GABA-induced inactivation of Cebus apella V2 neurons: effects on orientation tuning and direction selectivity

We investigated the GABA-induced inactivation of V2 neurons and terminals on the receptive field properties of this area in an anesthetized and paralyzed Cebus apella monkey. Extracellular single-unit activity was recorded using tungsten microelectrodes in a monkey before and after pressure-injection of a 0.25 or 0.5 M GABA solution. The visual stimulus consisted of a bar moving in 8 possible directions. In total, 24 V2 neurons were studied before and after blocker injections in 4 experimental sessions following GABA injection into area V2. A group of 10 neurons were studied over a short period. An additional 6 neurons were investigated over a long period after the GABA injection. A third group of 8 neurons were studied over a very long period. Overall, these 24 neurons displayed an early (1-20 min) significant general decrease in excitability with concomitant changes in orientation or direction selectivity. GABA inactivation in area V2 produced robust inhibition in 80% and a significant change in directional selectivity in 60% of the neurons examined. These GABA projections are capable of modulating not only levels of spontaneous and driven activity of V2 neurons but also receptive field properties such as direction selectivity.

Neurochemical phenotype and birthdating of specific cell populations in the chick retina

The chick embryo is one of the most traditional models in developing neuroscience and its visual system has been one of the most exhaustively studied. The retina has been used as a model for studying the development of the nervous system. Here, we describe the morphological features that characterize each stage of the retina development and studies of the neurogenesis period of some specific neurochemical subpopulations of retinal cells by using a combination of immunohistochemistry and autoradiography of tritiated-thymidine. It could be concluded that the proliferation period of dopaminergic, GABAergic, cholinoceptive and GABAceptive cells does not follow a common rule of the neurogenesis. In addition, some specific neurochemical cell groups can have a restrict proliferation period when compared to the total cell population.

O embrião de galinha é um dos mais tradicionais modelosde estudos da neurociência do desenvolvimento e seu sistema visual tem sido um dos mais exaustivamente estudado. Aretina tem sido utilizada como modelo para estudar o desenvolvimento do sistema nervoso. Aqui, nós descrevemos as características morfológicas que caracterizam cada estádio da retina em desenvolvimento e os estudos do período de neurogênese de algumas subpopulações de células neuroquímicamente específicas da retina usando uma combinação de imunohistoquímica e autoradiografia de timidina-tritiada. Conclui-se que o período de proliferação das células dopaminérgicas, GABAérgicas, colinoceptivas e GABAceptivas não segue uma regra comum. Além disso, alguns grupos celulares neuroquimicamente distintos podem ter um período de proliferaçãomais restrito quando comparado ao da população total destas células.

Animal models of tardive dyskinesia--a review.

Tardive dyskinesia is a serious motor side effect of long term neuroleptic therapy, with an unknown pathophysiological basis. The leading hypothesis of the pathophysiology of tardive dyskinesia includes dopamine receptor supersensitivity, GABAergic hypofunction, excitotoxicity and oxidative stress. Many preclinical models have been developed to identify the underlying pathological processes of tardive dyskinesia, but none has yet produced a parsimonious results. A wide range of animal models, viz. Homologous, analogous and correlational models have been developed to explore the pathophysiology of tardive dyskinesia. Vacuous chewing movements in rodents induced by chronic neuroleptic treatment is the most frequently employed model. As the existing models suffer from several phenomenological and methodological problems, development of new models, highly predictive of pathological basis of tardive dyskinesia can accelerate tardive dyskinesia research for the better understanding of the pathophysiological processes underlying the syndrome and for the discovery of new therapeutic targets for the treatment of tardive dyskinesia.

Acquired Pendular Nystagmus with Voluntary Inhibition

This report documents a case of voluntary inhibition of acquired pendular nystagmus after head trauma. A 30-year-old male developed oscillopsia and decreased visual acuity, as well as findings of acquired pendular nystagmus with voluntary inhibition after head trauma. The EOG finding was horizontal 18-20Hz bilateral symmetrical pendular nystagmus in all directions of gaze at near and distant fixation. Nystagmus did not change with 14 Prism Diopter base-out prisms on both eyes, but it was possible to abolish it intentionally. Baclofen and Clonazepam had no effect in improving the patient's symptoms and EOG finding.

