Electrical stimulation of substantia nigra pars reticulata is anticonvulsant in adult and young male rats.

Electrical stimulation of deep brain structures has been used for pain relief and treatment of refractory Parkinson's disease. Recently, stimulation of the subthalamic nucleus or anterior nuclei of the thalamus was introduced for the treatment of refractory epilepsy when other treatments failed. The substantia nigra pars reticulata (SNR) is another crucial site involved in the control of seizures. We studied the effects of continuous electrical stimulation of the SNR as a function of age in male rats. Adult [postnatal day (PN) 60] and young (PN 15) rats with electrodes symmetrically implanted in the SNR were used. The rats were stimulated with continuous constant current pulses (130 Hz) and simultaneously challenged with flurothyl to induce seizures. Control rats had the electrodes implanted but were not stimulated. High-frequency electrical stimulation of the SNR had anticonvulsant effects in both age groups. However, we identified age-specific features: In PN 60 rats, both unilateral and bilateral stimulation of the anterior region of the SNR produced anticonvulsant effects against clonic seizures, while stimulation of the posterior region of the SNR was ineffective. Stimulation of either SNR region had no effects on tonic-clonic seizures. In PN 15 rats, irrespective of the stimulation site within the SNR, bilateral stimulations of the SNR produced anticonvulsant effects against both clonic and tonic-clonic flurothyl-induced seizures, while unilateral stimulation was without effect. The data suggest that the SNR may be a candidate site for deep brain stimulation for the treatment of epilepsy.     

Effect of ganaxolone on flurothyl seizures in developing rats

PURPOSE: To determine the effects of a newly synthesized epalon, ganaxolone (GNX), on primarily generalized seizures in rats of various ages during development. Epalons are classified as neuroactive steroids that interact at unique site of the GABAA receptor-Cl- channel complex in the central nervous system. METHODS: Sprague-Dawley male rats were used at 9, 15, 30, and 60 postnatal days (PN). GNX dissolved in 2-hydroxypropylbeta-cyclodextrine was administered intraperitoneally in different doses at various time points before flurothyl testing. The incidence and threshold of clonic and tonic-clonic flurothyl seizures were evaluated. Behavioral changes were also assessed. RESULTS: In all age groups, the effects of GNX were dose dependent and more prominent 10 min after its administration. In PN 60 and PN 30 rats, GNX had dose-dependent anticonvulsant effects; tonic-clonic seizures were more sensitive to GNX treatment than clonic seizures. In PN 15 and PN 9 rats, GNX demonstrated dose-and time-dependent anticonvulsant effects against both types of flurothyl-induced seizures. GNX was more effective in PN 15 rats than in other age groups, but at doses that altered motor behavior. CONCLUSIONS: GNX has anticonvulsant effects against flurothylinduced seizures in all age groups tested. Its effects are more prominent in the two younger age groups, especially in PN 15 rats, but are associated with motor side effects.     

Sex-specific control of flurothyl-induced tonic-clonic seizures by the substantia nigra pars reticulata during development

The substantia nigra pars reticulata (SNR) plays an important age- and sex-specific role in control of clonic seizures. Its involvement in control of tonic-clonic seizures is contradictory. We investigated the role of the SNR in the tonic-clonic seizures induced in male, female and neonatally castrated male rats using flurothyl. In adult female rats, vaginal impedance determined the changes in progesterone/estrogen ratio. Rats at various postnatal ages received infusions of muscimol or vehicle in the SNRanterior or SNRposterior. Furthermore, in 15-day-old (P15) and adult male rats, ZAPA (a GABA(A) receptor agonist) or AP7 (an NMDA receptor antagonist) was infused. The developmental profile of tonic-clonic seizure threshold differed between male and female rats possibly due to early postnatal testosterone surge in male rats. On the other hand, changing estrogen/progesterone ratio in cycling adult female rats had no effect on seizure threshold. Intranigral muscimol had proconvulsant effects on tonic-clonic seizures only in immature rats, and this effect was dependent on the perinatal testosterone surge. ZAPA had anticonvulsant effects in P15 rats but was not effective in adult rats. Only AP7 had anticonvulsant effects in both adult and P15 rats. Results indicate that thresholds for flurothyl-induced tonic-clonic seizures develop under the control of postnatal testosterone. Although GABAergic inhibition in the SNR affects tonic-clonic seizures in developing rats, only the NMDA antagonist had consistent anticonvulsant effects throughout development.     

