The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia.

The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants

Absence seizures are the most pure form of generalized epilepsy. They are characterized in the electroencephalogram by widespread bilaterally synchronous spike-wave discharges (SWDs), which are the reflections of highly synchronized oscillations in thalamocortical networks. To reveal network mechanisms responsible for the initiation and generalization of the discharges, we studied the interrelationships between multisite cortical and thalamic field potentials recorded during spontaneous SWDs in the freely moving WAG/Rij rat, a genetic model of absence epilepsy. Nonlinear association analysis revealed a consistent cortical "focus" within the peri-oral region of the somatosensory cortex. The SWDs recorded at other cortical sites consistently lagged this focal site, with time delays that increased with electrode distance (corresponding to a mean propagation velocity of 1.4 m/sec). Intra-thalamic relationships were more complex and could not account for the observed cortical propagation pattern. Cortical and thalamic sites interacted bi-directionally, whereas the direction of this coupling could vary throughout one seizure. However, during the first 500 msec, the cortical focus was consistently found to lead the thalamus. These findings argue against the existence of one common subcortical pacemaker for the generation of generalized spike-wave discharges characteristic for absence seizures in the rat. Instead, the results suggest that a cortical focus is the dominant factor in initiating the paroxysmal oscillation within the corticothalamic loops, and that the large-scale synchronization is mediated by ways of an extremely fast intracortical spread of seizure activity. Analogous mechanisms may underlie the pathophysiology of human absence epilepsy.

https://www.jneurosci.org/content/jneuro/22/4/1480.full.pdf

Cortical Focus Drives Widespread Corticothalamic Networks during Spontaneous Absence Seizures in Rats

OBJECTIVE: Research has implicated dysfunction of glutamatergic neurotransmission in the pathophysiology of schizophrenia. This review evaluates evidence from preclinical and clinical studies that brain glutamatergic neurotransmission is altered in schizophrenia, may affect symptom expression, and is modulated by antipsychotic drugs. METHOD: A comprehensive review of scientific articles published over the last decade that address the role of glutamate in the pathophysiology of schizophrenia was carried out. RESULTS: Glutamatergic neurons are the major excitatory pathways linking the cortex, limbic system, and thalamus, regions that have been implicated in schizophrenia. Postmortem studies have revealed alterations in pre- and postsynaptic markers for glutamatergic neurons in several brain regions in schizophrenia. The N-methyl-d-aspartic acid (NMDA) subtype of glutamate receptor may be particularly important as blockade of this receptor by the dissociative anesthetics reproduces in normal subjects the sym...

https://ajp.psychiatryonline.org/doi/pdfplus/10.1176/appi.ajp.158.9.1367

The Emerging Role of Glutamate in the Pathophysiology and Treatment of Schizophrenia

Which animal models should be used in the search for new antiepileptic drugs? A proposal based on experimental and clinical considerations

Spontaneous paroxysmal electroclinical patterns in rat: A model of generalized non-convulsive epilepsy

Summary: Of 100 randomly chosen, adult male Wistar rats in the breeding colony at the Centre de Neurochimie, Strasbourg, 31 presented spontaneous, nonconvulsive epileptic seizures: wave-and-spike discharges, 7–11 cy-cles/s, 200–600 μV, accompanied by behavioral arrest and myoclony of the vibrissae and of the facial and cervical muscles. Pentylenetetrazol (PTZ) 10 and 20 mg/kg increased the duration and number of seizures by 100–150% in these spontaneously epileptic animals, and caused identical seizures in apparently normal rats. Sodium valproate, diazepam, trimethadione, and ethosux-imide suppressed the spontaneous seizures and protected against PTZ-induced seizures in a dose-dependent fashion. Carbamazepine and diphenylhydantoin were inefficacious or aggravative in the two cases. The clinical, EEG, and pharmacological observations suggest that the Wistar rats displaying spontaneous seizures constitute a valid physiological and pharmacological model of petit mal absences, presenting advantages compared to the usual models in which seizures are induced byinjected epileptogenic drugs.



