Chronic Electroconvulsive Shock Research Articles

Electroconvulsive Shock, but Not Transcranial Magnetic Stimulation, Transiently Elevates Cell Proliferation in the Adult Mouse Hippocampus.

Hippocampal plasticity is hypothesized to play a role in the etiopathogenesis of depression and the antidepressant effect of medications. One form of plasticity that is unique to the hippocampus and is involved in depression-related behaviors in animal models is adult neurogenesis. While chronic electroconvulsive shock (ECS) strongly promotes neurogenesis, less is known about its acute effects and little is known about the neurogenic effects of other forms of stimulation therapy, such as repetitive transcranial magnetic stimulation (rTMS). Here, we investigated the time course of acute ECS and rTMS effects on markers of cell proliferation and neurogenesis in the adult hippocampus. Mice were subjected to a single session of ECS, 10 Hz rTMS (10–rTMS), or intermittent theta burst stimulation (iTBS). Mice in both TMS groups were injected with BrdU 2 days before stimulation to label immature cells. One, 3, or 7 days later, hippocampi were collected and immunostained for BrdU + cells, actively proliferating PCNA + cells, and immature DCX + neurons. Following ECS, mice displayed a transient increase in cell proliferation at 3 days post-stimulation. At 7 days post–stimulation there was an elevation in the number of proliferating neuronal precursor cells (PCNA + DCX +), specifically in the ventral hippocampus. iTBS and rTMS did not alter the number of BrdU + cells, proliferating cells, or immature neurons at any of the post-stimulation time points. Our results suggest that neurostimulation treatments exert different effects on hippocampal neurogenesis, where ECS may have greater neurogenic potential than iTBS and 10–rTMS.

Effect of acute and chronic electroconvulsive shock on 5-hydroxytrypamine 6 receptor immunoreactivity in rat hippocampus.

Electroconvulsive shock (ECS) induces not only an antidepressant effect but also adverse effects such as amnesia. One potential mechanism underlying both the antidepressant and amnesia effect of ECS may involve the regulation of serotonin (5-hydroxytryptamine) 6 (5-HT6) receptor, but less is known about the effects of acute ECS on the changes in 5-HT6 receptor expression in the hippocampus. In addition, as regulation of 5-HT receptor expression is influenced by the number of ECS treatment and by interval between ECS treatment and sacrifice, it is probable that magnitude and time-dependent changes in 5-HT6 receptor expression could be influenced by repeated ECS exposure. To explore this possibility, we observed and compared the changes of 5-HT6 receptor immunoreactivity (5-HT6 IR) in rat hippocampus at 1, 8, 24, or 72 h after the treatment with either a single ECS (acute ECS) or daily ECS for 10 days (chronic ECS). We found that acute ECS increased 5-HT6 IR in the CA1, CA3, and granule cell layer of hippocampus, reaching peak levels at 8 h and returning to basal levels 72 h later. The magnitude and time-dependent changes in 5-HT6 IR observed after acute ECS were not affected by chronic ECS. These results demonstrate that both acute and chronic ECS transiently increase the 5-HT6 IR in rat hippocampus, and suggest that the magnitude and time-dependent changes in 5-HT6 IR in the hippocampus appear not to be influenced by repeated ECS treatment.

Effects of Acute and Chronic Electroconvulsive Shocks on Glycogen Synthase Kinase 3β Level and Phosphorylation in Mice

