Electroconvulsive Seizures Research Articles

Correlation between electroconvulsive seizure and HSC70 mRNA induction in mice brain

The effects of electroconvulsive seizure and anti-convulsant drugs on induction of mRNA of heat shock protein were studied in mouse brain. Electrical shock induced mRNA of heat shock cognate protein (HSC70), but not heat shock protein (HSP70) mRNA. The induction was maximum 1 h after the ECS and continued for several hours, followed by long-lasting depression. Diazepam slightly prevented the ECS, but strongly attenuated the induction of HSC70 mRNA. Whereas phenytoin, which blocked the seizure, did not decrease but delayed the induction of HSC70 mRNA. The present results suggest that HSC70 mRNA level is increased with the ECS and that the induction level did not necessarily correlate the severity of the seizure.

Electroconvulsive shock increases tyrosine hydroxylase and neuropeptide Y gene expression in the locus coeruleus

Electroconvulsive seizures (ECS) increase tyrosine hydroxylase (TH) activity in the locus coeruleus (LC) but not in the substantia nigra (SN). To determine whether new enzyme synthesis contributes to the increase in TH activity, we carried out in situ hybridization histochemistry to determine the effect of ECS on TH mRNA levels in the LC and SN. The effect of ECS on neuropeptide Y (NPY) mRNA levels in the LC was also studied because NPY coexists with norepinephrine in the LC neurons and has been implicated in depressive disorders. A significant increase was observed in TH mRNA and NPY mRNA levels in LC neurons in the ECS group. There was no difference between TH or NPY mRNA levels in the left and right LC. No change was observed in TH mRNA expression in the SN compacta or SN reticulata. We conclude that the regionally selective increase in TH activity after ECS is at least partly due to increased gene expression and that NPY gene expression is regulated in a similar fashion following ECS.

Regulation of beta 1-adrenergic receptor mRNA and ligand binding by antidepressant treatments and norepinephrine depletion in rat frontal cortex.

The number of beta 1-adrenergic receptor (beta 1AR) binding sites is decreased by chronic antidepressant treatments, including electroconvulsive seizure (ECS) and imipramine, whereas administration of agents that deplete norepinephrine (NE) increases the number of beta 1AR binding sites in cerebral cortex. The present study was carried out to examine the influence of these treatments on levels of beta 1AR mRNA in frontal cortex to study the molecular mechanisms that underlie the regulation of beta 1ARs in brain. Levels of beta 1AR mRNA were measured by RNase protection analysis using a riboprobe derived from rat beta 1AR cDNA, and the levels of beta AR binding were measured using the nonselective ligand [3H]CGP-12177. Studies to verify the specificity of the RNase protection assay revealed that the distribution of beta 1AR mRNA was in agreement with the reported distribution of beta 1AR ligand binding: Levels of beta 1AR mRNA were highest in cerebral cortex or frontal cortex, intermediate in neostriatum, hippocampus, lung, and heart, and lowest in cerebellum, kidney, and liver. Chronic ECS treatment (once daily for 10 days) significantly decreased levels of beta AR ligand binding and resulted in a corresponding, time-dependent down-regulation of beta 1AR mRNA levels in frontal cortex. However, imipramine administration regulated levels of beta 1AR mRNA in a biphasic manner, with treatments for 7-14 days increasing and treatments for 18-21 days decreasing levels of beta 1AR mRNA in frontal cortex. In contrast, levels of [3H]CGP-12177 ligand binding were decreased at all time points examined (3-21 days).(ABSTRACT TRUNCATED AT 250 WORDS)

O-306 - Correlation between electroconvulsive seizure and HSC70 mRNA induction in mice brain.

The effects of electroconvulsive seizure and anti-convulsant drugs on induction of mRNA of heat shock protein were studied in mouse brain. Electrical shock induced mRNA of heat shock cognate protein (HSC70), but not heat shock protein (HSP70) mRNA. The induction was maximum 1 h after the ECS and continued for several hours, followed by long-lasting depression. Diazepam slightly prevented the ECS, but strongly attenuated the induction of HSC70 mRNA. Whereas phenytoin, which blocked the seizure, did not decrease but delayed the induction of HSC70 mRNA. The present results suggest that HSC70 mRNA level is increased with the ECS and that the induction level did not necessarily correlate the severity of the seizure.

Amygdala kindling potentiates seizure-stimulated immediate-early gene expression in rat cerebral cortex.

