Seizures evoked from area tempestas are subject to control by GABA and glutamate receptors in substantia nigra

The functional relationship between the substantia nigra (SN) and the area tempestas (AT), an epileptogenic site in the deep prepiriform cortex, was investigated. Stimulation of GABA receptors in SN with muscimol, or blockade of nigral excitatory amino acid receptors with 2-aminophosphonoheptanoic acid (AP7), protected against convulsions evoked by the unilateral focal injection of bicuculline in the AT. The protective effects were obtained only with bilateral nigral injections; unilateral manipulations were without anticonvulsant effect. Bilateral intranigral morphine did not exert an anticonvulsant effect against convulsions evoked from the AT, although this treatment induced stereotyped sniffing and gnawing behavior similar to that evoked by intranigral muscimol and AP7. The data indicate that seizures evoked from the AT of one hemisphere are susceptible to suppression by inhibition in the SN, but only when the inhibition occurs in the SN of both hemispheres. This suggests that the seizure suppressant action evoked from the SN is exerted during the course of the propagation of the seizure, once it has spread bilaterally.     

The role of the nigrotegmental GABAergic pathway in the propagation of pentylenetetrazol-induced seizures

Recent evidence suggests that the substantia nigra (SN) may be involved in the modification of various experimental epilepsy models. We determined the role of γ-aminobutyric acid (GABA)ergic activity of the SN and the target sites of SN efferents, the pedunculopontine nucleus (PPN) and superior colliculus (SC), in pentylenetetrazol-induced seizures in rats. Bilateral administration of a GABA agonist (muscimol) into the SN significantly reduced seizure severity; its administration into the PPN significantly augmented seizure severity; administration into the SC did not alter the seizure severity. On the other hand, infusion of a GABA antagonist (bicuculline) into the PPN revealed a protective effect against seizures. Our findings indicate that the nigral GABAergic projection to the PPN play an important role in seizure propagation. Thus, PPN neurons may be a possible target site of nigral output modulating seizure propagation.     

Decrease in excitatory transmission within the lateral habenula and the mediodorsal thalamus protects against limbic seizures in rats

We have used limbic convulsions induced by systemic pilocarpine in rats combined with focal intracerebral injections concurrently to study the initiation and spread of seizure activity. Protection against pilocarpine-seizure development by antagonism of excitatory or facilitation of inhibitory neurotransmission at focal sites establishes the anatomical circuits involved in the propagation of seizures. The excitatory amino acid antagonist 2-amino-7-phosphonoheptanoate (APH, selective for the NMDA preferring glutamate receptor subtype) is potently anticonvulsant after bilateral focal injections into the habenula or mediodorsal thalamus. The dose of APH required to give sustained protection against pilocarpine-induced convulsions is 10 pmol for lateral habenula and 50 pmol for mediodorsal thalamus. The GABA agonist muscimol produces a similar sustained protection following focal injections (100 pmol/side) into either the lateral habenula or the mediodorsal thalamus. An overall decrease in the efferent neurotransmission of these two brain regions results in a strong anticonvulsant effect indicating their importance in modulating limbic seizure activity.     

Testing the disinhibition hypothesis of epileptogenesis in vivo and during spontaneous seizures.

The "disinhibition" hypothesis contends that (1) seizures begin when granule cells in the dentate gyrus of the dorsal hippocampus are disinhibited and (2) disinhibition occurs because GABAergic interneurons are excessively inhibited by other GABAergic interneurons. We tested the disinhibition hypothesis using the experimental model that inspired it-naturally epileptic Mongolian gerbils. To determine whether there is an excess of GABAergic interneurons in the dentate gyrus of epileptic gerbils, as had been reported previously, GABA immunocytochemistry, in situ hybridization of GAD67 mRNA, and the optical fractionator method were used. There were no significant differences in the numbers of GABAergic interneurons. To determine whether granule cells in epileptic gerbils were disinhibited during the interictal period, IPSPs were recorded in vivo with hippocampal circuits intact in urethane-anesthetized gerbils. The reversal potentials and conductances of IPSPs in granule cells in epileptic versus control gerbils were similar. To determine whether the level of inhibitory control in the dentate gyrus transiently decreases before seizure onset, field potential responses to paired-pulse perforant path stimulation were obtained from the dorsal hippocampus while epileptic gerbils experienced spontaneous seizures. Evidence of reduced inhibition was found after, but not before, seizure onset, indicating that seizures are not triggered by disinhibition in this region. However, seizure-induced depression of inhibition may amplify and promote the spread of seizure activity to other brain regions. These findings do not support the disinhibition hypothesis and suggest that in this model of epilepsy seizures initiate by another mechanism or at a different site.     

Activation of the Locus Coeruleus After Amygdaloid Kindling

Summary: Purpose: Substnatia nigra (SN) and locus coeruleus (LC) neurons are implicated in the propagation and suppression of amygdaloid seizures. Both structures are activated concomitant with amygdaloid seizure discharges. Their rnechanisms of activation, however, remain to be elucidated. SN firing is not associated with the induction of Fos imrnunoreactiv-ity (ir), a marker of excitatory neuronal activation. LC has not been studied. The purpose of this investigation was to determine if amygdala-kindled generalized seizures could induce Fos-ir in the LC. Methods: Female Sprague-Dawley rats were killed after generalized seizures induced by amygdala electrical stimulation and stained by using Fos irnmunocytochemistry. The number of Fos-ir neurons was compared between 15 animals with generalized seizures and four implanted, unstimulated controls. Results: LC-ir neurons were significantly (p < 0.05) more prevalent after seizures than in control animals. Their numbers correlated very highly with Fos-ir in the central nucleus of the amygdala (p < 0.0001). No Fos induction was observed in LC in controls or in the SN in either group. Conclusions: Amygdala-induced generalized seizures result in Fos-ir in the LC but not in the SN. This is consistent with different mechanisms of activation possibly involving disinhi-bition in the SN and direct excitation in the LC.     

