaform events in the entorhinal cortex changed their characteristics after one to two hours to recurrent discharges of 0.8 to 10 s. Afterdischarges and interictal events were absent. 50 microM AO-242 showed a similar efficacy to 50 microM AO-33 in reducing and blocking epileptiform discharges in areas CA1 and CA3 while 50 microM AO-294 and 50 microM AO-23 had weaker effects than 50 microM AO-33. Concentrations of 50 microM and 100 microM AO-242 showed a similar efficacy to AO-33 on ictaform events in the entorhinal cortex. Late recurrent discharges were also blocked by AO-33 and AO-242 although at higher concentrations (300 microM). The in vitro observations are with respect to order of efficacy in accordance with the in vivo data obtained in the maximal electroshock test in mice. The order of potency in the MES test was AO-242 greater than AO-33 much greater than AO-294 much greater than AO-23.(ABSTRACT TRUNCATED AT 250 WORDS)
The effect of some tryptaminergic drugs on electroshock fighting behaviour in rats was determined. Reserpine and tetrabenazine reduced the fighting responses while 5-hydroxytryptophan increased the fighting responses in normal as well as reserpine-treated animals. p-Chlorophenylalanine, a specific depletor of brain serotonin, also reduced the fighting responses. The results suggest that an increase of brain serotonin may have a facilitatory effect on electroshock fighting behaviour and a decrease of brain serotonin may impair fighting behaviour.
The effect of electroshock and treatment with reserpine, amphetamine or lithium chloride on protein kinase activity in synaptic membrane fragments prepared from rat brain was investigated. Naive rats subjected to electroshock procedures showed significant increases in both basal and cyclic AMP-stimulated activity irrespective of whether the treatment was sham, acute or chronic. These increases did not occur in animals which had been tamed by daily handling for 15 days prior to treatment, suggesting that the response was induced by the stress of an unfamiliar situation. Administration of lithium chloride and reserpine caused a small but significant increase in the stimulated activity. Doses of d-amphetamine of 5 mg/kg had no effect on either basal or stimulated activity, but higher doses (up to 15 mg/kg) resulted in a pronounced increase in both activities, which may have been related to drug-induced stress.
Lesion evidence suggests that the superior colliculus is essential for mediating the anticonvulsant properties of nigral suppression in the electroshock model of epilepsy. However, our companion paper [Redgrave et al. (1991) Neuroscience 46, 379-390] established that the region of dorsal midbrain where bicuculline was most effective in suppressing tonic hindlimb extension did not correspond well with the known distribution of nigrotectal terminals. The purpose of the present anatomical study was, therefore, to investigate in more detail ventral midbrain connections to the dorsal midbrain anticonvulsant zone in rat. Small injections (10-20 nl) of a 1% solution of wheatgerm agglutinin conjugated with horseradish peroxidase were made specifically into the region of dorsal midbrain where bicuculline was maximally effective. Numerous retrogradely labelled cells were found in substantia nigra pars lateralis and adjacent peripeduncular area but not in substantia nigra pars reticulata. Retrogradely labelled cells were also located in ventral zona incerta. When wheatgerm agglutinin-horseradish peroxidase injections were made into lateral substantia nigra, a region of anterogradely transported reaction product characteristic of nerve terminals was observed in the caudolateral deep layers and underlying reticular tissue; this area corresponded well to the dorsal midbrain anticonvulsant zone. These data suggest that, in the electroshock model of epilepsy, direct connections between substantia nigra pars lateralis and adjacent peripeduncular area and the dorsal midbrain anticonvulsant zone could be critical for mediating the anticonvulsant properties previously attributed to substantia nigra pars reticulata. During the course of this study, anterograde projections from substantia nigra pars lateralis and adjacent peripeduncular area to both superficial and intermediate layers of the ipsilateral superior colliculus were noted. Additional experiments using retrograde transport of the fluorescent tracer Fast Blue confirmed these projections.
