Dissociation of analgesic and gastrointestinal effects of electroconvulsive shock-released opioids

Activation of endogenous opioid systems by electroconvulsive shock (ECS) produced naloxone-reversible thermal analgesia (52 degrees C hot plate) 5 min after ECS administration. Although opioid peptides injected intracerebroventricularly have previously been found to inhibit gastrointestinal motility, ECS treatment did not affect gastric emptying, small or large intestinal transit. These results suggest that centrally-mediated opioid analgesia and changes in gastrointestinal motility are initiated through independent mechanisms.     

Perspectives on the Mechanism of Action of Electroconvulsive Therapy: Anticonvulsant, Peptidergic, c-fos Proto-oncogene Effects

Although the mechanism of action of electroconvulsive therapy (ECT) in affective illness has remained elusive, it is hoped that the consideration of mechanisms underlying the anticonvulsant efficacy of ECT will provide new insights into its biochemical and neuroanatomical substrates. In the amygdala-kindling model, electroconvulsive seizures (ECS) inhibit both the development and completed phases of kindled seizure evolution, and therefore, ECS is a more potent anticonvulsant modality than carbamazepine, which inhibits only completed kindled seizures. Carbamazepine is increasingly recognized for its acute and prophylactic efficacy in bipolar affective illness. Thus, comparing and contrasting effects of ECS and carbamazepine may provide insights into overlapping mechanisms of anticonvulsant and psychotropic action. Anticonvulsant effects of ECS have been most closely linked to endogenous opiate substances, perhaps acting on delta-opiate receptors, but a wide variety of other neurotransmitter and peptidergic effects are also potential candidates. Electroconvulsive seizures in mice activate the proto-oncogene c-fos in many discrete areas of brain, including a variety of limbic sites, the ventromedial nucleus of the hypothalamus, and the cerebellum. As such, c-fos induction may provide both an anatomical map of areas potentially activated by ECS and a potential mechanism for initiating a sequence of events that may be important to the mechanism of action of ECT. Although the anticonvulsant effects of ECT may ultimately prove to be separable from those mediating its therapeutic effects in affective illness, seizures and anticonvulsant effects provide easily measurable endpoints for preclinical and clinical studies. Given this clarity of effect, potential anticonvulsant mechanisms can rapidly be identified, enabling direct testing of whether or not these same mechanisms are also critical to the therapeutic effects of ECT in affective illness.     

Accumulated increase in neuropeptide Y and somatostatin gene expression of the rat in response to repeated electroconvulsive stimulation

The mechanisms by which electroconvulsive therapy (ECT) causes its antidepressive effect are unknown. Because ECT requires repeated induction of electroconvulsive seizures, adaptive changes in the brain and regulation of gene expression, are likely to be the fundamental basis on which ECT acts. Neuropeptide Y (NPY) gene expression is increased after multiple electroconvulsive stimulations (ECS) and since it also has anticonvulsant and antidepressant properties, it has led to the hypothesis that the beneficial effect of ECT is mediated via its activation of NPY-dependent neurotransmission. We have therefore examined in detail the temporal profile of NPY gene expression, using in situ hybridisation histochemistry in the rat dentate gyrus and piriform cortex - two brain areas centrally involved in seizure regulation. NPY mRNA in both regions was found to increase gradually with the number of ECS, reaching a maximum (550-700%) after approximately 14 ECS where no further increase was achieved by additional ECS. A number of 14 ECS was also shown to exert anticonvulsant activity against kainic acid seizures. In the dentate gyrus, repeated ECS also caused a gradual, but smaller, increase in the expression of somatostatin (SS) - a neuropeptide that is co-localised with NPY and also has anticonvulsant effects. These results shows that NPYergic and, to a lesser extent, SSergic neurotransmission is activated by ECS and support the hypothesis that these neuropeptides could play a central role in the anticonvulsant and antidepressant effect of ECT.     

