Seizure Threshold In Rats Research Articles

Partial protective effects of cannabidiol against PTZ-induced acute seizures in female rats during the proestrus–estrus transition

Approximately 70% of women with epilepsy experience additional challenges in seizure exacerbation due to hormonal changes, particularly during fluctuations of estrogen–progesterone levels in the menstrual cycle, which is known as catamenial epilepsy. In animal models of epilepsy, a sustained increase in seizure frequency has been observed in female rats during the proestrus–estrus transition when estrogen levels are high and progesterone levels are low resembling catamenial epilepsy. Cannabidiol (CBD) has been proposed to have anticonvulsant and anti-inflammatory effects, able to decrease seizure duration and increase seizure threshold in rats with epilepsy. However, most studies have used males to investigate the pharmacological effects of CBD on seizures, and the neuroprotective effects of CBD against seizures exacerbated by hormonal fluctuations in females are still little explored. Given this scenario, the aim of the present study was to investigate whether CBD would protect against acute seizures induced by pentylenetetrazole (PTZ) in female rats during a pro-convulsant hormonal phase. Therefore, CBD (50 mg/kg) or saline was administered during the proestrus–estrus transition phase, 1 h prior to induction of seizures with PTZ (60 mg/kg), and the following parameters were recorded: duration, latency to first seizure, as well as percentage of convulsing animals (incidence), mortality, and severity of seizures. Brains were processed for immunohistochemistry for microglial cells (Iba-1), and blood was collected for the analysis of cytokines (IL-1β, IL-6, IL-10, and TNF-α). Cannabidiol pre-treated rats showed a significant reduction in duration and severity of seizures, and IL-1β levels, although the latency, incidence of seizures, and mortality rate remained unchanged as well the quantification of microglia in the selected areas. Therefore, acute administration of CBD in a single dose prior to seizure induction showed a partial neuroprotective effect against seizure severity and inflammation, suggesting that female rats in the proconvulsant phase of proestrus–estrus have a low seizure threshold and are more resistant to the anticonvulsant effects of CBD. It appears that other doses or administration windows of CBD may be required to achieve a full protective effect against seizures, suggesting that CBD could be used as an adjunctive therapy during fluctuations of estrogen–progesterone levels. In this sense, considering the hormonal fluctuation as a seizure-potentiating factor, our study contributes to understand the anticonvulsant activity of CBD in females in a pro-convulsant hormonal phase, similar to catamenial seizures in humans.

The Effect of Low-Doses of Caffeine and Taurine on Convulsive Seizure Parameters in Rats.

Introduction: Caffeine, an adenosine-receptor blocker, is believed to have neuronal excitatory effects, while Taurine, a mammalian amino acid, was shown to have neuroinhibitory effects. Aim: The aim of this study was to investigate the effects of acute and chronic administration of low doses of Caffeine and Taurine on the seizure threshold in rats. Methods: Six-week-old Sprague-Dawley male rats (n = 280) were divided randomly into five groups (control, acute caffeine intake, acute taurine intake, chronic caffeine intake and chronic taurine intake), with five subgroups per group according to five different doses of Pentylenetetrazole (PTZ) injections. Each subgroup consisted of eight rats. Data was entered and analyzed using Microsoft EXCEL and AddinsoftTM XLSTAT (Version 2012.6.06; New York, NY, USA). p-value = 0.05 was regarded as statistically significant. Results: There was a significant decrease in the latency of PTZ-induced seizures with both acute (p-value < 0.05) and chronic (p-value < 0.01) Caffeine treatment groups. Chronic exposure to Caffeine exhibited an increase in the probability of seizures (p-value < 0.05). However, acute exposure to Caffeine did not show a significant impact on the probability of seizures. Neither acute nor chronic exposures to Taurine had an effect on the probability of seizures, nor on the latency of PTZ-induced seizures. Discussion: Our study found that acute as well as chronic exposure to low doses of Caffeine (50 and 80 mg/kg) reduces the threshold, and hence increases the likelihood for seizures since it favors a state of neuronal hyper excitability through blocking of all adenosine receptors. On the other hand, acute or chronic exposure to Taurine did not show a significant effect on the PTZ-induced seizures parameters.