Ethanol, GABA end epilepsy

Ethanol exerts its behavioral effects largely by interacting with receptors to brain neurotransmitters. The molecular mechanisms involving these interactions are still not well known since an ideal model for their study is currently unavailable. In addition, responses to alcohol may vary due to factors such as genetic predisposition, ethanol concentration consumed, and stimuli such as stress, socialization, etc. The chronc consumption of alcohol, similar to that of other drugs such as benzodiazepines and barbiturates, is linked to GABAerigc neurotransmission. GABA is the predominant inhibitory neurotransmitter in the brain. In context of substance abuse, these three drugs first cause a gratifying effect, later tolerance and finally, physical and psychological dependence. If cosumption is interrupted abruptly, a withdrawal syndrome occurs. The Alcohol Withdrawal Syndrome (AWS) is state of hyperexcitability characterized by anxiety, fear, muscular rigidity and tonic-clonic seizures with epileptiform-type charactermental epilepsy models such as "Kindling" or GABA Withdrawal Syndrome (GWS) models. A possible correlation between these models and AWS will allow for a better understanding of the cellular and molecular effects that alcohol exerts on the brain

The effects of laminin on the characteristics and differentiation of neuronal cells from epidermal growth factor-responsive neuroepithelial cells

Many extracellular matrix molecules are expressed in the embryonic nervous system and there is some evidence that they are important regulators of neural development. Of these molecules, laminin appears to be the most potent, affecting virtually all neurons of the peripheral and central nervous system. This study was undertaken to investigate the effects of laminin on the proliferation and differentiation of cultured neuroepithelial cells taken from fetal rat forebrains (embryonic day 17-19). The results are summarized as follows. 1) Neuroepithelial cells cultivated in epidermal growth factors containing serum-free medium subsequently differentiated into neurons, astrocytes, and oligodendrocytes. 2) Neuronal cells derived from neuroepithelial cells were immunoreactive for gamma-aminobutyric acid (GABA) or substance P, but were not for serotonin and tyrosine hydroxylase. 3) In western blot analysis, the phosphorylated neurofilament content in neuronal cells was higher in culture on laminin than in culture on poly-L-lysine (PLL). 4) The proliferation rate of GABAergic neurons was higher in culture on laminin than in culture on PLL. These results suggest that GABAergic and substance P-ergic neurons can be differentiated from neuroepithelial cells and that laminin promotes the differentiation of neuronal cells from neuroepithelial cells and the increased proliferation rate of GABAergic cells.

Neurotransmitter release in aggregate cultures of chick embryo retina cells

The study of neurotransmitter release using aggregate cell cultures has been limited by the fact that cell aggregates are obtained only when cells are maintained in suspension with rotatory agitation. In this report we describe a simple and easy method that uses aggregate cell cultures to study the release of neurotransmitters. The results demonstrate that this relatively simple technique can be of great value to address the problem of neurotransmitter release and study the mechanisms of action of natural and synthetic compounds on the differentiation of functional synapses in the CNS.

Efectos de la DL-3-hidroxi, 3-etil, 3-fenil propionamida (HEPP) sobre un nuevo modelo de status epilepticus focal: el síndrome de abstinencia al GABA (SAG) / Efects of DL-3-hydroxy, 3-ethil, 3-phenyl propionamide (HEPP) on a new model of focal status epilepticus: the gaba withdrawal syndrome