Glycogen synthase kinase 3β (GSK-3β) is recently proposed as a novel target in the treatment of mood disorders. Recent evidence has suggested that acute and chronic administration of antidepressants led to inhibition of GSK-3β via phosphorylation of Serine9 residue. Acute electroconvulsive shock (ECS) has been reported to increase GSK-3β phosphorylation transiently. In this study, the changes in the level of GSK-3β and its phoshorylated form (phospho-Ser9-GSK-3β) following chronic ECS (cECS) were investigated in mice. Mice were given daily ECS via bilateral corneal electrodes for 10 consecutive days in the chronic group and a single ECS in the acute group. Electrodes were applied without stimulation in corresponding sham groups. Immunoblotting for GSK-3β and phospho-Ser9-GSK-3β was performed with the frontal cortex and hippocampus samples, extracted 10 minutes after single ECS, and 24 hours after the last ECS in the chronic group. The optical densities of the bands obtained were compared between the active treatment and sham groups for each condition separately. The level of phospho-Ser9-GSK-3β was not different following chronic ECS, but significantly higher following acute ECS, compared with the corresponding sham group, in the hippocampus and frontal cortex. The level of GSK-3β was similar to sham following both acute and chronic ECS, in both regions. The transient increase in GSK-3β phosphorylation observed following acute ECS in the mice hippocampus and frontal cortex was not found to persist 24 hours following chronic ECS. The mechanism of action of ECS does not seem to involve persistent change in the level and phosphorylation of GSK-3β.

Effects of chronic antidepressant drug administration and electroconvulsive shock on activity of dopaminergic neurons in the ventral tegmentum: a reply to Chenu et al. (2011)

We have read the letter commenting on our article entitled ‘Effects of chronic antidepressant drug administration and electroconvulsive shock on activity of dopaminergic neurons in the ventral tegmentum’. We offer the following response. The authors of the letter direct attention to our mean spontaneous firing rate for dopaminergic neurons in the ventral tegmental area (VTA-DA neurons) being lower than typically found and particularly note that we included neurons with firing rates as low as 1.0 Hz. Our mean rates of firing are indeed somewhat lower than often reported by other investigators. We were clearly aware of this, specifically describing in our Methods section that we included slow-firing neurons. Our criteria for DA neurons in the VTA depended upon ( a ) stereotaxic location and then ( b ) the specific wave form of the unit as stated in the Procedure section, which is widely acknowledged for these neurons. Because we were recording multiple neurons in each animal, there was no way to mark individual neurons and identify their locations and/or characteristics histologically; consequently, we included neurons based on waveform. Given these criteria, we saw no basis for discarding neurons because their firing rate was slow and, consequently, such neurons were included. The writers of the letter call attention to an article by Ungless et al. (2004), who described differences between DA and non-DA neurons in the VTA. The writers noted that our mean spontaneous firing rate was closer to that of non-dopaminergic cells than dopaminergic cells. However, the main point of the article by Ungless et al. was that VTA-DA neurons were inhibited by aversive or stressful stimuli whereas non-DA neurons were excited by such stimuli; they reported 10 of 12 DA neurons were inhibited by 10-s foot pinch whereas four of six non-DA neurons were excited by this stimulus. We have examined the …

Glial cell-line derived neurotrophic factor is essential for electroconvulsive shock-induced neuroprotection in an animal model of Parkinson's disease

Sustained motor improvement in human patients with idiopathic Parkinson's disease has been described following electroconvulsive shock (ECS) treatment. In rats, ECS stimulates the expression of various trophic factors (TFs), some of which have been proposed to exert neuroprotective actions. We previously reported that ECS protects the integrity of the rat nigrostriatal dopaminergic system against 6-hydroxydopamine (6-OHDA)-induced toxicity; in order to shed light into its neuroprotective mechanism, we studied glial cell-line derived neurotrophic factor (GDNF) levels (the most efficient TF for dopaminergic neurons) in the substantia nigra (SN) and striatum of 6-OHDA-injected animals with or without ECS treatment. 6-OHDA injection decreased GDNF levels in the SN control animals, but not in those receiving chronic ECS, suggesting that changes in GDNF expression may participate in the ECS neuroprotective mechanism. To evaluate this possibility, we inhibit GDNF by infusion of GDNF function blocking antibodies in the SN of 6-OHDA-injected animals treated with ECS (or sham ECS). Animals were sacrificed 7 days after 6-OHDA infusion, and the integrity of the nigrostriatal system was studied by tyrosine hydroxylase immunohistochemistry and Cresyl Violet staining. Neuroprotection observed in ECS-treated animals was inhibited by GDNF antibodies in the SN. These results robustly demonstrate that GDNF is essential for the ECS neuroprotective effect observed in 6-OHDA-injected animals.