Vitamin E modifies high-fat diet-induced reduction of seizure threshold in rats: Role of oxidative stress

There is increasing evidence that oxidative stress is a causal factor in different neurodegenerative disorders such as Alzheimer's disease and epilepsy. High-fat diet (HFD) has been shown to induce oxidative stress and neuronal damage that may increase susceptibility to seizures. The present study was undertaken to investigate the relationships between vitamin E, a potent antioxidant, HFD, and chemically induced seizures, using the PTZ seizure model in rats. Animals were randomly assigned into four groups: control, HFD, vitamin E (Vit E), and high-fat diet with vitamin E (HFD + Vit E) group. Vitamin E and/or HFD were administered to animals for 6 weeks. Thereafter, PTZ seizure threshold was measured in control and treated rats, and different brain regions were analyzed for levels of oxidative stress biomarkers. Current results revealed a significant reduction in PTZ seizure threshold in rats consuming HFD, which could be prevented by vitamin E supplement. Alongside, vitamin E supplement prevented HFD induced changes in oxidative stress biomarkers and capacity enzymes. Therefore, current results suggest that prolonged consumption of HFD increases susceptibility to PTZ induced seizures, which may be related to HFD induced oxidative stress. This increase in the PTZ susceptibility could be prevented by the administration of vitamin E, probably through its antioxidant effect, particularly at the brain hippocampal region.

Dietary Omega-3 Polyunsaturated Fatty Acid Deprivation Does Not Alter Seizure Thresholds but May Prevent the Anti-seizure Effects of Injected Docosahexaenoic Acid in Rats.

Background: Brain concentrations of omega-3 docosahexaenoic acid (DHA, 22:6n-3) have been reported to positively correlate with seizure thresholds in rodent seizure models. It is not known whether brain DHA depletion, achieved by chronic dietary omega-3 polyunsaturated fatty acid (PUFA) deficiency, lowers seizure thresholds in rats.Objective: The present study tested the hypothesis that lowering brain DHA concentration with chronic dietary n-3 PUFA deprivation in rats will reduce seizure thresholds, and that compared to injected oleic acid (OA), injected DHA will raise seizure thresholds in rats maintained on n-3 PUFA adequate and deficient diets.Methods: Rats (60 days old) were surgically implanted with electrodes in the amygdala, and subsequently randomized to the AIN-93G diet containing adequate levels of n-3 PUFA derived from soybean oil or an n-3 PUFA-deficient diet derived from coconut and safflower oil. The rats were maintained on the diets for 37 weeks. Afterdischarge seizure thresholds (ADTs) were measured every 4–6 weeks by electrically stimulating the amygdala. Between weeks 35 and 37, ADTs were assessed within 1 h of subcutaneous OA or DHA injection (600 mg/kg). Seizure thresholds were also measured in a parallel group of non-implanted rats subjected to the maximal pentylenetetrazol (PTZ, 110 mg/kg) seizure test. PUFA composition was measured in the pyriform-amygdala complex of another group of non-implanted rats sacrificed at 16 and 32 weeks.Results: Dietary n-3 PUFA deprivation did not significantly alter amygdaloid seizure thresholds or latency to PTZ-induced seizures. Acute injection of OA did not alter amygdaloid ADTs of rats on the n-3 PUFA adequate or deficient diets, whereas acute injection of DHA significantly increased amygdaloid ADTs in rats on the n-3 PUFA adequate control diet as compared to rats on the n-3 PUFA deficient diet (P < 0.05). Pyriform-amygdala DHA percent composition did not significantly differ between the groups, while n-6 docosapentaenoic acid, a marker of n-3 PUFA deficiency, was significantly increased by 2.9-fold at 32 weeks.Conclusion: Chronic dietary n-3 PUFA deficiency does not alter seizure thresholds in rats, but may prevent the anti-seizure effects of DHA.

Chemical biomarkers of epileptogenesis and ictogenesis in experimental epilepsy

Epilepsy produces chronic chemical changes induced by altered cellular structures, and acute ones produced by conditions leading into individual seizures. Here, we aim to quantify 24 molecules simultaneously at baseline and during periods of lowered seizure threshold in rats. Using serial hippocampal microdialysis collections starting two weeks after the pilocarpine-induced status epilepticus, we evaluated how this chronic epilepsy model affects molecule levels and their interactions. Then, we quantified the changes occurring when the brain moves into a pro-seizure state using a novel model of physiological ictogenesis. Compared with controls, pilocarpine animals had significantly decreased baseline levels of adenosine, homovanillic acid, and serotonin, but significantly increased levels of choline, glutamate, phenylalanine, and tyrosine. Step-wise linear regression identified that choline, homovanillic acid, adenosine, and serotonin are the most important features to characterize the difference in the extracellular milieu between pilocarpine and control animals. When increasing the hippocampal seizure risk, the concentrations of normetanephrine, serine, aspartate, and 5-hydroxyindoleacetic acid were the most prominent; however, there were no specific, consistent changes prior to individual seizures.