Kindling induces long-term adaptations in neuronal function that lead to a decreased threshold for induction of seizures. In the present study, the influence of amygdala kindling on levels of mRNA for the immediate-early genes (IEGs) c-fos, c-jun, and NGF1-A were examined both before and after an acute electroconvulsive seizure (ECS). Although amygdala kindling did not significantly influence resting levels of c-fos mRNA in cerebral cortex, ECS-stimulated levels of c-fos mRNA (examined 45 min after ECS) were approximately twofold greater in the cerebral cortex of kindled rats relative to sham-treated controls. The influence of kindling on IEG expression was dependent on the time course of kindling, as ECS-stimulated levels of c-fos mRNA were not significantly increased in stage 2 kindled animals. ECS-stimulated levels of c-jun and NGF1-A mRNA were also significantly increased in cerebral cortex of kindled rats relative to sham-treated controls. The influence of kindling on IEG expression was long-lasting because an acute ECS stimulus significantly elevated levels of c-fos and c-jun mRNA in the cerebral cortex of animals that were kindled 5 months previously. In contrast to these effects in cerebral cortex, kindling did not influence ECS-stimulated levels of c-fos mRNA in hippocampus. Finally, immunohistochemical studies revealed lamina-specific changes in the cerebral cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

Protein kinase C activity and subcellular distribution in rat brain following repeated electroconvulsive seizures

Protein kinase C (PKC) activity was measured in samples of neocortex, cerebellum, and hippocampus from adult rats receiving a series of 10 electroconvulsive seizures (ECS). Rats were sacrificed immediately and at various intervals from 15 min to 24 h after the last seizure. From 77 to 84% of total PKC activity was found in the cytosol versus the membrane fraction. PKC activity in cerebellum was significantly higher than in neocortex (15%, P < 0.05). Repeated ECS treatment did not affect total PKC activity nor its distribution between membrane and cytosolic fractions when compared with sham ECS controls. This finding is in keeping with reports that adrenergic-stimulated phosphoinositol turnover is not altered 24 h following repeated ECS.

Naloxone blocks antiepileptogenic properties of an in vitro electroconvulsive shock model

Electroconvulsive shock-induced seizures elevate seizure thresholds in humans and interfere with kindling in animals; opioids may mediate the anticonvulsant mechanism. In a potential model of acute electroconvulsive shock in hippocampal slices, a high-intensity tetanus via the mossy fibers substantially delayed subsequent in vitro kindling through the Schaffer collaterals. Naloxone blocked this effect, implicating the opioid system in the antiepileptogenic properties of this model.

Histamine in brain — its role in regulation of seizure susceptibility

The influence of drugs affecting the turnover and levels of histamine in brain and histamine antagonists on pentetrazole (PTZ)-induced and electroconvulsive seizure threshold in mice was studied. A 1.5-2-fold rise in histamine brain concentration (induced by treatment with histidine or metoprine), led to a concomitant increase of PTZ-induced seizure threshold. A histidine decarboxylase inhibitor (brocresine) induced a depletion of brain histamine by about 75% for at least 8 h, the seizure threshold was, however, only reduced at 6 and 8 h after the injection. At shorter intervals, the seizure threshold was substantially increased. Treatment with centrally acting H 1 antagonists (dimethindene and promethazine) in non-sedative dosage diminished the PTZ seizure threshold significantly; no changes were seen after treatment with H 2 and H 3 antagonists (oxmetidine, ranitidine, zolantidine or thioperamide) and a H 3 agonist ( R- α-methylhistamine). The electroconvulsive threshold was hardly influenced. It is concluded that histamine has a certain anticonvulsant effect which is mediated through H 1 receptors.

Effects of amygdala kindling and electroconvulsive seizures on the expression of corticotropin-releasing hormone in the rat brain

Wjile low doses of corticotropin-releasing hormone (CRH) induce behavioral activation as part of the stress response, higher doses cause pathological excitability and seizures. Single CRH-induced convulsions resemble those following amygdala “kindling” in which intermittent exposure to a subconvulsive electrical stimulus eventually produces a motor seizure. To examine the possibility that alterations in CRH activity occur in kindling we used in situ hybridization to determine if electrical kindling of the amygdala or electroconvulsive seizures (ECS) could alter the expression of CRH mRNA in the rat brain. Amygdala kindling resulting in either after-discharges alone or full-blown motor seizures produced a dramatic increase in CRH but not glutamic acid decarboxylase (GAD) mRNA in the dorsal hippocampus, specifically in the large interneurons of the polygonal layer of the dentate hilus. CRH mRNA per cell and the number of cells expressing CRH increased at 30 min, 2 h, and 24 h but not at 3 weeks following the last kindled seizure. Repeated ECS also induced an up-regulation of CRH mRNA in the dentate hilus. Immunohistochemistry confirmed that seizures increased the number of hilar cells expressing CRH peptide. This induction of CRH could not be explained by nonspecific stress effects as neither restraint stress nor adrenalectomy had any influence on CRH mRNA in the dentate hilus. Both repeated ECS and kindled seizures also caused an increase in CRH mRNA in the hypothalamic paraventricular nucleus similar to that induced by chronic stress. Our results indicate that epileptiform activity induces CRH mRNA in the dentate hilus where normally very little CRH is expressed, suggesting that CRH may be important in mediating electrical excitability in the dentate gyrus and hippocampus.