Chronic electroconvulsive shock alters hypothermic response of B-HT 920 and SKF 38393 in rats

The hypothermic response of B-HT 920, a D2-dopamine agonist remained unaltered while that of apomorphine, a mixed D1-/D2-agonist was significantly reduced following chronic electro-convulsive shock (ECS) treatment. SKF 38393 (5 mg kg-1), a selective D1-agonist potentiated the hypothermic response of B-HT 920 in non-ECS-treated rats. The response of the combination was, however, attenuated following chronic ECS treatment. These observations suggested a reduction in D1-receptor density following chronic ECS treatment in rats.

Repeated electroconvulsive shock (ECS) alters the phosphorylation of glutamate receptor subunits in the rat hippocampus

Glutamate and its receptors are involved in the pathophysiology of mood disorders and have recently emerged as potential targets for the pharmacotherapy of depression. In rats, we investigated plasticity changes of the glutamatergic system evoked by electroconvulsive shock (ECS), which represents the most effective therapy for patients who are refractory to antidepressants. Chronic ECS produced a marked increase in the phosphorylation of the regulatory NMDA receptor subunit NR2B (Ser1303) and the AMPA receptor subunit GluR-A (Ser831) in the hippocampus, with no effects on the obligatory subunit NR1. No effects were found on total receptor subunit expression levels. We suggest that, at least in part, ECS exerts its clinical activity through the modulation of the glutamatergic synapses, via potentiation of AMPA currents mediated by GluR-A (Ser831) phosphorylation, and a reduction of NMDA receptor activity through the phosphorylation of NR2B (Ser1303), presumably uncoupling NR2B from its signalling partner CaMKII. These effects functionally resemble the recently described antidepressant effects of ketamine.

Immunohistochemical evaluation of the protein expression of nerve growth factor and its TrkA receptor in rat limbic regions following electroshock seizures

Repeated (but not acute) exposure to brief, non-injurious seizures evoked by minimal electroconvulsive shock (ECS) decreases neuronal death in limbic system and increases mRNA levels for nerve growth factor (NGF). Thus, the induction of NGF is a potential mechanism for the neuroprotection evoked by repeated ECS. The neuroprotective action of NGF is mediated by the TrkA receptor. This study determined whether repeated ECS exposure increased TrkA and NGF protein levels. To determine the functional significance of changes in these proteins, we compared the effects of ECS given daily either for 7 days (chronic ECS) or for 1 day (acute ECS). After chronic ECS, upregulation of both NGF and TrkA was found in perirhinal cortex, thalamus, and amygdala. In hippocampus, TrkA was upregulated in CA2, CA3 and CA4. NGF increase in hippocampus was found in CA1 and dentate gyrus. In frontal cortex and substantia innominata, an increase in NGF (but not in TrkA) was found. In most brain regions, TrkA and NGF remained unchanged after acute ECS. Our results demonstrate that repeated exposure to ECS causes an upregulation of TrkA and NGF proteins in several limbic areas in which neuroprotective effects are observed suggesting that NGF contributes to ECS-evoked neuroprotection.

