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It was shown that central chemical sympathectomy by 6-hydroxydopamine and central chemical serotoninectomy by 5,6-dihydroxytryptamine diminish the level of gamma-aminobutyric acid in discrete areas of rat brain.
The N-4,4-diphenyl-3-butenyl derivative of the glial selective gamma-aminobutyric acid (GABA) uptake inhibitor 4,5,6,7-tetrahydroisoxazolo [4,5-c]pyridin-3-ol (N-DPB-THPO), was tested for its ability to block sound-induced seizures in the audiogenic seizure-susceptible Frings mouse model of epilepsy. Following intracerebroventricular (i.c.v.) administration, N-DPB-THPO blocked tonic hindlimb extension in a dose- and time-dependent manner. At the doses tested no gross behavioral effects were noted.
In ovariectomized rats the intraventricular administration of ethanolamine-O-sulfate (EOS, 300 micrograms), a specific, competitive and catalytic inhibitor of gamma-aminobutyric acid (GABA) transaminase, induced 3-4 h later a marked reduction in serum prolactin (PRL) concentrations and a 3- to 4-fold rise in the concentration of GABA in pituitary stalk, but not systemic, plasma. The administration of EOS also resulted in an elevation of GABA concentrations in the hypothalamus. These results demonstrate that GABA in pituitary stalk plasma is derived from the central nervous system and that an abrupt increase in the concentration of GABA in hypophysial portal blood is associated with a suppression of PRL secretion.
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Postembedding immunocytochemistry with a gamma-aminobutyric acid (GABA) antiserum was done on semithin sections of cat lateral geniculate nucleus (LGN) previously processed with the rapid-Golgi and gold-toning procedures, to determine which of the three main morphological types (1, 2,3) of neurons in the A-laminae show immunoreactivity and are, therefore, presumably GABAergic. Only type 3 cells were found to be GABA positive. These cells were characterized by small somata and few, scarcely branched dendrites bearing almost exclusively appendages with long slender stalks. Some of these cells have extensive filiform "axonlike" processes originating from different regions of dendrites and having appendages similar to those originating directly from dendrites. Many of these Golgi gold-toned impregnated dendritic appendages of type 3 cells were analyzed in the electron microscope and were identified as typical F2 terminals by their content of pleomorphic synaptic vesicles; by being postsynaptic to retinal (RLP), cortical (RSD), and perigeniculate (F1) terminals; and by being presynaptic to dendrites. In addition, since it was previously demonstrated that glutamic acid decarboxylase (GAD) and GABA-positive cells are not retrogradely labeled with horseradish peroxidase (HRP) from the visual cortex, the present results, by showing that GABA-positive cells have type 3 morphology, provide supporting evidence for the interneuronal nature of type 3 cells in cat LGN.
The thin-layer electrophoretic separation at pH 4.8 of brain extracts and a procedure for fluorescent staining of the plates with fluorescamine are described for the rapid routine determination of 4-aminobutyric acid (GABA), glutamic acid and aspartic acid in brain extracts and in particulate fractions of brain tissue. Automated sample application, electrophoretic separation using two chambers, and quantitation by in situ fluorescence scanning allows the assay of 280 samples within three working days. The method is reproducible (S.D. less than 8% of the mean) within the range of 0.2--2 nmole per spot. The staining procedure can be applied to a variety of related analytical problems. The method has proved useful for the determination of the specific radioactivities of GABA, glutamic acid and aspartic acid in metabolic studies.
A method was developed to determine pharmacologically relevant concentrations of the gamma-aminobutyric acid agonistic compound THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) in serum. THIP is extracted from serum by a cation-exchange column, derivatized by dansyl chloride, and further separated and quantitated by reversed-phase high-performance liquid chromatography using measurement of ultraviolet absorption at the optimal wave-length (265 nm). The lower detection limit of the method is 0.07 mumol 1(-1) (10 ng ml-1) when 2 ml of serum are used for extraction. This sensitivity is sufficient for pharmacokinetic studies in man following administration of a presumably therapeutic dose of THIP. Blood samples collected from 28 patients treated with one or more of 26 drugs relevant for coadministration with THIP did not contain substances which would affect the reliable quantitation of THIP, if present.
Single-channel measurements were performed with the aim of constructing a detailed molecular scheme for the reaction between gamma-aminobutyric acid (GABA) and a chloride channel of crayfish deep extensor abdominal muscle (DEAM). GABA was applied in pulses to outside-out patches of muscle membrane, and, based on the dose-response of the peak currents and of their rise times, a linear model with five binding steps has been proposed. Evaluation of the single-channel kinetics indicated at least three open states. Two of them originate most probably from the fully liganded receptor state and are grouped in mixed bursts due to their different life times. The third one appears independently, outside the bursts, and originates from a lower liganded receptor state. Simulations of the dose-responses and the open time distributions with this model led to a set of rate constants which generated relatively optimal fits.