Effective inhibition of substantia nigra by deep brain stimulation fails to suppress tonic epileptic seizures

Experimental and clinical data suggest that high-frequency deep brain stimulation (DBS) of different subcortical structures can be used to control or modulate epileptic seizures. Recent studies showed that DBS of the substantia nigra reticulata (SNr) in rats has an anticonvulsant effect on forebrain clonic seizures. The aim of this study was to determine whether DBS of SNr could also suppress tonic epileptic seizures evoked in hindbrain structures. DBS with high frequency often mimics the effects of surgical ablation of a particular area of the brain. However, the optimal parameters of DBS stimulation to induce ablation-like effects on seizures are not well defined. Consequently, in the first experiment we examined the effects of different stimulation frequencies (80, 130, 260 and 390 Hz) on neuronal activation induced in SNr, using c-fos immunocytochemistry. The results showed that the stimulation of the SNr with 80 Hz has no inhibitory effect while stimulation with 130, 260 and 390 Hz produced a remarkable suppressive effect compared with the control unstimulated side. The aim of the second experiment was to determine whether bilateral inhibition of SNr with DBS could suppress tonic seizures induced by electric shock. Statistical analysis showed that the mean tonic seizure scores following SNr stimulation with either 130 or 260 Hz were not significantly different from scores following the application of the electrode without current. The data suggest that DBS of the SNr produces neuronal inhibition but fails to suppress tonic seizures. We conclude, therefore, that DBS of SNr with frequencies used in this study might not be effective for treatment of patients who suffer from tonic epileptic seizures.     

丘脑底核电刺激对大鼠黑质网状部及苍白球细胞外神经递质的影响

目的 通过电刺激正常及癫痫大鼠丘脑底核(STN),研究黑质网状部(SNr)及苍白球(GP)细胞外液中谷氨酸(Glu)、γ-氨基丁酸(GABA)的变化,探讨电刺激治疗癫痫的机制.方法 正常大鼠和癫痫大鼠各加只,将刺激电极植入一侧STN,分别用130 Hz和260 Hz进行刺激,同时在同侧的SNr和GP收集细胞外液,用高压液相色谱法检测其Glu和GABA的含量.结果 癫痫大鼠SNr的GABA基础值明显高于正常大鼠.电刺激使两组SNr的GABA明显升高.130 Hz和260 Hz刺激明显增高两组GP和SNr的Glu含量,但130 Hz的更显著.结论 SNr细胞外GABA升高在STN电刺激治疗中起重要作用.电刺激增加了GP细胞的活动,STN电刺激治疗癫痫机制不能单纯解释为"功能的毁损".     

Does prenatal methamphetamine exposure affect seizure susceptibility in adult rats with acute administration of the same drug?

The aim of the present study was to investigate whether sensitivity to flurothyl seizures after an acute methamphetamine (MA) administration is different in prenatally MA-exposed adult rats than in controls without prenatal drug exposure. Adult male and female rats exposed prenatally to MA (5mg/kg), saline or neither (controls) were divided into groups; one group received acute MA (1mg/kg s.c.) injection and the other group received saline. Rats were then challenged with flurothyl at a constant flow rate to induce seizures. The threshold of the first focal clonus, clonic seizures and tonic-clonic seizures were analyzed. EFFECTS OF PRENATAL DRUG EXPOSURE: In animals without acute MA administration prior to seizure testing, prenatal MA exposure decreased threshold of the first clonus relative to control animals. This decrease in threshold was not apparent in groups pretreated with acute MA injection. EFFECTS OF ACUTE MA ADMINISTRATION: There was an increased threshold to both, first focal clonus and clonic seizures in animals with acute MA injection than in animals without it. The increase induced by acute MA pretreatment was higher in prenatally MA-exposed animals relative to controls. Further, clonic seizures were shorter and developed faster into tonic-clonic seizures in these acutely injected animals compared to animals without acute MA injection. EFFECTS OF HORMONES: The threshold of all measured attributes was decreased in males. Estrous cycle influences did not lead to changes between groups of prenatal exposure or acute MA administration. Threshold of tonic-clonic seizures was increased in females in proestrus/estrus stage of the estrous cycle relative to diestrous females. Our study suggests that prenatal MA exposure affects the sensitivity of adult rats to the effect of acute MA treatment prior to flurothyl seizures relative to controls.     

