Electroconvulsive Seizure Treatment Research Articles

Regulation of GFRalpha-1 and GFRalpha-2 mRNAs in rat brain by electroconvulsive seizure.

The influence of both acute and chronic electroconvulsive seizure (ECS) or antidepressant drug treatments on expression of mRNAs encoding glial cell line-derived neurotrophic factor (GDNF) and its receptors, GFRalpha-1, GFRalpha-2, and c-Ret proto-oncogene (RET) in the rat hippocampus was examined by in situ hybridization. Two hours after acute ECS, levels of GFRalpha-1 mRNA in the dentate gyrus were significantly increased. This increase peaked to nearly 3-fold at 6 h after acute ECS and returned to basal levels 24 h after treatment. Chronic (once daily for 10 days) ECS significantly increased the expression of GFRalpha-1 mRNA nearly 5-fold after the last treatment. Levels of GFRalpha-2 mRNA in the dentate gyrus were also significantly increased by acute and chronic ECS, although this effect was less than that observed for GFRalpha-1. Maximum induction of GFRalpha-2 was 30% and 70% compared to sham in response to acute or chronic ECS, respectively. Levels of GDNF and RET mRNAs were not significantly changed following either acute or chronic ECS treatment at the time points examined. Chronic (14 days) administration of different classes of antidepressant drugs, including tranylcypromine, desipramine, or fluoxetine, did not significantly affect the GDNF, GFRalpha-1, GFRalpha-2, or RET mRNA levels in CA1, CA3, and dentate gyrus areas of hippocampus. The results demonstrate that acute ECS increases the expression of GFRalpha-1 and GFRalpha-2 and that these effects are enhanced by chronic ECS. The results also imply that regulation of the binding components of GDNF receptor complex may mediate the adaptive responses of the GDNF system to acute and chronic stimulation.

Alterations in heavy and light neurofilament proteins in hippocampus following chronic ECS administration

Chronic administration of electroconvulsive seizures (ECS), one of the most effective treatments for depression, induces sprouting of the mossy fibers in the hippocampus. This sprouting requires chronic ECS administration and appears to occur in the absence of hilar neuronal loss. Dynamic regulation of cytoarchitecture plays a vital role in such profound alterations of neuronal morphology. In particular, alterations in the neurofilament protein subunits have been implicated in neurite sprouting, neuronal regeneration, and growth. The present study was carried out to determine the influence of chronic ECS administration on the neurofilament subunits and other molecular markers of neuronal plasticity. Chronic ECS administration decreases the level of phosphorylated heavy neurofilament subunit (NF-H). In addition, the total level of the light neurofilament subunit (NF-L) but not the medium neurofilament subunit (NF-M) is decreased following chronic ECS treatment. Other cytoskeletal proteins, including actin, microtubule-associated protein (MAP-2), and tau, are not influenced by chronic ECS administration. Expression of the growth-associated protein (F1/GAP-43) also remains unchanged following chronic ECS treatment. The changes observed in neurofilaments may be part of the cytoskeletal remodeling that contributes to the mossy fiber sprouting induced by chronic ECS treatment. Synapse 35:137–143, 2000. © 2000 Wiley-Liss, Inc.

Alterations in heavy and light neurofilament proteins in hippocampus following chronic ECS administration.

Chronic administration of electroconvulsive seizures (ECS), one of the most effective treatments for depression, induces sprouting of the mossy fibers in the hippocampus. This sprouting requires chronic ECS administration and appears to occur in the absence of hilar neuronal loss. Dynamic regulation of cytoarchitecture plays a vital role in such profound alterations of neuronal morphology. In particular, alterations in the neurofilament protein subunits have been implicated in neurite sprouting, neuronal regeneration, and growth. The present study was carried out to determine the influence of chronic ECS administration on the neurofilament subunits and other molecular markers of neuronal plasticity. Chronic ECS administration decreases the level of phosphorylated heavy neurofilament subunit (NF-H). In addition, the total level of the light neurofilament subunit (NF-L) but not the medium neurofilament subunit (NF-M) is decreased following chronic ECS treatment. Other cytoskeletal proteins, including actin, microtubule-associated protein (MAP-2), and tau, are not influenced by chronic ECS administration. Expression of the growth-associated protein (F1/GAP-43) also remains unchanged following chronic ECS treatment. The changes observed in neurofilaments may be part of the cytoskeletal remodeling that contributes to the mossy fiber sprouting induced by chronic ECS treatment.