Naloxone fails to prolong seizure length in ECT

Electroconvulsive shock (ECS) in animals has been shown to enhance endogenous opiate systems. The anticonvulsant effects of ECS are also partially blocked by the opiate receptor antagonist naloxone, leading some investigators to postulate that the anticonvulsant effects of ECS are mediated by activation of endogenous opiates. If such a phenomenon occurs in humans, then naloxone might prolong seizure length in electroconvulsive therapy (ECT). In the present study, nine patients were given 2.0 mg intravenous (i.v.) naloxone 2 minutes prior to one-half of their ECT treatments. Motor seizure length was measured via the cuff technique. EEG tracings were read by an investigator blind to naloxone status. There was no difference between the two groups in either EEG or nonblindly evaluated motor seizure length. It is concluded that a dose of 2 mg naloxone does not effectively increase seizure length in ECT.     

Electroconvulsive therapy as an anticonvulsant: a possible role of neuropeptide Y (NPY)

Seizure threshold increases during a series of electroconvulsive therapy (ECTs). Based on assumptions that the effect of ECT may be related to its anticonvulsant effect we were interested in identifying transmitters that are activated by the treatment and play an anticonvulsant role. Animal studies reveal that neuropeptide Y (NPY) neurotransmission is increased by repeated electroconvulsive shock (ECS), and NPY has been found to inhibit glutamate-mediated synaptic transmission in the rat hippocampus. The increase of NPY gene expression in highly sensitive areas of the rat hippocampus (dentate gyrus) and piriform cortex accompanied by a reduction of NPY binding sites in the same regions after ECS supports this notion. Further studies have shown that NPY exerts a seizure-suppressing activity of NPY after kainic acid injections in vivo. Taken together the present series of experiments in rats strongly points to the seizure suppressing properties of NPY and suggests that this peptide may be involved in the seizure threshold increase during effective ECT in humans.     

Effects of MK-801 and electroconvulsive shock on c-Fos expression in the rat hippocampus and frontal cortex

Both the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 and electroconvulsive shock (ECS) have been reported to induce c-Fos in rat brain. However, the former has anticonvulsant and psychotomimetic effects and the latter has proconvulsant and antipsychotic effects. To understand the mode of action of these treatments, the authors examined the effect of MK-801 and the interaction between MK-801 and ECS on the induction of c-Fos in the rat hippocampus and frontal cortex. MK-801 induced c-Fos in these brain regions in a nonlinear dose-response relationship. Maximum effect was achieved with 1-2 mg/kg of MK-801. The level of c-Fos paralleled animal hyperkinetic behavior, suggesting the role of c-Fos in the induced psychotomimetic behaviors. Pretreatment with MK-801 dose-dependently attenuated both the seizures and c-Fos expression by ECS. However, at an MK-801 pretreatment dose of 8 mg/kg, which completely blocked ECS-induced seizure, the induction of c-Fos was not completely blocked, suggesting non-NMDA mediated pathways of the induction of c-Fos by ECS.     

The effect of prolonged treatment with imipramine and electroconvulsive shock on the levels of endogenous enkephalins in the nucleus accumbens and the ventral tegmentum of the rat

Summary The present study was designed to find out whether the prolonged administration of imipramine (IMI) or electroconvulsive shock (ECS) influences levels of endogenous enkephalins in the nucleus accumbens (NAS) and the ventral tegmentum (VTA) of the rat. Ressults indicate that treatment with IMI as well as with ECS has a profound effect on the levels of enkephalins in both structures. In the NAS both treatments lead to an increase in the levels of endogenous enkephalins and this effect is accompanied by an increase in mRNA coding for proenkephalin (measured by in situ hybridization) in this structure, indicating the enhancement of biosynthesis of endogenous enkephalinergic peptides following antidepressant treatment. The results are discussed in the light of the hypothesis concerning the influence of endogenous enkephalins on mesolimbic dopamine neurons, the activity of which plays a crucial role in the etiology of depression.     

Changes in cholecystokinin mRNA expression after amygdala kindled seizures: an in situ hybridization study

Cholecystokinin (CCK) can be a potent anticonvulsant neuropeptide in certain seizure models. Therefore, we examined whether seizures produced by electrical kindling of the amygdala or electroconvulsive seizures (ECS) would affect the expression of CCK mRNA in rat brain. Following a single kindled seizure, CCK mRNA expression was decreased about 20–58% in the amygdala. In contrast, after multiple consecutive kindled seizures, CCK mRNA expression was increased in the amygdala, cerebral cortex, CA1 pyramidal cell layer of the hippocampus and dentate hilus. A single ECS produced no effect on CCK mRNA expression, but multiple ECS increased expression in the interneurons of the hippocampus 24 h after the last seizure. Since seizures produced by ECS can be anticonvulsant to further ECS or kindled seizures, the CCK increases in the hippocampus may represent a compensatory anticonvulsant adaptation observed in both models. Overall, the kindling-induced alterations in CCK expression appear to be more complex involving multiple brain regions and distinct temporal properties.     