Chronic Treatment With Electroconvulsive Shock May Modulate the Immune Function of Macrophages

To determine the effect of single and chronic electroconvulsive shock (ECS) administration on the immunoregulatory functions of macrophages. Male Wistar rats received single or chronic treatment with ECS (150 mA, 50 Hz, 0.5 seconds) delivered through ear clips, once a day for 10 consecutive days, or sham ECS administered likewise. The rats were killed 24 hours after the last treatment, and peritoneal macrophages were cultured in vitro for 3 or 36 hours for a subsequent determination of their metabolic activity. The ability of macrophages to reduce Alamar Blue, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT), and nitrotetrazolium blue chloride and pinocytosis, adherence, and vitality, as well as synthesis of nitric oxide and arginase activity, was assessed. We found statistically significant changes in the biological properties of macrophages which occurred after 36 hours of incubation, especially in cultures stimulated with lipopolysaccharide; in contrast, no differences were observed between groups assessed after 3 hours of incubation. Rats receiving chronic 10-fold ECS showed a substantial increase in the metabolic activity of macrophages, reflected as their ability to reduce Alamar Blue and MTT and to increase arginase activity, accompanied with a marked but statistically insignificant decrease in nitric oxide synthesis compared with respective controls. Our results suggest that chronic treatment with ECS may induce long-lasting changes in the activity of peritoneal macrophages. Attenuation of their proinflammatory properties indicates that ECS can change the primarily immunoregulatory functions of macrophages.

Electroconvulsive shock alters the rat overt rhythms of motor activity and temperature without altering the circadian pacemaker

The hypothetical relationship between circadian rhythms alterations and depression has prompted studies that examine the resultant effects of various antidepressants. Electroconvulsive therapy (ECT) exerts significant antidepressant effects that have been modelled in the laboratory via the use of electroconvulsive shock (ECS) in rats. However, data on the effects of ECT or ECS vis-à-vis the circadian rhythms remain scarce. Thus, we report here the effects of acute and chronic ECS administration on the temperature and motor activity circadian rhythms of rats. The motor activity and core body temperature of rats were continuously recorded to determine the circadian rhythms. We carried out three experiments. In the first, we analyzed the effects of acute ECS on both the phase and period when applied at different times of the subjective day. In the second and third experiments ECS was nearly daily applied to rats for 3 weeks: respectively, under dim red light, which allows a robust free-running circadian rhythm; and under light–dark cycles of 22h (T22), a setting that implies dissociation in the circadian system. Acute ECS does not modify the phase or the period of circadian rhythms. Chronic administration of ECS produces an increase in motor activity and temperature, a decrease in the amplitude of circadian rhythms, although the period of the free-running rhythm remains unaffected. In conclusion, while chronic ECS does alter the overt rhythms of motor activity and temperature, it does not modify the functioning of the circadian pacemaker.

Astroglia: Not Just Glue

Astroglia: Not Just Glue

Regulation of rat cortical 5-hydroxytryptamine 2A receptor-mediated electrophysiological responses by repeated daily treatment with electroconvulsive shock or imipramine

Down-regulation of 5-hydroxytryptamine 2A (5-HT 2A) receptors has been a consistent effect induced by most antidepressant drugs. In contrast, electroconvulsive shock (ECS) up-regulates the number of 5-HT 2A receptor binding sites. However, the effects of antidepressants on 5-HT 2A receptor-mediated responses on identified cells of the cerebral cortex have not been examined. The purpose of the present study was to compare the effects of the tricyclic antidepressant imipramine and ECS on 5-HT 2A receptor-mediated electrophysiological responses involving glutamatergic and GABAergic neurotransmission in the rat medial prefrontal cortex (mPFC) and piriform cortex, respectively. The electrophysiological effects of activating 5-HT 2A receptors were consistent with 5-HT 2A receptor binding regulation for imipramine and ECS except for the mPFC where chronic ECS decreased the potency of 5-HT at a 5-HT 2A receptor-mediated response. These findings are consistent with the general hypothesis that chronic antidepressant treatments shift the balance of serotonergic neurotransmission towards inhibitory effects in the cortex.