Regulation of GFR?-1 and GFR?-2 mRNAs in rat brain by electroconvulsive seizure

The influence of both acute and chronic electroconvulsive seizure (ECS) or antidepressant drug treatments on expression of mRNAs encoding glial cell line-derived neurotrophic factor (GDNF) and its receptors, GFRalpha-1, GFRalpha-2, and c-Ret proto-oncogene (RET) in the rat hippocampus was examined by in situ hybridization. Two hours after acute ECS, levels of GFRalpha-1 mRNA in the dentate gyrus were significantly increased. This increase peaked to nearly 3-fold at 6 h after acute ECS and returned to basal levels 24 h after treatment. Chronic (once daily for 10 days) ECS significantly increased the expression of GFRalpha-1 mRNA nearly 5-fold after the last treatment. Levels of GFRalpha-2 mRNA in the dentate gyrus were also significantly increased by acute and chronic ECS, although this effect was less than that observed for GFRalpha-1. Maximum induction of GFRalpha-2 was 30% and 70% compared to sham in response to acute or chronic ECS, respectively. Levels of GDNF and RET mRNAs were not significantly changed following either acute or chronic ECS treatment at the time points examined. Chronic (14 days) administration of different classes of antidepressant drugs, including tranylcypromine, desipramine, or fluoxetine, did not significantly affect the GDNF, GFRalpha-1, GFRalpha-2, or RET mRNA levels in CA1, CA3, and dentate gyrus areas of hippocampus. The results demonstrate that acute ECS increases the expression of GFRalpha-1 and GFRalpha-2 and that these effects are enhanced by chronic ECS. The results also imply that regulation of the binding components of GDNF receptor complex may mediate the adaptive responses of the GDNF system to acute and chronic stimulation.

Transcriptional and translational regulation of phosphodiesterase type IV isozymes in rat brain by electroconvulsive seizure and antidepressant drug treatment.

We examined the influence of electroconvulsive seizure (ECS) and imipramine (IMI) treatment on the transcription and translation of cyclic nucleotide phosphodiesterase type IV (PDE IV) isozymes in the rat brain. Our in situ hybridization studies revealed an increase of PDE IV-B mRNA level in various brain regions after acute ECS. However, the increase of PDE IV activity was produced not by acute but by chronic ECS treatment in the frontal cortex. Increased PDE IV-B mRNA expression in frontal but not in hippocampal subfields was induced also after chronic ECS treatment. Although an increase in PDE IV-A mRNA expression of the dentate gyrus in the hippocampus was observed, no change of PDE IV activity was produced in the hippocampus by acute or chronic ECS treatment. These results suggest that the repeated increases of PDE IV-B mRNA expression are attributable to the increase of PDE IV translation. Increased PDE IV-B transcription and PDE IV translation in the frontal cortex were also produced after chronic IMI treatment. This is the first report demonstrating an expressional regulation of Drosophila melanogaster dunce (dnc) gene homologue PDE IV isozymes in the brain. Although no pathophysiological conditions with reduced PDE IV activity in the nervous system are known except for a learning deficit in the mutant fly dnc-, our results suggest possible treatments to cope with reduced PDE IV activity.

Essential Role of thefosB Gene in Molecular, Cellular, and Behavioral Actions of Chronic Electroconvulsive Seizures

The role of Fos-like transcription factors in neuronal and behavioral plasticity has remained elusive. Here we demonstrate that a Fos family member protein plays physiological roles in the neuronal, electrophysiological, and behavioral plasticity associated with repeated seizures. Repeated electroconvulsive seizures (ECS) induced isoforms of DeltaFosB in frontal cortex, an effect that was associated with increased levels of the NMDA receptor 1 (NMDAR1) glutamate receptor subunit. Induction of DeltaFosB and the upregulation of NMDAR1 occurred within the same neurons in superficial layers of neocortex. Activator protein-1 (AP-1) complexes composed of DeltaFosB were bound to a consensus AP-1 site in the 5'-promoter region of the NMDAR1 gene. The upregulation of NMDAR1 was absent in mice with a targeted disruption of the fosB gene. In addition, repeated ECS treatment caused progressively shorter motor seizures (tolerance) in both rats and wild-type mice, as well as reduced NMDA-induced inward currents in pyramidal neurons from superficial layers of the neocortex of wild-type mice. These behavioral and electrophysiological effects were also significantly attenuated in fosB mutant mice. These findings identify fosB gene products as transcription factors critical for molecular, electrophysiological, and behavioral adaptations to motor seizures.

Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments

The influence of chronic electroconvulsive seizure (ECS) or antidepressant drug treatments on expression of brain-derived neurotrophic factor (BDNF) and its receptor, trkB, was examined by in situ hybridization and Northern blot. In frontal cortex, acute ECS increased BDNF mRNA approximately twofold, an effect significantly augmented by a prior course of chronic ECS treatment (10 d). In the hippocampus, the influence of chronic ECS varied between the major subfields. In the dentate gyrus granule cell layer, chronic ECS decreased the acute induction of BDNF and trkB mRNA by approximately 50%, but prolonged their expression: levels remained elevated two- to threefold 18 hr later after the last chronic ECS treatment, but returned to control 18 hr after acute ECS. In CA3 and CA1 pyramidal cell layers, chronic ECS significantly elevated the acute induction of BDNF, and tended to prolong the expression of BDNF and trkB mRNA. A similar effect was observed in layer 2 of the piriform cortex, where chronic ECS significantly increased the acute induction and prolonged the expression of BDNF and trkB mRNA. Chronic (21 d), but not acute (1 d), administration of several different antidepressant drugs, including tranylcypromine, sertraline, desipramine, or mianserin, significantly increased BDNF mRNA and all but mianserin increased trkB mRNA in hippocampus. In contrast, chronic administration of nonantidepressant psychotropic drugs, including morphine, cocaine, or haloperidol, did not increase levels of BDNF mRNA. Furthermore, chronic administration of ECS or antidepressant drugs completely blocked the down-regulation of BDNF mRNA in the hippocampus in response to restraint stress. The enhanced induction and prolonged expression of BDNF in response to chronic ECS and antidepressant drug treatments could promote neuronal survival, and protect neurons from the damaging effects of stress.

Chronic antidepressant treatment down-regulates the induction of c-fos mRNA in response to acute stress in rat frontal cortex

The present study examines the influence of electroconvulsive seizure (ECS), as well as several antidepressant drug treatments, on the induction of c-fos mRNA in response to acute restraint stress. Acute (45-minute) restraint stress resulted in five- to sixfold elevation of c-fos mRNA levels in rat frontal cortex. Chronic administration of ECS significantly decreased the induction of c-fos mRNA levels in response to acute restraint stress, and this effect was observed after chronic (6 to 9 days) but not acute (1 or 3 days) of ECS treatment. In addition, c-fos induction in response to acute restraint stress was down-regulated by chronic, but not acute, administration of tranylcypromine or imipramine, two drugs that nonselectively increase synaptic levels of norepinephrine and serotonin by inhibition of monoamine oxidase or neurotransmitter reuptake, respectively. Moreover, chronic administration of desipramine or sertraline, selective re-uptake inhibitors of norepinephrine, or serotonin, respectively, also significantly down-regulated the induction of c-fos mRNA in response to restraint stress. Chronic administration of ECS, tranylcypromine, or imipramine also decreased stressed-induced levels of NGFI-A mRNA, another immediate early gene transcription factor, whereas levels of c-jun mRNA were not influenced by either stress or antidepressant treatments. The results demonstrate that chronic, but not acute, administration of ECS and several different classes of antidepressant drugs down-regulates stress-induced levels of c-fos mRNA, suggesting that this effect may be a common, postreceptor action of antidepressant treatments.

Chronic Antidepressant Treatment Down-Regulates the Induction of c-fos mRNA in Response to Acute Stress in Rat Frontal Cortex

The present study examines the influence of electroconvulsive seizure (ECS), as well as several antidepressant drug treatments, on the induction of c-fos mRNA in response to acute restraint stress. Acute (45-minute) restraint stress resulted in five- to sixfold elevation of c-fos mRNA levels in rat frontal cortex. Chronic administration of ECS significantly decreased the induction of c-fos mRNA levels in response to acute restraint stress, and this effect was observed after chronic (6 to 9 days) but not acute (1 or 3 days) of ECS treatment. In addition, c-fos induction in response to acute restraint stress was down-regulated by chronic, but not acute, administration of tranylcypromine or imipramine, two drugs that nonselectively increase synaptic levels of norepinephrine and serotonin by inhibition of monoamine oxidase or neurotransmitter reuptake, respectively. Moreover, chronic administration of desipramine or sertraline, selective re-uptake inhibitors of norepinephrine, or serotonin, respectively, also significantly down-regulated the induction of c-fos mRNA in response to restraint stress. Chronic administration of ECS, tranylcypromine, or imipramine also decreased stressed-induced levels of NGFI-A mRNA, another immediate early gene transcription factor, whereas levels of c-jun mRNA were not influenced by either stress or antidepressant treatments. The results demonstrate that chronic, but not acute, administration of ECS and several different classes of antidepressant drugs down-regulates stress-induced levels of c-fos mRNA, suggesting that this effect may be a common, postreceptor action of antidepressant treatments.