Flurothyl seizures susceptibility is increased in prenatally methamphetamine-exposed adult male and female rats

The purpose of the present study was to examine the effect of prenatal methamphetamine (MA) exposure on flurothyl seizures. Adult prenatally MA-exposed male rats had decreased threshold of the first fasciculation and clonic seizure. In adult female rats, prenatal MA exposure decreased the threshold of the first fascicualtion in diestrous females, while there were no changes in proestrous or estrous females. The tonic-clonic seizure threshold was not altered by prenatal MA exposure.     

Effects of Valproate, Phenytoin, and MK-801 in a Novel Model of Epileptogenesis

Summary: Purpose: We have developed and characterized a novel model of epileptogenesis based on the convulsive actions of flurothyl in mice. The hallmark feature of this model is a reliable change in the type of seizure expressed in response to flurothyl from generalized clonic to generalized tonic seizures. The purpose of our study was to evaluate the effects of chronic administration of valproate (VPA), phenytoin (PHT), and MK-801 on the change in seizure phenotype observed in our model system.
Methods: Male C57BL/6J mice received flurothyl seizures on 8 consecutive days. Two hours after the last generalized seizure, chronic drug or vehicle was administered twice daily at 12-h intervals for 28 days. The drugs evaluated were VPA (250 mg/kg), PHT (30 mg/kg), and MK-801 (0.5 mg/kg). After a 7-day drug washout period, mice were retested with flurothyl.
Results: Among uninjected or vehicle-injected control mice, there was a significant increase in the proportion of animals expressing tonic seizures after the 28-day stimulation-free interval. Chronic administration of VPA or MK-801, but not PHT, blocked the characteristic change in seizure type from clonic to tonic.
Conclusions: The change in seizure phenotype observed after exposure to our paradigm indicates a fundamental reorganization in the propagation of flurothyl-initiated seizures. As in electrical kindling, VPA and MK-801 are effective at blocking or retarding the reorganization, whereas PHT is not. The concordance in pharmacologic profiles between kindling and our model suggests that the processes underlying changes in seizure susceptibility in these two models share mechanisms in common.     

Electrical Stimulation of the Mammillary Nuclei Increases Seizure Threshold to Pentylenetetrazol in Rats

Summary: High-frequency electrical stimulation of mammillary nuclei (MN) of rat posterior hypothalamus resulted in a significant increase in seizure threshold induced by pentylenetetrazol (PTZ). The anticonvulsant effect was frequency and intensity specific. Stimulation at 100 Hz (1–5V, 30–200 μA) afforded protection against EEG and behavioral manifestations of PTZ seizures. Stimulation of either low frequency (5 Hz), high intensities (8–20 V, 300–800 μA), or outside the histologically verified MN target region did not increase seizure threshold. In some instances, high-intensity stimulation of MN alone elicited spike-wave epileptiform EEG activity accompanied by either arrest of behavior or myoclonic seizures. In animals with ongoing seizure activity, electrical stimulation of MN disrupted the high-voltage synchronous wave forms on cortical EEG. These data support the concept that electrical perturbation of MN in hypothalamus may functionally inhibit generalization of paroxysmal activity required for expression of the EEG and, in particular, the behavioral component of PTZ seizures. These studies provide additional insight into forebrain-brainstem interactions mediating generalized seizure expression.     

Prenatal morphine exposure differentially alters seizure susceptibility in developing female rats.

We examined the effect of prenatal morphine exposure (5-10 mg/kg on days 11-18 of gestation) on seizure susceptibility in female rats during development. The effect of morphine exposure on flurothyl-induced seizures was age-dependent. At postnatal day (PN) 15, morphine exposure decreased both clonic and tonic-clonic seizure thresholds compare to saline controls. At PN 25, morphine exposure did not alter the clonic seizure threshold but increased the threshold to tonic-clonic seizure. At PN 38, morphine exposure did not influence either threshold. The data suggest that the effects of prenatal exposure to opioids on seizures are age-related and transient.