Dopamine-sensitive anticonvulsant site in the rat striatum

The basal ganglia are involved in the organization of movement and function in the initiation and expression of generalized and limbic seizures. Dopamine is the principal neurotransmitter of the mesencephalic efferent pathways terminating in the mammalian striatum. No function has been ascribed to mesostriatal dopamine in the control of seizure spread in the brain. This work presents evidence that bilateral application of picomole amounts of apomorphine (a dopamine agonist) into the striatum confers protection against seizures produced by pilocarpine (a cholinergic agonist) in rats. The anticonvulsant effect of apomorphine is topographically confined to the caudate-putamen, nucleus accumbens, and olfactory tubercle. Bilateral application of nanomolar amounts of haloperidol (a dopamine antagonist) into the caudate-putamen or systemic application of haloperidol both lower the threshold for pilocarpine-induced seizures. Local application of an excitatory amino acid N-methyl-D-aspartate, into the substantia nigra pars compacta, ventral tegmental area, or retrorubral area, sites of origin of mesostriatal dopaminergic pathways, protects rats against seizures produced by pilocarpine. These results suggest that dopaminergic transmission in the striatum may be operative in complex neuronal networks modulating the seizure threshold.     

Age-Dependent Differences in the Anticonvulsant Effects of 2–Amino-7-Phosphono-Heptanoic Acid or Ketamine Infusions Into the Substantia Nigra of Rats

Infusions of 2-amino-7-phosphonoheptanoic acid (AP7) or ketamine into the substantia nigra pars reticulata (SNPR) of adult rats increase the latency of onset to seizures induced by the convulsant ether flurothyl. Nigral infusions of AP7 or ketamine in concentrations up to 10 times greater than the adult dose are ineffective in 16-day-old rats. These results suggest that differences in seizure susceptibility between adult and immature rats may be related to differences in excitatory amino acid neurotransmission in the SN.     

Treating acute seizures with benzodiazepines: does seizure duration matter?

Several clinical trials have shown improved seizure control and outcome by early initiation of treatment with benzodiazepines, before arrival in the emergency department and before intravenous access can be established. Here, evidence is provided and reviewed for rapid treatment of acute seizures in order to avoid the development of benzodiazepine pharmacoresistance and the emergence of self‐sustaining status epilepticus. Alterations in the physiology, pharmacology, and postsynaptic level of GABA‐A receptors can develop within minutes to an hour and hinder the ability of synaptic inhibition to stop seizures while also impairing the efficacy of GABAergic agents, such as benzodiazepines, to boost impaired inhibition. In addition, heightened excitatory transmission further exacerbates the inhibitory/excitatory balance and makes seizure control even more resistant to treatment. The acute increase in the surface expression of NMDA receptors during prolonged seizures also may cause excitotoxic injury, cell death, and other pathological expressions and re‐arrangements of receptor subunits that all contribute to long‐term sequelae such as cognitive impairment and chronic epilepsy. In conclusion, a short window of opportunity exists when seizures are maximally controlled by first‐line benzodiazepine treatment. After that, multiple pathological mechanisms quickly become engaged that make seizures increasingly more difficult to control with high risk for long‐term harm.     

The Substantia Nigra is an Important Site for the Containment of Seizure Generalization in the Kindling Model of Epilepsy

To investigate the role of the substantia nigra (SN) in kindling, electrical stimulation of the SN was delivered at various times before or after stimulation of the amygdala (AM) or pyriform cortex during or after kindling in rats. The results were as follows: Ipsilateral SN stimulation delivered prior to each AM kindling stimulation for 14 days significantly retarded the appearance of Stage 4 and 5 seizures and shortened the afterdischarge (AD) duration. Bilateral SN prestimulation blocked seizure generalization in some AM- or pyriform cortex-kindled animals, prolonged the latency to bilateral forelimb clonus in others, and shortened the AD duration of the kindled seizure in a current intensity-dependent fashion. These effects were only partially antagonized by haloperidol, but were completely abolished by picrotoxin. The picrotoxin alone significantly reduced the latency. Almost no effect was found when the SN stimulation was delivered after the onset of bilateral forelimb clonus. We conclude that the SN might be an important mediator of the early aspects of seizure generalization from limbic epileptic foci. The relative involvements of GABAergic gamma-aminobutyric acid and dopaminergic systems of the SN in this inhibitory function are discussed.     

Nitric oxide synthase expression in the cerebral cortex of patients with epilepsy

PURPOSE: Nitric oxide (NO), a short-lived radical synthesized from L-arginine by activation of the enzyme nitric oxide synthase (NOS), has been implicated in the pathophysiology of epilepsy by some investigators. However, the current data about NO and NOS in epilepsy are controversial and are derived only from animal models of epilepsy. In this study we investigated possible changes in NOS expression in the cerebral cortex of patients with epilepsy. METHODS: Qualitative and quantitative parameters of the immunolabeling pattern of the neuronal, endothelial, and inducible isoforms of NOS were analyzed in biopsy material obtained from patients with short and long seizure history and from patients without epilepsy. RESULTS: The comparative study showed that in the cerebral cortex of patients with epilepsy, particularly in those with a long seizure history, the number and labeling intensity of NOS-positive neurons increased, and that a subpopulation of nonpyramidal GABAergic neurons (type II NOS neurons) was responsible for this phenomenon. CONCLUSIONS: The fact that NOS upregulation is more evident in patients with a long seizure history suggests that this is a consequence of seizures, acting probably as an adaptative response to the sustained release of excitatory amino acids.