Extracellular levels of NPY in the dorsal hippocampus of freely moving rats are markedly elevated following a single electroconvulsive stimulation,irrespective of anticonvulsive Y1 receptor blockade

Neuropeptide Y (NPY) has been proposed to play a role in the pathophysiology of depression and also to act as an endogenous anticonvulsant. Repeated administration of electroconvulsive stimulations (ECS) has been shown to induce a long-term increase in hippocampal NPY neurotransmission, while the effects of single ECS are largely unexplored. In this study, we assessed extracellular levels of NPY in the dorsal hippocampus of freely moving rats following a single ECS. We also studied the effect of locally administered BIBP3226, a selective NPY Y1 receptor antagonist with reported anticonvulsant properties, on the duration of the ECS-induced seizure and NPY release in freely moving animals. Our data demonstrate that a single ECS increases extracellular NPY-like immunoreactivity (LI) levels in the dorsal hippocampus, reaching statistical significance 2h following the treatment. KCl transiently and calcium-dependently increased extracellular levels of NPY, suggesting that the measured NPY-LI is derived from functional neurons. Local BIBP3226 perfusion essentially abolished the ECS-induced seizure but had no effect on the basal NPY-LI outflow or on the ECS-induced rise in extracellular NPY levels. Our data are in line with the hypothesis that one mechanism of action of ECS is to release NPY in the hippocampus and suggest that the increase is in itself not associated with anticonvulsant activity but may represent other properties of NPY.     

Repeated electroconvulsive shock downregulates the opioid receptors in rat brain

Ten consecutive daily electroconvulsive shocks (ECSs), which produce maximal tonic and clonic convulsions, caused reductions of mu- and delta-opioid receptor binding in the hypothalamus, hippocampus and caudate nucleus, but not in the frontal cortex and brainstem. These changes of opioid receptor binding were not observed in rats receiving a single ECS. Scatchard analysis revealed that ECS-induced reduction of mu- and delta-receptor binding was due to a decrease in the binding sites but not to a change in the binding affinity. Time course studies showed that 7 days after the end of 10 consecutive daily ECSs, both mu- and delta-receptor binding remained lower than those of sham controls. However, the effects of ECS on the opioid receptor binding disappeared in 2-3 weeks. These observations are consistent with the hypothesis that ECS treatments increase the release of opioid peptides in certain brain regions which in turn down-regulate the opioid receptors.     

Dynorphin- and enkephalin-like immunoreactivity is altered in limbic-basal ganglia regions of rat brain after repeated electroconvulsive shock

In an attempt to determine whether the opioid peptides derived from prodynorphin participate in the effects of electroconvulsive shock (ECS), we used radioimmunoassay and immunocytochemistry to measure dynorphin-like immunoreactivity (DN-LI) in various rat brain regions after repeated ECS treatments. Ten daily ECSs caused a significant increase in dynorphin A (1-8)-LI in most limbic-basal ganglia structures, including hypothalamus (50%), striatum (30%), and septum (30%). No significant change was found in the frontal cortex or the neurointermediate lobe of the pituitary. In contrast, 10 ECS treatments depleted DN-LI in hippocampal mossy fibers by 64%. A detailed time-course study revealed that a single shock caused a small but significant increase in hippocampal DN-LI, whereas three consecutive shocks depleted DN-LI by 30%. The maximal decrease in DN-LI was reached after six daily ECSs. The level of DN-LI in the hippocampus partly recovered, but remained lower than the control value 4, 7, and 14 d after the cessation of six daily ECSs (50, 77, and 83% of control value, respectively). In contrast with the ECS-induced depletion of hippocampal dynorphin, 10 daily ECSs caused a significant increase (40%) in (Met5)-enkephalin-LI in the hippocampus, as well as in other limbic-basal ganglia structures. Immunocytochemistry revealed that enkephalin-LI was increased in the perforant pathway, which is presynaptic to the dynorphin-containing mossy fiber pathway in the hippocampus. These observations suggest that different mechanisms may regulate these two opioid peptide systems in the hippocampus.(ABSTRACT TRUNCATED AT 250 WORDS)     

