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The intergeniculate leaflet (IGL) of the thalamus constitutes a small but important part of the neural network controlling circadian activity in rodents. It appears that IGL integrates photic cues from retina with non-photic information originating from different nonspecific brain systems. Subsequently, this integrated signal is passed to the master biological clock - the suprachiasmatic nuclei (SCN). The common neurotransmitter of biological clock neural structures, the y-amino-butyric acid (GABA) is expressed in many, if not all, IGL and SCN neurons. Whole-cell patch clamp in vitro electrophysiological experiments were performed in order to evaluate GABA's influence on single IGL neurons in rat. Most neurons were hyperpolarized by GABA application and this effect was caused by activation of GABAa as well as GABAb receptors. The presence of GABAB receptors in rat's IGL has been suggested for the first time.
The effect of γ-aminobutyric acid-receptor agonists, GABA and muscimol on the pituitary-adrenocortical activity, measured indirectly through corticosterone secretion, and the receptors involved were investigated in conscious rats. GABA given ip induced a dual effect, in lower dose (10mg/kg) it significantly decreased the resting serum corticosterone levels while in higher doses (100-500mg/kg) it considerably raised that level. Muscimol (0.5mg/kg ip) also increased the corticosterone concentration. Both GABA and muscimol given intracerebroventricularly (icv) induced a significant, dose-related increase in serum corticosterone levels. Bicuculline, a GABAA-receptor antagonist, totally abolished the corticosterone response to GABA but did not influence the response to muscimol. Pretreatment with atropine did not affect the corticosterone response to GABA but significantly diminished the response to muscimol. These results suggest that GABA moderately inhibits the pituitary-adrenal axis at the pituitary level but significantly stimulates it at the hypothalamic level. The stimulatory effect of GABA, but not muscimol, is mediated by hypothalamic GABA A-receptors, and in the effect of muscimol hypothalamic cholinergic, muscarinic receptors are involved to a significant extent.
It was shown in this study that isolated porcine coronary arteries (PCA) contracted by depolarization with high Ko or by histamine are dose-dependently relaxed by glutamic acid, aspartic acid, N-methyl-asparate (NMDA) and γ-aminobutyric acid (GABA). Zn2+ was also shown to relax dose-dependently PCA contractions induced by 50 mM KCl with an ED50 value of about 1.5 mM and to inhibit dose-dependently histamine-induced contractions, shifting ED50 values from 6μM to 40 μM, not affecting however corresponding cumulative concentration-response (CCR) curves established for acetylcholine-induced contractions. Furthermore, since Zn2+ ions are co-localized in many glutamatergic synapses of the central nervous system, it has been postulated in analogy to glutamate neurotoxicity that perturbations of the synaptic zinc concentrations might be a triggering factor in several cerebral diseases, such as ischemic strokes and sustained seizures. Unfortunately, little is known so far about effects of glutamate and zinc ions on the vascular tone. Although the nature of the glutamatergic receptors occurring in the blood vessels investigated in this study remains unclear, the results suggest that glutamate and Zn2+ ions interact with voltage-gated as well with ligand-operated Ca-channels. An interesting aspect might be the putative role of glutamate and zinc as long-term toxic agents in the early steps of the pathomechanisms leading to degenerative vascular lesions.
The paper reviews recent advances in vagal nerve stimulation for the control of food intake and body weight. The vagal nerves are the predominant pathway in the "brain-gut axis" responsible for short term regulation of food intake. Stimulation of afferent vagal traffic attenuates food intake by vagal projections to nucleus tractus solitarius, arcuate nucleus and its convergence’s to thalamic center of satiety. A few studies have been published in this field so far. All of them are consistent and show significant decrease in body mass during vagal stimulation. Due to promising results of experimental studies, clinical trials are expected in the near future.
The purpose of the study was to define if anaesthetic action of xylazine could conceivably result from the potentiation of inhibitory neurotransmitters or the inhibition of excitatory neurotransmitter systems in the brain. Rats were injected with xylazine at a dose of 50 mg/kg b.w., and then the hippocampus and thalamencephal were removed at 0.1, 0.25, 0.5, 1, 1.5, 2, 4, and 6 h after the injection. Glutamate (Glu) and γ-aminobutyric-acid (GABA) were measured in the brain tissue by reversed-phase high-performance liquid chromatography. The results revealed that the hippocampus Glu level decreased significantly 0.1 h after the injection of xylazine, the thalamencephal GABA increased significantly 0.1 h after the injection, while the changes in hippocampus GABA and thalamencephal Glu were not significant. However, all of these changes returned to the normal level after 2 and 4 h, respectively. The results indicated the relative effects of xylazine on Glu and GABA levels in the hippocampus and thalamencephal.