RESUME

Sur 100 rats Wistar, mâles, adultes, preleves au hasard dans Ľe1evage du Centre de Neurochimie de Strasbourg, 31 ont presente spontanement des crises epileptiques nonconvulsives (de-charges de pointes-ondes de 7–11 c/s et de 200–600 μ V accom-pagnees ďun arret de Ľactivite et de myoclonies des vibrisses et de la musculature faciale et cervicale). Le pentylenetetrazol a 10 et 20 mg/kg augmente de 100–150% la duree et le nombre des crises chez les animaux spontanement epileptiques; aux memes doses, le pentylenetetrazol fait apparaitre des crises iden-tiques chez les animaux apparemment indemnes. Le valproate de sodium, le diazepam, la trimethadione, et Ľethosuximide sup-priment les crises spontanees et protegent contre les crises induces par 20 mg/kg de PTZ de facon dose-dependante. La car-bamazepine et la diphenylhydantoine sont inefficaces ou aggravates sur les deux types de crises. Ľensemble des resultats cliniques, electroencephalographiques, et pharmacologiques permettent de penser que les crises spontanees du rat Wistar constituent un bon modele physiologique et pharmacologique ďabsences. Ce modele semble presenter quelques avantages par rapport aux modeles usuels induits par des injections de drogues epileptogenes.



RESUMEN

De las 100 ratas Wistar machos y adultos, seleccionadas al azar de la colonia de crias del Centro de Neuroqui'mica en Es-trasburgo, 31 presentaron ataques epilepticos no convulsivos: descargas punta-onda de 7 a 11 ciclos por segundo y 200 a 600 μ.V, acompanadas de interrupcion del comportamiento y mio-clonias de las vibrisas y de los musculos faciales y cervicales. La administracion de 10 a 20 mg/kg de pentilentetrazol (PTZ) incrementaron en un 100 a 150% la duracion y el numero de los ataques en estos animales espontaneamente epilepticos y causo ataques identicos en ratas aparentemente normales. El valproato sodico, el diazepan, la trimetadiona y la etosuximida suprimieron los ataques espontaneos y protegieron a las ratas de las crisis inducidas por el PTZ. La carbamazepina y la difenilhidantoina fueron ineficaces o perjudiciales en dos casos. Las observa-ciones clinicas, electroencefalograficas y farmacologicas sugi-eren que las ratas Wistar que muestran ataques espontaneos con-stituyen un valido modelo fisiologico y farmacologico de las au-sencias petit-mal. Este modelo presenta ventajas con respecto a modelos comunes en los que los ataques se inducen inyectando drogas epileptogenicas.



ZUSAMMENFASSUNG

Von 100 zufallig ausgewahlten mannlichen erwachsenen Wistar-Ratten aus der Zuchtkolonie am Centre de Neurochimie, Strasburg zeigten 31 spontane, nicht konvulsive epileptische Anfalle: wave and spike Entladungen von 7 bis 11 c/s und 200 bis 600 uV, die von einem Verharren und Myokloni der Schnau-zhaare sowie der facialen und cervikalen Muskeln begleitet waren. Pentylentetrazol (PTZ) in einer Dosis von 10 und 20 mg/ kg verlangerte bei diesen spontan epileptischen Tieren die Dauer und erhohte die Anzahl der Anfalle um 100 bis 150%. Daruber hinaus verursachte diese Dosis identische Anfalle bei scheinbar normalen Ratten. Natrium Valproat, Diazepam, Trimethadion und Ethosuximid unterdruckten die spontanen Anfalle und schutzten, in Abhangigkeit von der Dosis, vor PTZ-induzierten Anfallen. Carbamazepin und Diphenylhydantoin waren wir-kungslos; in 2 Fallen verstarkten sie die Anfalle. Die klinischen, EEG, und pharmakologischen Beobachtungen legen nahe, daβ die Wistar-Ratten mit spontanen Anfallen ein gutes physiolo-gisches und pharmakologisches Modell der Petit Mai Absencen darstellen, das Vorteile gegenuber den ubrigen Modellen bietet, bei denen epileptogene Medikamente injiziert werden mussen.

Gabriel Micheletti

Papers

Spontaneous paroxysmal electroclinical patterns in rat: A model of generalized non-convulsive epilepsy

A Model of Chronic Spontaneous Petit Mal‐like Seizures in the Rat: Comparison with Pentylenetetrazol‐Induced Seizures

Spontaneous spike and wave discharges in thalamus and cortex in a rat model of genetic petit mal-like seizures

Enhancement of spike and wave discharges by GABAmimetic drugs in rats with spontaneous petit-mallike epilepsy

Kindling of audiogenic seizures in Wistar rats: An EEG study