Phobic memory and somatic vulnerabilities in anorexia nervosa: a necessary unity?

Anorexia nervosa is a clinically significant illness that may be associated with permanent medical complications involving almost every organ system. The paper raises a question whether some of them are associated with premorbid vulnerability such as subcellular ion channel abnormalities ('channelopathy') that determines the clinical expression of the bodily response to self-imposed malnutrition. Aberrant channels emerge as a tempting, if rather speculative alternative to the notion of cognitively-driven neurotransmitter modulation deficit in anorexia nervosa. The concept of channelopathies is in keeping with some characteristics of anorexia nervosa, such as a genetically-based predisposition to hypophagia, early onset, cardiac abnormalities, an appetite-enhancing efficacy of some antiepileptic drugs, and others. The purpose of this article is to stimulate further basic research of ion channel biophysics in relation to restrictive anorexia

Winning a Won Game: Caffeine Panacea for Obesity Syndemic

Over the past decades, chronic sleep reduction and a concurrent development of obesity have been recognized as a common problem in the industrialized world. Among its numerous untoward effects, there is a possibility that insomnia is also a major contributor to obesity. This attribution poses a problem for caffeine, an inexpensive, “natural” agent that is purported to improve a number of conditions and is often indicated in a long-term pharmacotherapy in the context of weight management. The present study used the “common target” approach by exploring the tentative shared molecular networks of insomnia and adiposity. It discusses caffeine targets beyond those associated with adenosine signaling machinery, phosphodiesterases, and calcium release channels. Here, we provide a view suggesting that caffeine could exert some of its effects by acting on several signaling complexes composed of HIF-1α/VEGF/IL-8 along with NO, TNF-α, IL1, and GHRH, among others. Although the relevance of these targets to the reported therapeutic effects of caffeine has remained difficult to assess, the utilization of caffeine efficacies and potencies recommend its repurposing for development of novel therapeutic approaches. Among indications mentioned, are neuroprotective, nootropic, antioxidant, proliferative, anti-fibrotic, and anti-angiogenic that appear under a variety of dissimilar diagnostic labels comorbid with obesity. In the absence of safe and efficacious antiobesity agents, caffeine remains an attractive adjuvant

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

Discriminative stimulus effects of pentobarbital in pigeons

Pigeons were trained to discriminate the IM injection of pentobarbital (5 or 10 mg/kg) from saline in a task in which 20 consecutive pecks on one of two response keys produced access to mixed grain. Pentobarbital (1.0–17.8 mg/kg) produced a dose-related increase in the percentage of the total session responses that occurred on the pentobarbital-appropriate key. The concomitant administration of bemegride (5.6–17.8 mg/kg) antagonized the discriminative control of behavior exerted by the training dose of pentobarbital. Benzodiazepines, diazepam (1.0 mg/kg) and clobazam (3.2 mg/kg), and barbiturates, methohexital (10 mg/kg), phenobarbital (56 mg/kg), and barbital (56 mg/kg), produced responding on the pentobarbital-appropriate key similar to that produced by pentobarbital. In contrast, narcotics such as morphine, ethylketazocine, cyclazocine, and SKF-10,047, at doses up to and including those that markedly suppressed response rates, produced responding predominantly on the saline-appropriate key. Similarly, the anticonvulsants, valproate, phenytoin, and ethosuximide occasioned only saline-appropriate behavior, indicating that not all anticonvulsants share discriminative stimulus effects with pentobarbital. Muscimol, a direct GABA agonist, and baclofen, a structural analogue of GABA, also failed to produce pentobarbital-appropriate responding. Ketamine, dextrorphan, and ethanol (0.3–3.2 g/kg, orally) produced intermediate levels of pentobarbital-appropriate responding, suggesting that the discriminative effects of these drugs may be somewhat like those of pentobarbital.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46416/1/213_2004_Article_BF00433247.pd

An inability of [gamma]-acetylenic GABA to block eating evoked by hypothalamic stimulation

Several lines of evidence have implicated the nigrostriatal dopamine system and the neocortex for eating occurring either spontaneously or in response to electrical stimulation of the lateral hypothalamus (ESLH). GABA-ergic neural systems are known to modulate activity in the nigrostriatal system and neocortex. The GABA-transaminase inhibitor, [gamma]-acetylenic GABA (GAG) was administered to rats eating in response to ESLH. This drug produced hypersynchronization of the cortical EEG and behavioral sedation, but did not alter the current threshold for evoking eating by ESLH. Implications of results for understanding mechanisms underlying ESLH-induced eating are discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/23181/1/0000108.pd