Amygdaloid Kindling and the GABA System

The effect of increased brain GABA levels on fully kindled amygdala seizures was investigated in Long-Evans rats. The newly synthesized GABA-transaminase inhibitor, -Γ-acetylenic GABA (GAG) administered on four consecutive days (100 mg/kg, followed by 50 mg/kg, i.p.) was found to either significantly reduce, or eliminate entirely, the behavioral seizures normally produced by amygdala stimulation. The effect is seen after the first injection of GAG although its magnitude was greater on subsequent days. Behavioral seizures reappeared 2 to 3 days after termination of GAG treatment. The duration of electrographic seizures (self-sustained amygdala after-discharge) was either unchanged or greater on the first day of GAG treatment, but was briefer on subsequent days. The duration of afterdischarges returned to normal levels 1 to 2 days earlier than the behavioral seizures after the termination of GAG. Picrotoxin (1.5-2 mg/kg, i.p.) did not antagonize either electrographic or behavioral effects of inhibition produced with GAG. Electrical stimulation of amygdala delivered during the initial sedation stage induced by picrotoxin resulted in further regression of kindled seizures in the majority of animals. Although in doses employed, GAG alleviates amygdaloid-kindled seizures its use requires caution in view of its ability to reduce arousal level. RÉSUMÉ L'effet de l'ÉlÉvation des taux cÉrÉbraux de GABA sur les crises amygdaliennes par effet d'embrasement complet a ÉtÉÉtudiÉ chez des rats Long-Evans. l'injection pendant 4 jours consÉcutifs de 100 mg/kg suivis de 50 mg/kg i.p. d'un inhibiteur de la GABA. Transaminase nouvellement synthÉtisÉ (Γ-acetylenic GABA ou GAG) a significativement rÉduit ou mÊme supprimÉ les crises normalement provoquÉes par la stimulation amygdalienne. l'effet est observÉ aprÈs la premiere injection de GAG, mais son importance s'accroit les jours suivants. Les crises rÉapparaissent 2 ou 3 jours aprÈs la fin du traitement au GAG. Du point de vue Électrographique, la durÉe de la postdÉcharge amygdalienne autoentretenue est inchingÉe ou accrue le premier jour du traitement, mais elle diminue les jours suivants pour retourner À la normale un ou deux jours avant que les crises ne rÉapparaissent aprÈs la fin de ('administration du GAG. l'injection de picrotoxine (1.5-2 mg/kg i.p.) ne s'oppose pas aux effets inhibiteurs du GAG sur les crises ou leur accompagnement EEG. La stimulation Électrique de l'amygdala pendant l'Étape sÉdative initiate induite par la picrotoxine provoque une rÉgression supplÉmentaire des crises d'embrasement chez la majoritÉ des animaux. Bien que, aux doses utilisÉes, le GAG attÉnue les crises amyg-daliennes d'embrasement, son utilisation nÉcessite des prÉcautions compte tenu de sa tendance À rÉduire le niveau d'Éveil. RESUMEN En ratas Long-Evans se ha investigado el efecto del aumento de los niveles cerebrales de GABA, sobre los ataques originados en la amÍgdala totalmente condicionada, (Kindling). El recientemente sintetizado in-hibidor de la GABA