The effect of high-fat diet on seizure threshold in rats: Role of oxidative stress

There is increasing evidence advocating for the causal association between oxidative stress and different neurodegenerative disorders such as Alzheimer disease and epilepsy. We have previously shown that consumption of High-fat diet (HFD) induces oxidative stress, which results in hippocampal neuronal damage hence impairment of learning and memory. This impairment was prevented by antioxidants. The reported damage in the hippocampus caused by oxidative stress following consumption of HFD could alter synaptic transmission in the hippocampus and may increase susceptibility to seizures. The present study was undertaken to determine if chronic consumption of HFD changes susceptibility to chemically induced seizures using the pentylenetetrazol (PTZ) seizure threshold model in rats. In this study, HFD was administered to animals for 6 weeks. Thereafter, the PTZ seizure threshold was measured in control and HFD rats. Different brain regions were analyzed for the levels of oxidative stress biomarkers. Results revealed a significant reduction (50.0 ± 2.5%) in PTZ seizure threshold in rats consuming HFD. This was accompanied by a decrease in the oxidative stress biomarkers and capacity enzymes such as reduced/oxidized glutathione (GSH/GSSG) ratio, glutathione peroxidase (GPx) and catalase activities and increase in oxidized glutathione (GSSG) levels in the hippocampus and cortex regions of the brain of HFD rats. Collectively, current data suggest that prolonged consumption of HFD increases susceptibility to PTZ-induced seizures. Such an effect may be related to HFD- induced oxidative stress in the brain.

Different preparations, doses, and treatment regimens of cyclosporine A cause adverse effects but no robust changes in seizure thresholds in rats

Neuronal transplantation is a promising experimental treatment approach for intractable epilepsies, but rejection of porcine or human cells in rodent epilepsy models requires adequate immunosuppression to enable long-term survival of xenografts. The commonly used immunosuppressive drug cyclosporine A (CsA) itself was suggested to affect seizure thresholds. However, putative pro- or anticonvulsant effects of CsA have not yet been sufficiently explored in a direct comparison study involving different preparations, dosages, and application routes. We therefore comprehensively investigated the effects of acute versus chronic treatment using different dosages (5mg/kg, 10mg/kg), application routes (i.p., s.c.), and preparations of CsA (pure substance solved in polyethoxylated castor oil and a ready-to-use drug additionally containing ethanol) on acute seizure thresholds in rats in the pentylenetetrazole seizure threshold test and verified the most harmless protocol in the chronic amygdala-kindling model for temporal lobe epilepsy. None of the CsA treatment regimens induced acute changes of seizure thresholds. Chronic CsA treatment also did not robustly change seizure thresholds. As evaluated by whole blood analyses, bioavailability of CsA was significantly higher after i.p. application of the ready-to-use preparation compared to the pure substance and compared to s.c. Observed adverse effects differed between CsA treatment regimens and included reversible diarrhea, lowered body temperature, and tremor, the latter two of which were also induced by vehicle injections containing ethanol and/or polyethoxylated castor oil. Our data suggest that chronic treatment (2 weeks) with 10mg/kg CsA injected i.p. in the ready-to-use preparation is an appropriate protocol for use in neural transplantation in epilepsy research applying the presently used rat models. Transplantation studies in experimental epilepsy research require a careful assessment of putative CsA effects on seizure thresholds in the specific experimental settings to be used.