El síndrome de Abstinencia al GABA (SAG), es un nuevo modelo de epileptogénesis focal en el que la actividad paroxística se induce mediante la interrupción de infusiones intracorticales de GABA. En estudios preliminares hemos observado que esta actividad muestra una extraordinaria resistencia a los anticonvulsivantes clásicos. En ratas que mostraban un SAG inducido por la suspención de infusiones localizadas de GABA (50 µg ml por hora en 24 horas), se administró el nuevo anticonvulsivante HEPP (50 mg/kg ip) 60 minutos después del inicio del SAG. La HEPP produjo una disminución significativa de la frecuencia de descarga en 8 de 10 ratas, con efecto máximo aproximadamante a los 30 min después de la inyección y una duración del efecto de cerca de 90 min. Cuando la HEPP se administró a un nuevo grupo de ratas (n = 5) al segundo día del SAG, el compuesto no produjo efectos. A pesar de que se ignora aún el mecanismo de acción de la HEPP, el SAG representa un modelo útil para la evaluación de nuevos anticonvulsivantes

Asociación Fenitoína Carbamazepina: Relación Efecto Anticonvulsivante con Niveles GABA Glutamato en Hipocampo / Associationod Phenytoin and Carbamazepine: Relation of Anticonvulsant effect and GABA Glutamate Levels in the Hippocampus

En la epilepsia refractaria rebelde a monoterapia es beneficiosa la asociación de fármacos como la fenotoína y la carbamazapina para evitar efectos tóxicos por la monoterapia. Se administró fenitoína y carbamazapina por separado en dosis correspondientes a Dosis Efectiva (DE)50' DE40 y DE10 a un grupo de ratones. Luego se aplicaron combinaciones carbamazepina DE40 más fenitoína DE 10' y carbamazepina DE9 más fenitoína DE41 según protocolo de Weaver, aplicando el test convulsivo de electrochoque máximo, en todos los casos. Se determinaron los niveles de GABA y glutamato en el hipocampo observándose que la carbamazepina disminuía signigicativamente los niveles de glutamato mientras que la fenitoína no (P<0.01). Además ambos fármacos aumentaron los niveles de GABA (P<0.01). Se determinó que la combinación de los fármacos, independientemente de su porcentaje de asociación, aumentaba significativamente el porcentaje de protección con repecto al de cada fármaco por separado (P<0.01). De los resultados se concluye que la carbamazepina produce una disminución estadísticamente significativa del nivel basal de glutamato y que la asociación carbamazepina más fenitoína produce un aumento estadísticamente significativo de la protección ante los tests convulsivos

Encefalopatia hepática e o sistema GABAérgico: o papel dos benzodiazepínicos endógenos / Hepatic encephalopathy and GABA system: the role of endogenous benzodiazepinic agents

A Encefalopatia Hepática (EH) é uma síndrome neuropsiquiátrica decorrente da insuficiência hepática seja esta aguda ou crônica. Embora vários aspectos envolvidos na sua patofisiologia ainda näo estejam completamente esclarecidos, há um consenso de que esta seja multifatorial. Acredita-se que a falência hepática leve ao acúmulo de substâncias neuroativas e/ou potencialmente tóxicas responsáveis pelas alteraçöes no funcionamento cerebral. Desde o início da década de 80 o sistema GABAérgico vem sendo considerado potencialmente envolvido na patogênese da EH. Achados experimentais recentes, tanto em modelos animais quanto em humanos, confirmaram tal hipótese e levantam novas perspectivas na compreensäo e tratamento desta síndrome. Esta revisäo objetiva apresentar as bases teórico-experimentais que correlacionam o sistema GABAérgico e seus moduladores endógenos bem como a aplicabilidade de tais achados.

Neuroanatomy and neurotransmitter regulation of defensive behaviors and related emotions in mammals

1. There is suggestive evidence that the septo-hippocampal system and the amygdala are involved in risk assessment behavior, a response to potential threat possibly related to anxiety. In addition, experimental results have been reported implicating the medial hypothalamus in coordinated escape, while the periaqueductal gray matter (PAG) and the median raphe nucleus serotonergic projection to the hippocampus seem to mediate freezing. The latter defensive behaviors are evoked by distal danger stimuli and may be viewed as manifestations of fear. Finally, there is a sound body of evidence indicating that the PAG commands primitive fight or flight reactions elicited by proximal threat, acute pain or asphyxia. These defense reactions may be related to rage and panic, respectively. In contrast, the lateral septal area and the bed nucleus of the stria terminalis have been shown to exert tonic inhibitory influence on defense. 2. Experimental evidence indicates that gamma-aminobutyric acid (GABA) tonically inhibits defensive behavior in the amygdala, hypothalamus and the PAG, an effect opposed by excitatory amino acids. Among monoamines, serotonin (5-HT) has been suggested to facilitate anxiety in the amygdala while inhibiting panic in the PAG. The role of noradrenaline in defense is less clear, although hypotheses implicating the locus coeruleus in anxiety and panic have been suggested. Among peptides, corticotropin-releasing factor (CRF) acting as a central neurotransmitter is thought to mediate behavioral and physiological effects of acute stress, while opioid peptides have been shown to inhibit defense in the amygdala and in the dorsal PAG. Finally, acetylcholine seems to facilitate defensive behavior in the hypothalamus and the PAG.