High but not low ECS stimulus intensity augments apomorphine-stimulated dopamine postsynaptic receptor functioning in rats

BACKGROUND: Clinical research shows that the antidepressant and cognitive adverse effects of electroconvulsive therapy are both dependent on the administered electrical stimulus intensity (dose); however, dose-dependent neurotransmitter system changes in the brain, which might underlie the therapeutic or adverse effects, remain to be demonstrated. OBJECTIVE: We used a behavioral model to examine dose-related effects of electroconvulsive shock (ECS) on dopamine postsynaptic receptor functioning in the rat brain. METHODS: In a factorially designed study, rats (n = 100) were treated with five once-daily ECSs at three levels (sham ECS, 30 mC ECS, and 120 mC ECS), and with drug at two levels (saline, and 1 mg/kg s.c. apomorphine). Motility was assessed in the small open field. RESULTS: Apomorphine-elicited, dopamine postsynaptic receptor-mediated hypermotility was significantly increased by 120 mC ECS but not by 30 mC ECS. An additional but unrelated finding was that, while the ECS seizure duration expectedly decreased across time, no dose-dependent effects were observed. CONCLUSION: ECS-induced dopamine postsynaptic receptor up-regulation may depend on the intensity of the administered electrical stimulus.     

Studies on the effects of opioid, noradrenergic and serotonergic antagonists on the antinociceptive effects of electroconvulsive shock

Electroconvulsive shock (ECS) evoked a short-latencied elevation in the hot plate and tail flick response latencies. Naloxone administered before or immediately after ECS produced a dose-dependent antagonism of the antinociceptive effect measured at 7 min but not at 2 min after ECS. Intrathecally administered propranolol, methysergide or naloxone had no effect when administered either before or after ECS. In contrast, phentolamine given intrathecally produced a significant antagonism of the reflex latencies otherwise elevated after ECS. These effects appear mediated by an alpha 2-receptor as they were more readily antagonized by yohimbine than prazosin. These observations suggest the presence of two systems, one supraspinal and opioid in character and the other adrenergic with spinal receptors. The differential effects of injecting naloxone before and after ECS suggests that the opioid system is activated between 2 and 5 min after the ECS, while the adrenergic system, as examined by the effects of intrathecal alpha- and alpha 2-antagonists, appears to be activated immediately after the application of the ECS.     

Attenuation of reserpine-induced catalepsy by melatonin and the role of the opioid system

Several reports have indicated that melatonin influences motor activity in animals and humans. Melatonin has been reported to attenuate the rigidity and tremor of Parkinson's disease. Some of the behavioral effects (e.g., analgesic and anticonvulsant properties) of melatonin have been reported to be mediated through interactions with the endogenous opioid peptides. We investigated the effect of melatonin on reserpine-induced catalepsy in the rat and, additionally, examined whether this effect is modified by opioid peptides. Melatonin was found to attenuate markedly the duration of reserpine-induced catalepsy. These effects were potentiated by administration of the opiate agonist nalbuphine hydrochloride, while naloxone partially reversed the catalepsy reducing effect of melatonin. These findings suggest that the motor effects of melatonin may involve critical interactions with opioid peptides, and support the postulated reciprocal interactions between melatonin and opioid peptides that previously have been demonstrated for the analgesic and anticonvulsant properties of melatonin.     

Age related changes in the effect of electroconvulsive shock (ECS) on the in vivo hydroxylation of tyrosine and tryptophan in rat brain.