A minimum of 3 months of dietary fish oil supplementation is required to raise amygdaloid afterdischarge seizure thresholds in rats - implications for treating complex partial seizures

Complex partial seizures, which typically originate in limbic structures such as the amygdala, are often resistant to antiseizure medications. Our goal was to investigate the effects of chronic dietary supplementation with n−3 polyunsaturated fatty acids (PUFAs) derived from fish oil on seizure thresholds in the amygdala, as well as on blood and brain PUFA levels. The acute effects of injected n−3 PUFAs – eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) – were also tested in the maximal pentylenetetrazol (PTZ) seizure model. In amygdala-implanted subjects, fish oil supplementation significantly increased amygdaloid afterdischarge thresholds, as compared with controls at 3, 5, and 7months after the start of supplementation. Fish oil supplementation also increased serum EPA and DHA concentrations. DHA concentration in the pyriform-amygdala area increased in the fish-oil treated group by 17-34%, but this effect did not reach statistical significance (P=0.065). DHA significantly increased the latency to seizure onset in the PTZ seizure model, whereas EPA had no significant effect. These observations suggest that chronic dietary fish oil supplementation can raise focal amygdaloid seizure thresholds and that this effect is likely mediated by DHA rather than by EPA.

Dietary omega‐3 polyunsaturated fatty acid deprivation lowers seizure threshold in rats

Several candidate genes that play a role in seizure etiology have been identified. Yet, the impact of environmental influences such as dietary omega‐3 polyunsaturated fatty acids (n‐3 PUFA) is not known. We therefore tested the impact of chronic dietary n‐3 PUFA deprivation on seizure threshold in the cortex and amygdala. Rats were surgically implanted with electrodes in the cortex or amygdala, and subsequently randomized to the AIN‐93G diet containing n‐3 PUFA derived from soybean oil, or a modified n‐3 PUFA‐deficient version derived from coconut and safflower oil. The rats were maintained on the diets for 33 weeks. Seizure thresholds were measured monthly by electrically stimulating the cortex and amygdala. At the end of 33 weeks, seizure threshold was assessed following a bolus subcutaneous injection of oleic (OA) or docosahexaenoic acids (DHA). Dietary n‐3 PUFA deprivation resulted in a statistically significant decrease in cortical and amygdaloid thresholds by week 16, relative to baseline (P&lt;0.05). The decrease in thresholds was not observed in rats on the control, soybean oil diet. Compared to a bolus injection of OA, acute injection of DHA raised seizure threshold in rats on the control diet but not the n‐3 PUFA deficient diet (P&lt;0.05). These findings demonstrate for the first time that dietary n‐3 PUFA deficiency increases seizure susceptibility in rats.Grant Funding SourceCanadian Institutes of Health research

N-3 fatty acids (eicosapentanoic and docosahexanoic acids) in epilepsy and for the prevention of sudden unexpected death in epilepsy

As described in this journal, Bromfield et al. and Yuen et al. tested the hypothesis that n-3 fatty acids may reduce seizures [ 1 Bromfield E. Dworetzsky B. Huwitz S. et al. A randomized trial of polyunsaturated fatty acids for refractory epilepsy. Epilepsy Behav. 2008; 12: 187-190 Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar , 2 Yuen A.W. Sander J.W. Fluegel D. et al. Omega-3 fatty acid supplementation in patients with chronic epilepsy: a randomized trial. Epilepsy Behav. 2005; 7: 253-258 Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar ]. This is important work, founded in sound science. It is known that eicosapentanoic acid reduces the frequency of hippocampal pyramidal neuron firing rates [ [3] Xiao Y. Li X. Polyunsaturated fatty acids modify mouse hippocampal neuronal excitability during excitotoxic or convulsant stimulation. Brain Res. 1999; 846: 112-121 Crossref PubMed Scopus (114) Google Scholar ]. Furthermore, n-3 fatty acids reduce the number and increase the latency of pentylenetetrazole- and FeCl3-induced seizures, reduce seizure severity in rodents, and improve cognitive recovery after acute seizures [ 4 Yehuda S. Carasso R. Mostofsky D. Essential fatty acid preparation (SR-3) raises the seizure threshold in rats. Eur J Pharmacol. 1994; 254: 193-198 Crossref PubMed Scopus (121) Google Scholar , 5 Voskuyl R. Vregdenhil M. Kang J. et al. Anticonvulsant effect of polyunsaturated fatty acids in rats, using the cortical stimulation model. Eur J Pharmacol. 1998; 341: 145-152 Crossref PubMed Scopus (121) Google Scholar , 6 Rabinovitz S. Mostofsky D. Yehuda S. Anticonvulsant efficiency, behavioral performance, and cortisol levels: a comparison of carbamazepine (CBZ) and a fatty acid compound (SR-3). Psychoneuroendocrinology. 2004; 29: 113-124 Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar ]. Moreover, in an important discovery recently reported in this journal, Ferrari et al. found that n-3 fatty acids prevent or reduce hippocampal neuronal injury after status epilepticus [ [7] Ferrari D. Cysneiros R.M. Scorza C. et al. Neuroprotective activity of omega-3 fatty acids against epilepsy-induced hippocampal damage: quantification with immunohistochemical for calcium-binding proteins. Epilepsy Behav. 2008; 13: 36-42 Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar ].