Citalopram influences mGlu7, but not mGlu4 receptors' expression in the rat brain hippocampus and cortex

Earlier studies showed that chronic electroconvulsive shock (ECS) or imipramine treatment induced a sub-sensitivity of group I metabotropic glutamate receptors (mGluRs) in the hippocampus as well as an increase in the receptor protein level in this structure. In the present study, the effects of chronic imipramine (10 mg/kg, 21 days) or citalopram (10 mg/kg, 21 days) treatment on the mGlu4 or mGlu7 receptors' protein levels in the frontal cortex and hippocampus of the rat brain were examined using the Western blot analysis. We also examined the influence of these drugs' administration on forskolin-stimulated cAMP formation. A non-selective agonist of all receptors belonging to the III group of mGluRs, ACPT-1, was used to establish their effects on the cAMP production. It was found that mGluR7-immunoreactivity both in the hippocampus and in the cerebral cortex was decreased after citalopram, but not imipramine treatment. No changes were observed in the mGluR4-immunoreactivity. Prolonged treatment with these two drugs failed to change the action of group III mGluR agonist, ACPT-1, on the forskolin-stimulated cAMP accumulation. Our results suggest that the mGluR7 receptor is influenced by prolonged treatment of the antidepressant drug citalopram in the brain regions that are considered to be implicated in the clinical response to antidepressant therapy whilst the mGlu4 receptor is not.

Protection of dopaminergic neurons by electroconvulsive shock in an animal model of Parkinson’s disease

Electroconvulsive shock (ECS) improves motor function in Parkinson's disease. In rats, ECS stimulates the expression of various factors some of which have been proposed to exert neuroprotective actions. We have investigated the effects of ECS on 6-hydroxydopamine (6-OHDA)-injected rats. Three weeks after a unilateral administration of 6-OHDA, 85-95% nigral dopaminergic neurons are lost. Chronic ECS prevented this cell loss, protect the nigrostriatal pathway (assessed by FloroGold retrograde labeling) and reduce motor impairment in 6-OHDA-treated animals. Injection of 6-OHDA caused loss of expression of glial cell-line derived neurotrophic factor (GDNF) in the substantia nigra. Chronic ECS completely prevented this loss of GDNF expression in 6-OHDA-treated animals. We also found that protected dopaminergic neurons co-express GDNF receptor proteins. These results strongly suggest that endogenous changes in GDNF expression may participate in the neuroprotective mechanism of ECS against 6-OHDA induced toxicity.

Rapid activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway by electroconvulsive shock in the rat prefrontal cortex is not associated with TrkB neurotrophin receptor activation.

1. Emerging evidence indicates that brain-derived neurotrophic factor (BDNF) and its receptor TrkB play important roles in the mechanism of action of electroconvulsive shock (ECS) treatment. ECS produces a significant increase in brain BDNF synthesis together with a variety of neuroplastic changes including neurogenesis and axonal sprouting in the rodent brain, which is believed to be associated to the antidepressant effect of ECS. ERK1/2 (extracellular signal-regulated kinase-1/2) and Akt (protein kinase B), both intracellular signaling molecules being linked to neurotrophin signaling and synthesis, are important pathways triggered by TrkB autophosphorylation. 2. We have previously observed that chemical antidepressants induce a rapid activation of TrkB signaling in the rodent prefrontal cortex (PFC), which is likely a consequence of the stimulatory effect of antidepressants on BDNF synthesis. However, it is not known whether ECS triggers TrkB autophosphorylation and if any ECS-induced effect on TrkB function may be associated with the activation of the ERK1/2 and Akt pathways. 3. The present study assayed the phosphorylation levels of TrkB, ERK1/2, and Akt in the PFC of sham and ECS-treated rats. While the TrkB autophosphorylation (pTrkB) levels were decreased 30 min after both acute and chronic ECS, no change in pTrkB levels were observed at any other time points measured. In contrast, acute but not chronic ECS, transiently induced a very rapid and robust hyperphosphorylation of ERK1/2. Akt phosphorylation levels remained unchanged following acute or chronic ECS. Hence, although ECS effectively stimulates the ERK1/2 pathway in the PFC, this effect does not appear to involve upstream activation of TrkB.