Chronic Electroconvulsive Seizures Down–Regulate Expression of the Immediate‐Early Genes c‐fos and c‐jun in Rat Cerebral Cortex

Acute seizures and other stimuli that increase neuronal activity cause a rapid induction of the immediate-early genes c-fos and c-jun, also referred to as nuclear proto-oncogenes, in the nervous system. In the present study, rats were administered one or more electroconvulsive seizures (ECS) and the responsiveness of c-fos and c-jun to an acute, "test" seizure was examined. Four hours after a single ECS, the induction of c-fos mRNA by a test seizure was blocked, in agreement with earlier findings, but by 18 h the levels of c-fos mRNA could be reinduced by the test seizure, suggesting that 1 day is sufficient to "reset" the responsiveness of this system. However, it was found that chronic, daily ECS treatments resulted in a time-dependent decrease in the expression of c-fos mRNA in response to a test seizure administered 18 h after the last daily ECS; this effect was maximal after 8-10 days of treatment, at which time the induction of c-fos mRNA by the test seizure was blocked dramatically. Chronic ECS also blocked the induction of c-jun in response to an acute, test seizure. The effect of chronic ECS on levels of Fos protein was also investigated. It was found that basal levels of Fos protein were reduced after chronic (10 days) ECS and were not induced by a test seizure. Because levels of Fos protein remain elevated 4 h after a single seizure this finding suggests that the mechanisms by which acute (4 h) and chronic (8-10 days) ECS block the induction of c-fos may differ.

Age related changes in the effect of electroconvulsive shock on the blood brain barrier permeability in rats

Age-related changes in blood-brain barrier permeability to macromolecules were investigated during electrically induced seizures. Evans-blue was used as the barrier tracer. There was no change in the permeability of the blood brain barrier associated with aging in the rats. However, the extravasation of Evans-blue albumin was most pronounced in the brain after ten repeated electroshocks in old rats. In the adult group that was given a single electroconvulsive shock, there was no coloration of the brain tissue, whereas the group given ten repeated electroconvulsive seizures showed slight staining of the thalamic nuclei, hypothalamus, and midbrain in 5 out of 13 rats. In 30-day-old rats, Evans-blue leakage was similar to that of adults, except that the frequency and intensity of blood-brain barrier breakdown was less after ten repeated electroshocks. In 15-day-old rats, the blood-brain barrier breakdown to Evans-blue albumin was the same after a single and ten electroshocks and the same in control and electroshocked rats. According to our result ten repeated electroshocks have a more pronounced effect on the old animals and have less effect on the young animals in comparison to adult ones.

Chronic electroconvulsive shock treatment elicits up-regulation of CRF and AVP mRNA in select populations of neuroendocrine neurons

The effects of repeated electroconvulsive seizures (ECS) on expression of mRNAs coding for corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) in neuroendocrine neurons of the hypothalamo-pituitary-adrenocortical (HPA) axis and hypothalamo-neurohypophysial system (HNS) were assessed via semi-quantitative in situ hybridization histochemical analysis. Measures of mRNA content were accompanied by measurement of peptide- and hormone-expression in the relevant neuroendocrine systems. Following 7 daily ECS treatments, CRF mRNA was significantly increased in the medial parvocellular paraventricular nucleus (PVN) of treated rats relative to controls. CRF peptide content of whole PVN homogenates was decreased to 50% of control levels. Changes in CRF message and peptide levels were accompanied by increases in pituitary ACTH content and by elevated plasma corticosterone, suggesting ECS elicits long-term up-regulation of the HPA axis. AVP mRNA in the medial parvocellular PVN, which is known to up-regulate in response to HPA challenge by adrenalectomy, was not increased by ECS. Chronic ECS causes a clear up-regulation of HNS neurons of the supraoptic nucleus, characterized by increased AVP mRNA content, decreased AVP peptide content, and depletion of neurohypophysial AVP. However, no changes were observed in magnocellular vasopressinergic neurons of the PVN, indicating that magnocellular SON and PVN neurons respond differentially to stimulation by ECS. The data indicate that ECS is a potent stimulus for activation of select components of both the HPA axis and the HNS. As such, ECS provides a useful tool for examining mechanism underlying neuroendocrine processes.