S.25.03 Use of antidepressants in long treatment of bipolar depression

Testosterone modulates seizure susceptibility in animals and humans, but the underlying mechanisms are obscure. Here, testosterone modulation of seizure susceptibility is hypothesized to occur through its conversion to neurosteroids with “anticonvulsant” and “proconvulsant” actions, and hence the net effect of testosterone on neural excitability and seizure activity depends on the levels of distinct testosterone metabolites. Testosterone undergoes metabolism to neurosteroids via two distinct pathways. Aromatization of the A-ring converts testosterone into 17β-estradiol. Reduction of testosterone by 5α-reductase generates 5α-dihydrotestosterone (DHT), which is then converted to 3α-androstanediol (3α-Diol), a powerful GABAA receptor-modulating neurosteroid with anticonvulsant properties. Systemic doses of testosterone decreased seizure threshold in rats and increased the incidence and severity of pentylenetetrazol (PTZ)-induced seizures in mice. These proconvulsant effects of testosterone were associated with increases in plasma 17β-estradiol and 3α-Diol concentrations. Pretreatment with letrozole, an aromatase inhibitor that blocks the conversion of testosterone to 17β-estradiol, significantly inhibited testosterone-induced exacerbation of seizures. The 5α-reductase inhibitor finasteride significantly reduced 3α-Diol levels and also blocked letrozole's ability to inhibit the proconvulsant effects of testosterone. The 5α-reduced metabolites of testosterone, DHT and 3α-Diol, had powerful anticonvulsant activity in the PTZ test. Letrozole or finasteride had no effect on seizure protection by DHT and 3α-Diol, but indomethacin partially reversed DHT actions. 3α-Diol but not 3β-androstanediol, a GABAA receptor-inactive stereoisomer, suppressed 4-aminopyridine-induced spontaneous epileptiform bursting in rat hippocampal slices. Thus, testosterone-derived neurosteroids 3α-Diol and 17β-estradiol could contribute to the net cellular actions of testosterone on neural excitability and seizure susceptibility.

Sustained focal cortical compression reduces electrically-induced seizure threshold

Brain injury can often result in the subsequent appearance of seizures, suggesting an alteration in neural excitability associated with the balance between neuronal excitation and inhibition. The process by which this occurs has yet to be fully elucidated. The specific nature of the changes in excitation and inhibition is still unclear, as is the process by which the seizures appear following injury. In this study, we investigated the effects of focal cortical compression on electrically-induced localized seizure threshold in rats. Male Long Evans rats were implanted with stimulating screw electrodes in their motor cortices above the regions controlling forelimb movement. Initial seizure threshold was determined in the animals using a ramped electrical stimulation procedure prior to any compression. Following initial threshold determination, animals underwent sustained cortical compression and then following a 24 h recovery period had their seizure thresholds tested again with electrical stimulation. Reliability of threshold measurements was confirmed through repeated measurements of seizure threshold. Localized seizure threshold was significantly lowered following sustained cortical compression as compared with control cases. Taken together, the results here suggest a change in global brain excitability following localized, focal compression.

Dietary supplementation of fish oil enriched with omega‐3 polyunsaturated fatty acids elevates seizure threshold in rats

Epilepsy is a serious neurological disorder which is characterized by spontaneous, recurrent seizures. Simple partial seizures originating from the cortex are drug‐responsive, whereas complex‐partial seizures originating from the amygdala are drug‐resistant. Current anticonvulsant medications that are used to treat simple partial seizures have side effects including weight gain. Omega‐3 (n‐3) polyunsaturated fatty acids (PUFA) have been considered as a healthier alternative treatment for patients with epilepsy. Accordingly, we hypothesized that dietary supplementation of fish oil enriched with n‐3 PUFA would protect against epileptic‐like seizures originating from the cortex or amygdala, without altering body weight gain. Rats were surgically implanted with electrodes in the cortex or amygdala, and subsequently randomized to the AIN‐93G diet containing soybean oil or 40% fish oil for up to 34 weeks. Body weight gain, food intake and seizure thresholds were measured monthly. In contrast to soybean oil, fish oil supplementation elevated afterdischarge seizure threshold in the cortex (36%) and the amygdala (64%) relative to baseline (P&lt;0.05). Fish oil treatment did not alter food intake and body weight gain over time (P&gt;0.05). These findings indicate that n‐3 PUFA have anticonvulsant properties, and that they do not adversely affect body weight as seen with conventional anticonvulsant medications.