Effect of Electroconvulsive Shock on Mitochondrial Respiratory Chain in Rat Brain

It is well described that impairment of energy production has been implicated in the pathogenesis of a number of diseases. Although several advances have occurred over the past 20 years concerning the use and administration of electroconvulsive therapy (ECT) to minimize its side effects, little progress has been made in understanding its mechanism of action. In this work, our aim was to measure the activities of mitochondrial respiratory chain complexes II and IV and succinate dehydrogenase from rat brain after acute and chronic electroconvulsive shock (ECS). Our results showed that mitochondrial respiratory chain enzymes activities were increased after acute ECS in hippocampus, striatum and cortex of rats. Besides, we also demonstrated that complex II activity was increased after chronic ECS in cortex, while hippocampus and striatum were not affected. Succinate dehydrogenase, however, was inhibited after chronic ECS in striatum, activated in cortex and not affected in hippocampus. Finally, complex IV was not affected by chronic ECS in hippocampus, striatum and cortex. Our findings demonstrated that brain metabolism is altered by ECS.

Activation of extracellular signal-regulated kinase signaling by chronic electroconvulsive shock in the rat frontal cortex

The effects of chronic electroconvulsive shock (ECS), given daily for 1, 5 and 10 days, on the activation of extracellular signal-regulated kinase (ERK) were studied in the rat frontal cortex. The phosphorylation of MEK1/2 and ERK1/2 increased through 5 days of ECS. Thereafter, a plateau was achieved. The expression of brain-derived neurotrophic factor was continuously increased for 10 days. Our data show that the effect of ECS on ERK1/2 signaling is increased with chronic treatment.

Effects of electroconvulsive seizures on Na +,K +-ATPase activity in the rat hippocampus

Although several advances have occurred concerning the use of electroconvulsive therapy, little progress has been made in understanding the mechanisms underlying its therapeutic or side effects. Na +,K +-ATPase is an important enzyme of central nervous system, responsible for ionic gradient maintenance and consumption of approximately 40–50% of brain ATP. This work was performed in order to determine Na +,K +-ATPase activity after acute and chronic electroconvulsive shock. Results showed an inhibition of Na +,K +-ATPase activity in the hippocampus 48 h, 7, 30, 60 and 90 days after a single electroconvulsive shock. Chronic treatment diminished the enzyme activity in the hippocampus 7 and 30 days after electroconvulsive (ECS) sessions. Our findings demonstrated that Na +,K +-ATPase activity is altered by ECS.

Decreased Creatine Kinase Activity Caused by Electroconvulsive Shock

Although several advances have occurred over the past 20 years concerning the use and administration of electroconvulsive therapy to minimize side effects of this treatment, little progress has been made in understanding its mechanism of action. Creatine kinase is a crucial enzyme for brain energy homeostasis, and a decrease of its activity has been associated with neuronal death. This work was performed in order to evaluate creatine kinase activity from rat brain after acute and chronic electroconvulsive shock. Results showed an inhibition of creatine kinase activity in hippocampus, striatum and cortex, after acute and chronic electroconvulsive shock. Our findings demonstrated that creatine kinase activity is altered by electroconvulsive shock.

Long Lasting Effects of Electroconvulsive Seizures on Brain Oxidative Parameters

This work was performed in order to determine the level of oxidative damage and antioxidant enzymes activities late after acute and chronic electroconvulsive shock (ECS) in rats. We measured oxidative parameters in hippocampus, cortex, and striatum, at 45, 60, 90 and 120 days after a single or multiple ECS. We demonstrated an increase in lipid peroxidation after multiple ECS in the hippocampus and striatum. This was also the case for protein carbonyls in the single or multiple protocols. In this way, we demonstrated an increase in catalase in cortex in contrast to striatum and hippocampus, were there were decreases sometimes in chronic ECS. The superoxide dismutase activities decrease in different times after single and multiple ECS in the hippocampus. Our findings demonstrated that there is a delayed increase after ECS in oxidative damage and decrease in antioxidant enzymes activities in hippocampus and striatum.