transaminasa, Γ-acetilÉnico GABA (GAG), redujo significativamente o eliminÓ totalmente las crisis de comportamiento que habitualmente se producen con la estimulaciÓn de la amÍgdala. El efecto se observa despuÉs de la primera in-yecciÓn de GAG pero su magnitud aumentÓ en dias subsiguientes. Las crisis de comportamiento reaparecieron a los 2–3 dÍas de la interrupciÓn del tratamiento con GAG. La duraciÓn de los ataques electrogrÁficos (perservaciÓn de la post-descarga de la amigdala) no se modificÓ, o incluso aumentÓ, en el primer dia de la administraciÓn de GAG pero se redujo en los dias siguientes. La duraciÓn de las post-descargas volviÓ a sus niveles normales 1 o 2 dias antes que la reapariciÓn de las crisis de comportamiento una vez terminado el tratamiento con GAG. La picrotoxina (1.5-2 mg/kg, i.p.) no antagonizÓ los efectos inhibitorios producidos por el GAG sobre el electroencefalograma o las crisis de comportamiento. La estimulaciÓn elÉctrica sobre la amÍgdala, aplicada durante la fase de sedaciÓn inicial inducida por la picrotoxina, condujo a una regresiÓn aÚn mÁs intensa de las crisis condicionadas, en la mayorÍa de los animales. A pesar de que, con las dosis utilizadas, el GAG alivia las crisis de la amÍgdala previamente condicionada, se requiere gran precauciÓn en su utilizaciÓn en vista de su propiedad de reducir el nivel del despertar. ZUSAMMENFASSUNG Die Wirkung erhÖhter GABA-Spiegel des Gehirns auf AmygdalonkrÄmpfe nach Kindling wurden bei Long-Evans-Ratten untersucht. Der neuerdings synthetisierte GABA-TYansaminasen-Inhibitor, Gamma-Acetylen-GABA (GAG) wurde an 4 aufeinander-folgenden Tagen in einer Dosis von 100 mg/kg und anschlieliend 50 mg/kg i.p. verabfolgt. Er reduzierte entweder signifikant oder eliminierte vÖllig die anfalls-weisen VerhaltensÄnderungen, die normalerweise durch Stimulation des Amygdalon produziert wurden. Die Wirkung ist nach der Erstinjektion des GAG zu beobachten, obgleich ihr Ausmaß an folgenden Tagen grÖßer war. Die VerhaltensanfÄlle kamen 2 bis 3 Tagen nach Beendigung der GAG-Behandlung wieder. Die Dauer der elektrographischen AnfÄlle (sich selbst un-terhaltende Amydalonnachentladungen) blieben entweder gleich oder sie wurden grÖßer am 1. Tag der GAG-Behandlung, wurden aber kÜrzer an folgenden Tagen. Die Dauer der Nachentladungen nor-malisierte sich 1 bis 2 Tage frÜher als die VerhaltensanfÄlle nach Beendigung des GAG verschwanden. Picrotoxin (1.5 bis 2 mg/kg i.p.) wirken nicht als Antagonist gegenÜber der durch GAG produzierten Hemmung der elektrographischen-oder Verhalten-seffekte. Die elektrische Stimulierung des Amygdalon wÄhrend der initialen Sedierung nach Picrotoxin ver-ursachte bei der Mehrzahl der Tiere einen weiteren RÜckgang der durch Kindling entstandenen AnfÄlle. Obgleich das GAG in den verwandten Dosen, die durch Kindling des Amygdalon erzeugten KrÄmpfe leichter ablaufen lUßt, erfordert seine Anwendung Vorsicht hinsichtlich seiner FÄhigkeit, das Erreg-barkeitsniveau zu senken.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66112/1/j.1528-1157.1980.tb04058.x.pd