Effect of magnesium chloride and magnesium L-aspartate on seizure threshold in rats under conditions of dietary magnesium deficiency

We studied the effect of Mg-L-aspartate, MgCL2, and their combinations with vitamin B6, magneB6, and MgSO4 on seizure threshold in rats with dietary Mg2+ deficiency. Mg2+ deficiency was followed by a decrease in the threshold dose of corazol (from 79.20 to 49.48 mg/kg), shortening of the latency of the first jerk (by 33.6%, p=0.012), and reduction of the time to the first episode of clonic seizures (by 32.6%, p=0.011). Seizure threshold and latencies of the first jerk and first episode of clonic seizures increased over 3 weeks after peroral administration of Mg2+ salts. The combination of Mg2+ salts and pyridoxine was most effective in this respect.

Prolonged Exposure to Lead Lowers the Threshold of Pentylenetetrazole‐induced Seizures in Rats

The aim of this work was to study the effects of prolonged exposure to lead on the threshold of experimental seizures induced by pentylenetetrazole (PTZ). The 120 Wistar male rats were allocated randomly into four groups; (A) controls, and lead-treatment groups (B, C, and D) that received lead acetate in the drinking water for a period of 30 days at concentrations of 250, 500, and 1,000 ppm, respectively. After exposure, a trial of PTZ-induced seizures was conducted in all groups, and blood contents of lead were determined by atomic absorption spectrophotometry. Blood lead contents increased in a dose-dependent manner. Time elapsed to develop the first myoclonic jerk and the tonic-clonic seizure was less in all lead-exposed groups than in controls. This effect was greater in the groups administered 500 and 1,000 ppm of lead. The required doses of PTZ to induce myoclonic jerks and tonic-clonic seizures were lower in lead-exposed rats than in controls. We found a reduction in the threshold for seizures in rats whose blood contents of lead were similar to those of humans from some areas of urban centers with high levels of air pollution.

Chronic treatment with fluoxetine decreases seizure threshold in naïve but not in rats exposed to the learned helplessness paradigm: Correlation with the hippocampal glutamate release

The proconvulsive effect of the new generation of antidepressants remains controversial. The authors investigated in naïve rats the effect of chronic treatment with fluoxetine (FLX) on the convulsive threshold and on two parameters of the hippocampal glutamatergic neurotransmission: the in vitro glutamate release and the binding of [ 3H] MK801 to NMDA receptors. While the acute treatment with FLX provoked no change either in seizure susceptibility or in the glutamate release, the chronic treatment decreased the convulsive threshold in coincidence with an increment in the in vitro glutamate release. No significant effects on the binding of [ 3H] MK801 to NMDA receptors were found to be attributable to the FLX treatment. We also assessed the effect of the chronic treatment with FLX on the seizure threshold in rats exposed to an experimental model of depression, the learned helplessness paradigm (LH). While a decrease in the K +-stimulated glutamate release was observed in non treated LH animals, when they were chronically injected with FLX, no changes in the epileptic susceptibility and no increments in the glutamate release were found. Our results indicate that chronic treatment with FLX decreases the epileptic threshold in naïve but not in LH rats and that this effect correlates with the levels of the hippocampal glutamate release.