Chronic electroconvulsive seizure (ECS) treatment results in expression of a long-lasting AP-1 complex in brain with altered composition and characteristics

Gene transcription is likely to play a role in the biochemical adaptations thought to underlie the long-term behavioral changes observed following various chronic treatments. The AP-1 (activator protein-1) complex is a well-studied transcription factor capable of regulating gene transcription. We therefore examined the regulation of the AP-1 complex in rat cerebral cortex and hippocampus following electroconvulsive seizures (ECS), known to induce biochemical alterations in the brain after chronic treatment. We show that 10 d of chronic ECS treatment results in an AP-1 binding complex that persists for at least 7 d in the cortex and hippocampus. In contrast, AP-1 binding returns to control levels within 18 hr of a single acute ECS. Supershift experiments and Western blots show that the chronic AP-1 complex contains two novel Fos-related antigens (Fras) of 35 and 37 kDa that do not appear following a single acute ECS. The chronically induced 35 and 37 kDa Fras and the chronic AP-1 complex show similar time courses for induction by repeated ECS. Moreover, the 37 kDa Fra band persists for at least 7 d following chronic ECS treatment, as observed for the chronic AP-1 complex. Competition experiments indicate that the relative affinities of the acute and chronic AP-1 complexes for several AP-1-like sites are similar, although there was approximately a twofold difference in the affinity for one particular AP-1-like site. The altered composition of the chronic AP-1 complex, and differences in half-life, DNA binding affinity, and possibly transcriptional activating properties are likely to cause changes in the overall pattern of gene expression, which may underlie some of the long-term biochemical adaptations observed following chronic ECS and other chronic perturbations.

Chronic electroconvulsive seizures increase the expression of serotonin2 receptor mRNA in rat frontal cortex.

The present study examines the influence of electroconvulsive seizure (ECS), as well as antidepressant drugs, on levels of serotonin2 (5-HT2) receptor mRNA in rat frontal cortex. Using a sensitive RNase protective assay, preliminary studies demonstrated the predicted regional distribution for the 5-HT2 receptor mRNA: levels of 5-HT2 mRNA were highest in frontal cortex (2.58 amol/micrograms of total RNA), intermediate in neostriatum, thalamus, and midbrain, and lowest in hippocampus, cerebellum, and choroid plexus. Chronic (10 or 14 days), but not acute (1 or 3 days), ECS treatment significantly increased levels of 5-HT2 receptor mRNA. ECS treatment resulted in a similar time-dependent up-regulation of 5-HT2 receptor ligand binding; chronic, but not acute, ECS treatment significantly increased levels of [3H]ketanserin ligand binding, confirming previous reports. Northern blot analysis demonstrated that 5-HT2 receptor mRNA occurs as two bands (approximately 5 and 6 kb in size), both of which were increased by chronic ECS treatment. The influence of antidepressant drug treatments on 5-HT2 receptor mRNA was also examined. Chronic fluoxetine treatment increased levels of 5-HT2 receptor mRNA, although levels of [3H]ketanserin ligand binding were not altered. In contrast, chronic administration of imipramine, mianserin, and tranylcypromine, treatments that decreased ligand binding, did not decrease levels of 5-HT2 receptor mRNA. In fact, mianserin treatment caused a small, but significant, increase in levels of receptor mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)

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)

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.

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.

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.

Effects of electroconvulsive seizures on amine metabolism in the rat brain.

Effects of acute and repeated electroconvulsive seizures (ECS) on amine metabolism in the rat brain were studied. Acute ECS increased the rate of disappearance of intracisternally injected [ 3 H]norepinephrine (NE) and its conversion to [ 3 H]normetanephrine as well as the disappearance of endogenous serotonin (5HT) and appearance of its major metabolite 5-hydroxyindoleacetic acid (5HIAA). One day following a week of 14 ECS treatments, there was a small ( 3 H]NE, which had disappeared by day 3. Increased turnover of 5HT was also found one day following a week of ECS, but this was no greater than occurred after the stress of handling alone. There were no changes in the levels of histamine after acute or repeated ECS. It seems unlikely that these effects bear an important relationship to the mechanisms of action of clinical ECT as used in the treatment of depression in patients.