Regulation of luteinizing hormone-releasing hormone and luteinizing hormone secretion by hypothalamic amino acids

1. The present review discusses the proposed roles of the amino acids glutamate and GABA in the central regulation of luteinizing hormone-releasing hormone (LHRH) and in luteinizing hormone (LH) secretion. 2. Descriptions of the mechanisms of action of these neurotransmitters have focused on two diencephalic areas, namely, the preoptic-anterior hypothalamic area where the cell bodies of LHRH neurons are located, and the medial basal hypothalamus which contains the nerve endings of the LHRH system. Increasing endogenous GABA concentration by drugs, GABA agonists, or blockade of glutamatergic neurotransmission by selective antagonists in rats and non-human primates prevents ovulation and pulsatile LH release, and blunts the LH surges induced by estrogen or an estrogen-progesterone combination. In contrast, glutamate and different glutamate agonists such as NMDA, AMPA and kainate, can increase LHRH/LH secretion. 3. The simultaneous enhancement of glutamatergic activity and a decrease of GABAergic tone may positively influence the maturation of the pituitary-gonadal system in rats and non-human primates. Administration of glutamate receptor agonists has been shown to significantly advance the onset of puberty. Conversely, glutamate antagonists or increased endogenous GABA levels may delay the onset of puberty. The physiological regulation of LHRH/LH secretion may thus involve a GABA-glutamate interaction and a cooperative action of the various types of ionotropic glutamate receptors. 4. The inhibitory actions of GABA on LH release and ovulation may be exerted at the level of afferent nerve terminals that regulate LHRH secretion. A likely candidate is noradrenaline, as suggested by the synaptic connections between noradrenergic nerve terminals and GABAergic interneurons in the preoptic area. Recent experiments have provided complementary evidence for the physiological balance between inhibitory and excitatory transmission resulting in modulation of the action of noradrenaline to evoke LHRH release.

Avances en la fisiología de los ganglios basales / Advances in basal ganglia physiology

La organización del sistema de los Ganglios Basales está basada en una serie de circuitos paralelos, funcionalmente segregados pero que comparten un modelo básico común. La principal fuente de aferencias al sistema proviene de casi todas áreas corticales, sensitivo-motoras, asociativas y límbicas, siendo la corteza frontal el receptor final más importante de su actividad aferente. A través de la desinhibición selectiva de los circuitos apropiados, los Ganglios Basales especifican la combinación y secuencia de respuestas más adecuadas a los estímulos, sensoriales o endógenos que motivan una reacción del SNC. Se revisan las evidencias básicas que dan pie a esta interpretación así como a la comprensión de las principales manifestaciones clínicas del sistema

Fundamentos clínicos y neurobiológicos del uso de benzodiazepinas en la esquizofrenia / Clinical and neurobiological basis of the use of benzodiazepines in schizophrenia