Glutamine is involved in many metabolic pathways such as generation of amino acids, nucleotides and glutathione. Glutamine also serves in pH homeostasis, urea formation, immune response and wound healing. In addition, glutamine is considered to be the primary precursor of the fast neurotransmitters glutamate and GABA in the central nervous system (CNS). The prevailing hypothesis of a glutamate/GABA-glutamine cycle suggests that a large amount of released glutamate and GABA are translocated into perisynaptic astroglial cells, converted into glutamine, and subsequently shuttled back to neurons for regeneration of the neurotransmitters. This mechanistic view is supported by differential localization of glutamate and GABA transporters on perisynaptic glial processes, and demonstration of the key glutamine metabolizing enzymes glutamine synthetase (GS) and phosphate-activated glutaminase (PAG) in glial cells and nerve terminals, respectively. However, the molecular mechanisms involved in glutamine extrusion from glial cells and its transport into neurons have until recently eluded characterization. We have molecularly identified a family of amino acid transporters (Slc38) with isoform specific characteristics. We show that the system A transporters (SATs) mediate neuronal transport of glutamine. SAT1 is enriched in GAD67 expressing GABAergic neurons suggesting a role in GABA formation. SAT2 expression is pronounced in the somatodendritic domains of glutamatergic neurons where it sustains formation of glutamate and is intrinsic for retrograde signaling. Activity of the homologous system N transporter SN1 – expressed exclusively on astroglial cell membranes – is dynamically regulated by intracellular protein kinases and may fine-tune extracellular levels of glutamine accessible for neuronal uptake. SN2 – also expressed in the astroglial cells, but with differential subcellular localization – mediates glutamine release for neurotransmitter synthesis and glycine release to regulate NMDA receptors. Finally, we have shown that these transporters also contribute to pH restoration during chronic metabolic acidosis and regulation of insulin secretion. Recently, I have also contributed to the investigation of a child with congenital glutamine synthetase deficiency, who developed generalized hypotonia and hyperreflexia and treatment-resistant seizures postpartum and had very low serum and cerebrospinal fluid concentrations of glutamine and glutamate (Häberle et al. 2012). Glutamine supplementation restored serum levels of glutamine and glutamate, while corresponding values in the CNS approached normal. Ammonia toxicity was also prevented. The frequency of seizures abated and EEG showed significant improvement. Altogether, our data show the importance of glutamine and glutamine transporters in normal physiology and pathophysiology and bolster existence of a glutamate/GABA-glutamine cycle.
The present study investigated the effects of acute and chronic intraperitoneal administration of Triazolam on g-aminobutyric acid (GABA) levels in different brain areas of albino rats. Three experiments were conducted. In the first, five groups of rats were acutely treated with different doses of Triazolam (0.25 mg/kg-4.0 mg/kg). In the second experiment, rats were treated chronically with a single daily dose of Triazolam (started with 0.25 mg/kg and increased by time to 1.0 mg/kg) for 5 weeks, simulating clinical use. In the third, rats were treated chronically with three daily doses of Triazolam (started with 0.25 mg/kg and increased by time to 0.5 mg/kg) for 20 days, representing a form of drug abuse. Brain levels of GABA and plasma levels of Triazolam were measured using high performance liquid chromatography (HPLC). The acute Triazolam administration produced an increase in GABA levels in all brain areas studied. The chronic administration of single daily dose of Triazolam produced normal GABA levels in all brain areas except brain stem where the levels were significantly decreased; this indicates the development of tolerance to Triazolam action on increasing GABA content. The chronic administration of three daily doses of Triazolam produced a decrease in GABA levels in all brain regions studied. In conclusion, chronic single daily dose treatment (representing normal use) produces tolerance to Triazolam effects on brain GABA levels, while chronic three daily doses administration (akin to drug abuse) causes a fall in GABA levels.
Mer cu ric chlo ride, p-chloromercuribenzoate and 5,5-dithiobis(2-nitrobenzoic acid) irreversibly inhib ited the activityof Escherichiacoliglu ta matedecarboxyl ase. Their sec ond or der rate con stants for in ac ti va tion are 0.463m M-1min-1, 0.034 uM-1min-1, 0.018 uM-1min-1, respectively. The characteristics of the inhibition by the three thiol-group re agents sup ports the idea that cysteinyl res i dues at the bind ing sites for the co factor and/or the substrate are important for enzyme activity in E. coli.
Cell culture is a convenient model for pharmacokinetic studies, but during the culture period, GABAa receptors are likely to undergo different modulatory processes. In this study, the current responses to ultrafast GABA applications were recorded from patches excised from neurons cultured for either up to two days (short-term culture) or for more than two weeks (long-term culture). The dose-dependencies of the currentrising phases revealed significant differences between the two groups. In the short-term cultures, the responses to both saturating and non-saturating GABA concentrations were slower than in the case of the long-term cultures. We conclude that the GABAa receptors in cultured neurons undergo profound kinetic changes involving the modulation of the binding reaction and transitions between bound states.
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