Enantioselective detoxication of optical isomers of glycidyl ethers

The detoxication of the enantiomers of glycidyl 4-nitrophenyl ether (GNPE), (−)-(R)- and (+)-(S)-GNPE, and glycidyl 1-naphthyl ether (GNE), (−)-(R)- and (+)-(S)-GNE, by rat liver glutathione transferase and epoxide hydrolase was studied. Enantioselectivity was observed with both enzymes favoring the (R)-isomers as determined by the formation of conjugate, diol, and remaining substrate measured by HPLC. Enantiomers of GNE were detoxified by cytosolic epoxide hydrolase but those of GNPE were not. Substantial nonenzymatically formed conjugates of enantiomers of GNPE were detected showing (S)-GNPE the more reactive of the pair. © 1993 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38532/1/530050705_ftp.pd

Imaging epileptogenic tubers in children with tuberous sclerosis complex usingΑ-[ 11 C]Methyl- L -tryptophan positron emission tomography

Several reports have indicated that cortical resection is effective in alleviating intractable epilepsy in children with tuberous sclerosis complex (TSC). Because of the multitude of cortical lesions, however, identifying the epileptogenic tuber(s) is difficult and often requires invaise intracranial electroencephalographic (EEG) monitoring. As increased concentrations of serotonin and serotonin-immunoreactive processes have been reported in resected human epileptic cortex, we used Α-[ 11 C]methyl-L-tryptophan ([ 11 C]AMT) position emission tomography (PET) to test the hypothesis that serotonin synthesis is increased interictally in epileptogenic tubers in patients with TSC. Nine children with TSC and epilepsy, aged 1 to 9 years (mean, 4 years 1 month), were studied. All children underwent scalp video-EEG monitoring, PET scans of glucose metabolism and serotonin synthesis, and EEG monitoring during both PET studies. [ 11 C]AMT scans were coregistred with magnetic resonance imaging and with glucose metabolism scans. Whereas glucose metabolism PET showed multifocal cortical hypometabolism corresponding to the locations of tubers in all 9 children, [ 11 C]AMT uptake was increased in one tuber (n = 3), two tubers (n = 3), three tubers (n = 1), and four tubers (n = 1) in 8 of the 9 children. All other tubers showed decreased [ 11 C]AMT uptake. Ictal EEG data available in 8 children showed seizure onset corresponding to foci of increased [ 11 C]AMT uptake in 4 children (including 2 with intracranial EEG recordings). In 2 children, ictal EEG was nonlocalizing, and in 1 child there was discordance between the region of increased [ 11 C]AMT uptake and the region of ictal onset on EEG. The only child whose [ 11 C]AMT scan showed to no regions of increased uptake had a left frontal seizure focus on EEG; however, at the time of his [ 11 C]AMT PET scan, his seizures had come under control. [ 11 C]AMT PET may be a powerful tool in differentiating between epileptogenic and nonepileptogenic tubers in patients with TSC.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50368/1/410440603_ftp.pd

A sensitive fluorimetric procedure for the determination of aliphatic epoxides under physiological conditions

A highly sensitive fluorimetric procedure based on alkylation of nicotinamide is described for the determination of aliphatic epoxides. Subsequent reaction of the resulting N-alkylni-cotinamides with a ketone in basic medium yields strongly fluorescent products after final acidification. Sensitivity of the assay is in the picomole range with good reproducibility. The alkylation reaction proceeds under physiological conditions and thus shows potential for the analysis of epoxides in biological materials. Despite rapid enzymatic detoxification, styrene oxide could be directly detected in 9000g supernatant liver fractions using the present approach.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24310/1/0000576.pd

Alcoholism and animals

Studies in animals of alcohol-associated phenomena have begun to yield data which may provide a better understanding of human alcoholism. Four such phenomena, tolerance, dependence, hepatic damage and self-intoxication, have been demonstrated in both animals and man. The relationships among these phenomena, however, have not yet been determined in either human or nonhuman species. Tolerance to and physical dependence on alcohol have been clearly demonstrated in a number of animal species. The behavioral, physiological and biochemical correlates of tolerance and dependence are of considerable contemporary experimental interest. In particular, animal models of alcohol withdrawal signs will yield excellent preparations for the study of the management of problems associated with ethanol withdrawal in man. Chronic liver damage, a problem often associated with alcoholism, has been demonstrated in animals; however, it remains unclear whether the conditions necessary for its production are equivalent in animals and man. Through an approach based on operant conditioning, behavioral phenomena associated with ethanol-reinforced self-intoxication are being elucidated in animals and man. These findings provide a descriptive framework which could lead to a delimitation of the important variables that control ethanol intoxication in both animals and man; hence, new avenues for treatment and prevention of human alcoholism may be elaborated.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/22395/1/0000845.pd

Effects of morphine, nalorphine and naloxone on neocortical release of acetylcholine in the rat

The effects of morphine (10 mg/kg), nalorphine (1 and 10 mg/kg), and naloxone (1 mg/kg) were studied on the neocortical release of acetylcholine (ACh) in midpontine pretrigeminal transected rats. Morphine and, to a lesser extent, nalorphine decreased ACh release. Naloxone was ineffective alone but antagonized the action of morphine.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46384/1/213_2004_Article_BF00422643.pd