A single electroconvulsive shock (ECS) was applied to 40 young (9 months) and 40 old (24 months) male rats. The effect on brain catecholamine synthesis was determined at intervals after ECS by measuring the accumulation of dihydroxyphenylalamine (DOPA) and 5-hydroxytryptophan (5-HTP) in rats pretreated with a central decarboxylase inhibitor (M-hydroxybenzyl hydrazine, NSD 1015). This accumulation permitted an estimation of the in vivo rates of hydroxylation of tyrosine and tryptophan. Control brain DOPA and 5-HTP concentrations were both lower in the older animals. Following ECS there was an increase in brain DOPA concentration (maximal at 60 min after ECS) in both young and old rats, but the increase was much smaller in the older animals. There were no changes in brain 5-HTP at any time after ECS, in either age group. It appears that aging selectively affects the response of the brain dopaminergic neurotransmitter system to stress, and we suggest that this may be a factor in the decreased resistance to stress in older subjects.     

Posterior hypothalamic deafferentation abolishes the amnestic effect of electroconvulsive shock in rats

The amnestic effect of immediate post-training transcorneal electroconvulsive shock ECS (15.0 mA, 60 Hz, 2 sec) on step-down inhibitory avoidance learning (0.5 mA, 60 Hz training footshock) was studied in intact rats and in rats submitted to bilateral surgical transection of the dorsal fornix, to anterior or posterior hypothalamic deafferentation, and in sham-operated animals. Animals were tested for retention 24 hr after training. The amnestic effect of ECS was observed in all groups except in the one with the posterior hypothalamic lesion. Fornix-lesioned animals showed a moderate retention deficit which was considerably worsened by the ECS treatment. The results indicate that the amnestic effect of ECS requires integrity of posterior hypothalamic pathways. One possibility is that the amnestic effect of ECS may be mediated by posterior afferent fibers to the hypothalamus acting on hypothalamic opioid systems such as have been previously proposed to play a role in ECS-induced amnesia.     

Binding pattern of [35S]t-butylbicyclophosphorothionate is not altered following electroconvulsive shock treatment in rats

Single or repeated electroconvulsive shock (ECS) treatment-induced changes in [35S]t-butylbicyclophosphorothionate [( 35S]TBPS) binding patterns in specific regions, i.e., cerebral cortex, cerebellum, hippocampus, and striatum of rat brain were investigated. Specific [35S]TBPS binding in these brain regions was not altered following a single or repeated administration of ECS, nor was the inhibition of [35S]TBPS binding to GABA affected. These observations tend to suggest that the picrotoxin-site on the GABA receptor complex may not be directly involved in electroconvulsive shock.     

Choline rise in the rat hippocampus induced by electroconvulsive shock treatment.

BACKGROUND: Human hippocampal choline decreases in major depression episodes. This decrease was recently measured by 1H magnetic resonance spectroscopy (MRS), and it has been found that its level normalizes during antidepressive electroconvulsive therapy. We hypothesized a hippocampal choline increase in the rat brain under electroconvulsive shock (ECS) treatment. METHODS: Rat hippocampi (n = 28) were investigated via magnetic resonance spectroscopy and signal intensities of choline (Cho), total creatine (tCr), and N-acetyl aspartate (NAA) were measured and expressed as ratios before and after six ECS treatments. RESULTS: After ECS treatment, hippocampal choline increases significantly: Cho/tCr ratio: +13% and Cho/NAA ratio: +19% increase. CONCLUSIONS: We found a rise of relative choline concentration induced by ECS treatment in rat hippocampus measured in vivo with magnetic resonance spectroscopy. This increase corresponds to the increase of choline in human hippocampus after electroconvulsive shock treatment. Because choline measured via 1H-spectroscopy is believed to represent primarily phosphocholine and glycerophosphocholine, and therefore phospholipase A2 activity and membrane turnover, our results are in good agreement with reported ECS-induced hippocampal mossy fiber sprouting, increased synaptic plasticity, and neurogenesis.     

Activating endogenous opioid systems by electroconvulsive shock or footshock stress inhibits recurrent kindled seizures in rats

Electroconvulsive shock (ECS) significantly decreased the behavioral manifestations of seizures elicited by amygdaloid stimulation in kindled rats. This anticonvulsant effect was significantly reduced by the opiate antagonist, naloxone, and by the development of morphine tolerance. A form of footshock stress known to cause opioid-mediated analgesia had a similar anticonvulsant effect, whereas another form causing non-opioid analgesia did not. These results suggest that the anticonvulsant effects of ECS and stress are mediated by the release of endogenous opioids.