We reported earlier that brain activation by 10 s of cortical electroshock caused prolonged elevation of brain lactate without significant change in intracellular pH, brain high-energy phosphorylated metabolites, or blood gases. The metabolic state of the elevated lactate has been investigated in further experiments using combined, in vivo 1H-observed 13C-edited nuclear magnetic resonance spectroscopy (NMRS), homonuclear J-edited 1H-NMRS, and high-resolution 1H-NMRS of perchloric acid extracts to monitor concentrations and 13C-isotopic fractions of brain and blood lactate and glucose. We now report that electroshock-elevated lactate pool in rabbit brain approaches equilibrium with blood glucose within 1 h. There was nearly complete turnover of the raised lactate pool in brain; any pool of metabolically inactive lactate could not have been > 5% of the total. In the same experiments, blood lactate underwent < 50% turnover in 1 h. The new 1H-spectroscopic methods used for these experiments are readily adaptable for the study of human brain and may be useful in characterizing the metabolic state of elevated lactate pools associated with epilepsy, stroke, trauma, tumors, and other pathological conditions.
1. 6-Hydroxydopamine, injected intraperitoneally in rats and chicks, did not induce spontaneous seizures but produced significant alterations in the threshold to electroshock seizure in chicks; the particular effects were dose-dependent and time-dependent. 2. Administration of 6-hydroxydopamine to 3 day old chicks and rats in the first and third days after birth resulted in an increase in the proportion exhibiting tonic seizure with electroshock when tested after 10-12 weeks. 3. When 6-hydroxydopamine was injected intraperitoneally into adult rats and cocks, there was no significant alteration in seizure threshold. 4. The results suggest that 6-hydroxydopamine penetrates the central nervous system of young chicks and rats and that adrenergic mechanisms are probably involved in modulating seizure mechanisms in both the chick and rat.
Rats were cerebellectomized 72-96 hr prior to evaluation (1) during maximum electroshock seizures and (2) for their capacity to respond to pentylenetetrazol-induced clonic seizures. Cerebellectomized rats failed to exhibit tonic hindlimb extension, an endpoint characteristic of maximal electroshock seizures. The dose of pentylenetetrazol required to produce clonic seizures or death was not different in cerebellectomized and sham-operated controls. The anticonvulsant efficacy of diazepam, when assessed as a pentylenetetrazol antagonist, was not influenced by removal of the cerebellum. These data indicate that whereas cerebellar influences may suppress seizure activity which is largely focal, seizures of more diffuse origin are not markedly influenced by cerebellar activity. It is, therefore, essential that the role of the cerebellum in suppressing seizures be characterized for each kind of experimentally induced seizure process.
Effects of antiepileptics on both behavioral (TE) and electrographic seizure patterns induced by maximal electroshock were studied simultaneously in the same animal. The results obtained are as follows. All the antiepileptics used in this study depressed the TE seizure. Imipramine, biperiden, and lidocaine also depressed TE seizure, although they are not classified as antiepileptics. Phenobarbital, primidone, trimethadione, carbamazepine, ethosuximide, diazepam, clozapine, and imipramine had a depressant effect on electrographic seizures. However, phenytoin, ethotoin, phenacemide, and acetazolamide did not influence the electrographic seizure, in spite of having a strong effect on TE seizure. The present procedure, i.e., that of simultaneous observation of both behavioral and electrographic seizure patterns induced by maximal electroshock in the same animal, provides information which cannot be obtained from either behavior or EEG observation alone.
From a study on the interrelationship between electroshock-induced convulsions, autonomic function, catecholamines, and cardiovascular homeostasis in dogs, the authors found that: (1) the asystole of electroshock (ES) was significnatly prolonged by high spinal anesthesia but not by relative alpha- or beta-adrenergic blockade; (2) increased levels of circulating catecholamines were solely responsible for the marked hypertensive response to ES, since the pressor effect could be blocked by preventing the release of catecholamines with high spinal anesthesia or by inhibiting alpha-adrenergic receptors with phenoxybenzamine; (3) the adrenal medulla appeared to be the source of most of the ES-induced increase in circulating catecholamines; (4) the asystole and arrhythmias of ES were a cholinergic effect, since they were blocked by atropine; (5) there was a dose-response relationship between the coulombs of electricity administered and the catecholamine and cardiovascular responses; and (6) that the adverse cardiovascular effects of ES therapy could be ameliorated pharmacologically.