Testosterone modulation of seizure susceptibility is mediated by neurosteroids 3α-androstanediol and 17β-estradiol

Testosterone modulates seizure susceptibility in animals and humans, but the underlying mechanisms are obscure. Here, testosterone modulation of seizure susceptibility is hypothesized to occur through its conversion to neurosteroids with “anticonvulsant” and “proconvulsant” actions, and hence the net effect of testosterone on neural excitability and seizure activity depends on the levels of distinct testosterone metabolites. Testosterone undergoes metabolism to neurosteroids via two distinct pathways. Aromatization of the A-ring converts testosterone into 17β-estradiol. Reduction of testosterone by 5α-reductase generates 5α-dihydrotestosterone (DHT), which is then converted to 3α-androstanediol (3α-Diol), a powerful GABA A receptor-modulating neurosteroid with anticonvulsant properties. Systemic doses of testosterone decreased seizure threshold in rats and increased the incidence and severity of pentylenetetrazol (PTZ)-induced seizures in mice. These proconvulsant effects of testosterone were associated with increases in plasma 17β-estradiol and 3α-Diol concentrations. Pretreatment with letrozole, an aromatase inhibitor that blocks the conversion of testosterone to 17β-estradiol, significantly inhibited testosterone-induced exacerbation of seizures. The 5α-reductase inhibitor finasteride significantly reduced 3α-Diol levels and also blocked letrozole's ability to inhibit the proconvulsant effects of testosterone. The 5α-reduced metabolites of testosterone, DHT and 3α-Diol, had powerful anticonvulsant activity in the PTZ test. Letrozole or finasteride had no effect on seizure protection by DHT and 3α-Diol, but indomethacin partially reversed DHT actions. 3α-Diol but not 3β-androstanediol, a GABA A receptor-inactive stereoisomer, suppressed 4-aminopyridine-induced spontaneous epileptiform bursting in rat hippocampal slices. Thus, testosterone-derived neurosteroids 3α-Diol and 17β-estradiol could contribute to the net cellular actions of testosterone on neural excitability and seizure susceptibility.

Confirmation of whole-brain kindling with repeated subthreshold electroconvulsive shocks: a controlled study.

Repeated, subconvulsive electroconvulsive shock (ECS) stimuli, administered a day apart, lower the ECS seizure threshold in rats. It is not known, however, whether this kindling results from the repeated subconvulsive stimulation or from the stress induced by the experimental procedures. Adult, male Wistar rats were randomized to receive a 3-mC ECS stimulus (n = 20), a 30-V (0.3-s) footpad shock (n = 20), or sham ECS and sham footpad shock (n = 20). All procedures were conducted once daily for 3 consecutive days. On the fourth day, all rats received a 3-mC ECS stimulus. At the end of the experiment, 85% of the rats in the ECS group but only 35% of the rats in each of the other two groups had experienced a seizure with the 3-mC stimulus (p < 0.001). The lowering of the ECS seizure threshold by repeated, once-daily subconvulsive stimuli is caused by the subconvulsive stimulation itself, not by experimental stress.

Is Attenuation of Extracellular Dopamine Increase in the Nucleus Accumbens the Major Mechanism by which Dexmedetomidine Increases the Cocaine Seizure Threshold in Rats?

Is Attenuation of Extracellular Dopamine Increase in the Nucleus Accumbens the Major Mechanism by which Dexmedetomidine Increases the Cocaine Seizure Threshold in Rats?

ECS seizure threshold: normal variations, and kindling effects of subconvulsive stimuli.

The efficacy and adverse effects of electroconvulsive therapy are generally believed to depend upon the extent to which an administered stimulus is suprathreshold. The seizure threshold is therefore an important biologic marker. We sought to examine the variability of the electroconvulsive shock (ECS) seizure threshold in rats, and to identify factors influencing the threshold, to guide future research using animal models. We administered once-daily subconvulsive stimuli to Wistar rats beginning at a charge of either 1 mC (n = 25) or 5 mC (n = 25) and titrated the dose upward in 1-mC steps until the baseline seizure threshold was identified. Two weeks later, we divided each group into two subgroups and administered stimuli that were either at or 2 mC below the baseline threshold, and titrated the dose upward, again in 1-mC steps once daily, until the final threshold was identified. The mean baseline seizure threshold was 3.8 mC when upward titration was begun at 1 mC, and 6.7 mC when upward titration was begun at 5 mC (p < 0.001). Two weeks later, titration from baseline-subthreshold stimuli was associated with a lower final threshold in the 5-mC group, while titration from baseline-threshold stimuli was associated with a higher final threshold in the 1-mC group (p < 0.006). The ECS seizure threshold ranged from 3 to 7 mC in this sample of rats; since the twofold variation is very small relative to clinical contexts, it is unlikely that ECS research needs to be threshold-based. The administration of low-dose, once-daily subconvulsive stimuli significantly lowered the seizure threshold; while this kindling effect wore off within 2 weeks, thresholds otherwise identified remained stable at the 2-week time point.