Chronic antidepressant administration alters the subcellular distribution of cyclic AMP-dependent protein kinase in rat frontal cortex.

The influence of chronic administration of antidepressants on cyclic AMP-dependent protein kinase activity was examined in rat frontal cortex. Chronic administration of imipramine, tranylcypromine, or electroconvulsive seizures decreased cyclic AMP-dependent protein kinase activity in soluble fractions by approximately 25%, whereas enzyme activity was increased in the particulate fractions by approximately 20%. In contrast, enzyme activity in crude homogenates was not altered. This effect appears to be specific to antidepressant drugs, because representatives of several other classes of psychotropic drugs-namely, haloperidol, morphine, and diazepam--failed to alter either soluble or particulate levels of cyclic AMP-dependent protein kinase activity in this brain region following chronic administration. When the total particulate fraction was subfractionated, it was found that chronic imipramine treatment significantly increased the activity of cyclic AMP-dependent protein kinase in crude nuclear fractions but not in crude synaptosomal or microsomal fractions. Taken together, the data raise the possibility that chronic antidepressant treatments may stimulate the translocation of cyclic AMP-dependent protein kinase from the cytosol to the nucleus. This effect would represent a novel action of antidepressants that could contribute to the long-term adaptive changes in brain thought to be essential for the clinical actions of these treatments.

Effect of repeated versus single electroconvulsive seizures on adrenergic-mediated phosphatidylinositol hydrolysis in rat neocortex

Adrenergic-stimulated phosphatidylinositol (PI) hydrolysis was measured in cortical slices obtained from adult rats following electroconvulsive seizures (ECS). One group of animals received ECS daily for 15 days and a second group received a single ECS. Rats were then sacrificed at intervals of 15 min, 60 min, 4 h, and 24 h after the last ECS. Inositol 1-monophosphate (IP 1) accumulation was transiently reduced (20%, P < 0.01), at 15 min, in repeatedly shocked versus sham-shocked control animals. No changes were observed at later intervals nor at any time in rats submitted to a single ECS. These findings suggest that repeated but not single convulsive seizures transiently desensitize adrenergic-mediated PI metabolism. Although repeated ECS significantly increased the density ( B max) of α 1 recognition sites in cortical slices at 15 min, 4 h, and 24 h, this upregulation was not coupled to a functional change in PI hydrolysis.

Blood-brain barrier permeability after electrically induced seizure in normoglycemic, hypoglycemic, and hyperglycemic rats

The influence of hyperglycemia and moderate hypoglycemia plus electroconvulsive seizure on the permeability of the blood-brain barrier to protein was studied in rats. Evans blue was used as a blood-brain barrier tracer. Following a single electroconvulsive seizure, slight staining of brain tissue was seen. After 10 electroconvulsive stimuli followed by sustained seizure activity, this phenomenon was more pronounced in moderate hypoglycemic animals. In this group, Evans blue albumin extravasation occured in all regions of the hemispheres, but the most severe protein leakage was seen in the thalamus, hypothalamus, amygdala nuclei, and frontal, parietal, and occipital cortex. Ten repeated electroconvulsive stimuli applied in case of hyperglycemia made no important difference in blood-brain barrier dysfunction according to normoglycemic group. Our results suggest that moderate hypoglycemia provokes the effect of electroconvulsive seizure on the permeability of the blood-brain barrier.

Mouse brain c-fos mRNA distribution following a single electroconvulsive shock.

The regional distribution of c-fos mRNA in the mouse brain has been investigated by in situ hybridization autoradiography after seizures induced by an acute electroconvulsive shock (ECS). ECS led to a widespread induction of the proto-oncogene c-fos in the brain, with highest concentrations in discrete areas within the limbic system and also in the hypothalamus and cerebellum. The mild stress of sham treatment in earclipped animals induced a weaker and qualitatively different pattern of c-fos mRNA expression involving the cortex, hippocampus, and cerebellum. These data suggest the usefulness of c-fos in situ hybridization as a marker of neuronal stimulation and in mapping a range of effects from a mild stress to the robust changes of an electroconvulsive seizure.