En este trabajo se revisan los fundamentos clínicos y nerobiológicos del uso de benzodiazepinas en la esquizofrenia. Del análisis de los estudios clínicos se concluye que estos fármacos mejoran los síntomas psicóticos en algunos pacientes, mientras en otros son totalmente inefectivos. Desde el punto de vista neurobiológico se analiza el sistema gabaérgico y sus relaciones con el sistema dopaminérgico. Luego se revisan los estudios sobre Gaba en LCR y plasma de esquizofrénicos, y los estudios con drogas gabaérgicas. Se discuten las dificultades en la realización e interpretación de estos estudios. Se concluye que la fisiopatología de la esquizofrenia puede ser bastante compleja y que es necesario considerar las relaciones del sistema dopaminérgico con otros sistemas de neurotransmisión, y las variaciones temporales de estos sistemas interrelacionados. Se plantea la necesidad de investigar más el papel terapéutico de las benzodiazepinas en la esquizofrenia, ya que los pacientes que mejoran con estos fármacos pueden tener fisiopatología diferente

GAD-immunoreactive neurons are preserved in the hippocampus of rats with spontaneous recurrent seizures

In the present glutamate decarboxylase immunoreactivity (GAD-IR) was used to quantify GABAergic neurons in the hippocampus of rats exhibiting spontaneous recurtent seizures following pilocarpine-induced status epilepticus. Histological examination demonstrated marked neuronal damage to hippocampal neurons. However, in the same region, GAD-IR neurons were preserved. the present data demonstrate a selective resistance of GABAergic neurons to status epilepticus-induced neuronal damage, suggesting that loss of hippocampal GABAergic neurons does not underlie the recurrence of seizures in these animals

The projection of GABAergic neurons of the medial terminal accessory optic nucleus to the pretectum in the rat

Large numbers of neurons were retrogradely labeled in both the dorsal and ventral medial terminal nucleous (MTN) after fluoro-gold injections into the rat pretectal nucleus of the optic tract/dorsal terminal nucleus (NOT/DTN). Fluorescence immunocytochemistry for GABA in the same brains revealed GABA-positive neurons distributed mainly in the dorsal MTN. Approximately half of all the GABAergic neurons in the MTN were double-labeled. Therefore, GABAergic neurons comprise a significant component of the MTN-NOT-DTN projection which most likely inhibits the pretectal pathway mediating horizontal optokinetic nystagmus

The effect of beta-adrenoceptor antagonists alone and in combination with a GABA-elevating agent on isoniazid-induced convulsions in rats.

A delay in the onset of isoniazid-induced convulsions was found in rats pretreated with the beta 2-adrenoceptor blocker, butoxamine and the nonspecific beta-blocker, propranolol. In these animals the convulsive responses were inhibited in a dose dependent manner. These compounds were found to be effective even after the induction of convulsions. The beta 1-blocker, acebutolol was able to protect rats only when injected prior to the challenge. The anticonvulsant effect of acebutolol and propranolol but not that of butoxamine was found to be enhanced in animals pretreated with a gamma-aminobutyric acid (GABA) elevating agent, aminooxyacetic acid (AOAA). The findings indicate that the GABA-mediated anticonvulsant action of AOAA seems to be additive with that resulting from beta 1 but not beta 2-blockade.

Neurotrasmisión: sistema gaba, aplicación terapéutica, experiencia personal / Neurotransmitter gaba system: therapeutic application, personal experience

El ácido gama amino butírico (GABA) es el principal neurotransmisor inhibidor del S.N.C. En la función sináptica se distinguen por un lado los relacionados con el AMP Cíclico o segundo mensajero y por el otro, las variaciones de potencial a través de la membrana, donde interviene el Cl-entre otros y que está relacionado con la función gabaérgica. Se describen los receptores de GABA: A y B y de las benzodiacepinas: BZ1 y BZ2, que están interrelacionados. El GABA protege al animal de las Crisis Convulsivas Experimentales o bien, una vez producidas, yugula a ésta rápidamente por medio de inyecciones intravenosas, intracarotídeas o ventricular. Si bien se dice que Gaba no atraviesa la BHE o lo hace pobremente, hay numerosas evidencias en contrario. Siendo un amino ácido carboxílico necesita de transportadores para atravésarla. La BHE no está totalmente desarrollada hasta la vida adulta y por ello algunas sustancias son tóxicas para los niños y no para los adultos. Además los órganos circunventriculares no tienen BHE. Se presenta y postula el uso de GABA asociado a su cofactor piridoxal fosfato como inhibidor central y anticonvulsivo