Heterogeneity in the beta-endorphin response to ECT

Electroconvulsive seizures are accompanied by release into plasma of beta-endorphinIR from anterior lobe corticotrophs. Molecular sieving of this beta-endorphin-IR indicates that 2/3 of the released material is authentic beta-endorphin. When beta-endorphin levels following the first treatment are compared to beta-endorphin levels following the final treatment, on average patients release the same amount with their first treatment as their final treatment (N = 21 patients). However, a number of patients demonstrated substantially shorter seizures with the final treatment. When patients were subdivided into those patients with relatively constant seizure length (final seizure length = 75-125% of seizure 1, N = 10) and patients whose final seizure was <75% of first seizure in length (final seizure X = 50% seizure 1, N = 9), significantly different beta-endorphin response to both the initial seizures and to the course of ECT were found. Those individuals who maintained similar seizure lengths over the course of ECT demonstrated a greater release of beta-endorphin with the final seizure than first seizure as well as an increase in baseline beta-endorphin levels (chronic ECT X acute ECT, F = 6.03, df = 1, p = .018). These data are in agreement with animal data suggesting that repeated ECS can function as a chronic stressor and induces the HPA axis. Those individuals who demonstrate seizure shortening show a significantly greater beta-endorphin response to the first seizure (F = 4.88, p = .03) and a decreased response to the final seizure. Possible clinical variables influencing these responses and implications for treatment will be presented.

Transient changes in cortical alpha 1 adrenoceptors and seizure threshold following electroconvulsive seizures in rats

Alpha 1 adrenoceptor density (B max) is consistently decreased in actively spiking human cortical epileptic foci. Interpretation of these unique human data is limited because all surgical excisions are completed shortly after a period of active seizure discharge. To determine the temporal profile of seizure-induced changes in cortical alpha 1 adrenoceptors we examined rats primed by 15 daily electroconvulsive seizures (ECS). Since the noradrenergic system has an inhibitory effect on epileptic activity, we also measured the postictal rise in minimal ECS seizure threshold. Animals were sacrificed immediately before or at intervals after the last scheduled seizure. Cortical membranes were assayed using [ 3H]prazosin as specific radioligand. Repeated ECS produced an increase in the number of cortical alpha 1 sites from 4 to 24 h postictally, but following the last seizure there was a transient ‘normalization’ of alpha 1 receptor density which persisted for 3 h. The postictal ECS seizure threshold also remained elevated for a 2 h period. Both these transient postictal changes may in part result from activation of the central NA system. Decreased alpha 1 adrenoceptors in surgical specimens of spiking cerebral cortex may also be a secondary response to focal seizure activity.

N-methyl-D-aspartate receptor involvement in lactate production following ischemia or convulsion in rats

Intracerebral dialysis in conscious freely moving rats was used to examine the involvement of the N-methyl-D-aspartate (NMDA) receptor in the formation of lactic acid and its consequent appearance in extracellular fluid. Local administration of NMDA in the striatum of conscious, freely moving rats was found to produce a transient increase in extracellular lactate. Alternatively, administration of the NMDA antagonists 2-amino-7-phosphonoheptanoic acid or 2-amino-5-phosphonopentanoic acid delayed the onset of and attenuated the magnitude of teh lactate production induced by an electroconvulsive seizure. Pretreatment of the striatum with either of these antagonists reduced the total amount of lactate observed in extracellular fluid following ischemia induced by cardiac arrest, but did not affect the time course of the appearance of lactate in the extracellular space.

Effect of mu- and kappa-opioid agonists on the electroconvulsive seizure threshold in mice and antagonism by naloxone and MR 2266.

The effects of mu-agonists (morphine, fentanyl) and kappa-agonists (U-50,488, U-69,593, bremazocine, nalbuphine, tifluadom) on the electroconvulsive threshold were studied in mice. The threshold could be significantly elevated by all drugs tested in a dose range that was in the order of magnitude of the antinociceptive ED50. Mice tolerant to the antielectroshock effect of morphine still reacted to U-69,593. The antagonism of the anticonvulsant effect by the mu-antagonist naloxone and the kappa-antagonist MR 2266 was receptor-specific only with fentanyl and U-50,488. The other opioid agonists were either antagonized by both drugs (morphine, U-69,593, bremazocine, nalbuphine) or even by the opposite antagonist (tifluadom). A synergistic effect of mu- and kappa-stimulation is assumed for the mediation of the antielectroshock effect of opioid drugs, but drugs with high affinity and intrinsic activity at one receptor type (fentanyl, U-50,488) are obviously able to bring about their antielectroshock effect through the one respective opioid binding site.