The effect of chlorophenothane (pp'--DDT) and five structurally related compounds op-DDD (op'-DDD, pp'-DDD, DTE, DCMP and DCP see text) on the cerebral hemisphere gamma-aminobutyric acid (GABA), the main inhibitory transmitter in brain contents and possible correlation with central activities was demonstrated in rats. The tested compounds were given in oral doses of 600 mg/kg in peanut oil. Cerebral GABA content was determined 1, 3 and 6 hrs after the ingestion of pp'-DDT and 3 hrs after each of the other drugs. The mean GABA content in each group of rats was compared with control groups, either without any treatment, or receiving the equivalent volume of peanut oil. pp'-DDT produced a significant reduction in brain GABA contents 3 and 6 hrs after its administration. This was accompanied by excitability, tremor and clonic convulsions. Of the congenors, only DTE exerted a similar effect. The present results point to the possibility of partial involvement of GABA in the tremor and convulsions induced by pp'-DDT. They also indicate the importance of the CCl2 grouping in the molecule for the induction of central effects of pp'-DDT.
Intracellular recordings were made from CA1 pyramidal cells in the rat hippocampal slice to study the processes that influence the time course of inhibitory post-synaptic potentials (i.p.s.p.s) mediated by gamma-aminobutyric acid (GABA), and conductance changes evoked by ionophoretically applied GABA. The GABA-uptake inhibitors, nipecotic acid and cis-4-OH-nipecotic acid (1 mM), greatly prolonged conductance increases associated with both hyperpolarizing and depolarizing responses to ionophoretically applied GABA. In contrast to their effects on GABA-evoked conductances, uptake inhibitors only slightly prolonged antidromically evoked i.p.s.p.s. Their primary effect occurred after the i.p.s.p. had decayed to 5-30% of its peak. 4-OH-isonipecotic acid, a nipecotic acid analogue that does not inhibit GABA uptake, did not prolong i.p.s.p.s or ionophoretically evoked conductance changes. Sodium pentobarbitone (100 microM), a drug that prolongs the open time of GABA-activated chloride channels, potentiated both i.p.s.p.s and responses to ionophoretically applied GABA. Whereas pentobarbitone also prolonged i.p.s.p.s, it did not prolong responses to ionophoretically applied GABA. The prolongation of i.p.s.p.s by pentobarbitone occurred equally in both the early and late phases of the i.p.s.p., in contrast to the effects of GABA-uptake inhibitors. I.p.s.p.s did not usually decay exponentially. The observation that uptake inhibitors prolonged the late but not the early decay phase of the i.p.s.p., together with the previous finding that the conductance change persists for the duration of the i.p.s.p., indicate that GABA is present in the synapse throughout much of the i.p.s.p. These data suggest that diffusion of GABA out of the synapse, a non-exponential process, is an important determinant of the i.p.s.p. decay time course. Increasing the extracellular potassium concentration from 3.5 to 8.5 mM resulted in spontaneously occurring, synchronous burst firing of pyramidal cells. Cis-4-OH-nipecotic acid significantly reduced the number and amplitude of extracellularly recorded population spikes within each burst. We conclude that diffusion, channel open time and GABA uptake all influence the time course of GABA-mediated i.p.s.p.s. The time course of a single, brief i.p.s.p. is determined predominantly by post-synaptic channel kinetics and diffusion of GABA out of the synapse, whereas the inhibition produced by prolonged synaptic bursts or relatively long application of exogenous GABA can be markedly influenced by GABA uptake.(ABSTRACT TRUNCATED AT 400 WORDS)
Functional characterization of Arabidopsis thaliana GAT1 in heterologous expression systems, i.e. Saccharomyces cerevisiae and Xenopus laevis oocytes, revealed that AtGAT1 (At1g08230) codes for an H(+)-driven, high affinity gamma-aminobutyric acid (GABA) transporter. In addition to GABA, other omega-aminofatty acids and butylamine are recognized. In contrast to the most closely related proteins of the proline transporter family, proline and glycine betaine are not transported by AtGAT1. AtGAT1 does not share sequence similarity with any of the non-plant GABA transporters described so far, and analyses of substrate selectivity and kinetic properties showed that AtGAT1-mediated transport is similar but distinct from that of mammalian, bacterial, and S. cerevisiae GABA transporters. Consistent with a role in GABA uptake into cells, transient expression of AtGAT1/green fluorescent protein fusion proteins in tobacco protoplasts revealed localization at the plasma membrane. In planta, AtGAT1 expression was highest in flowers and under conditions of elevated GABA concentrations such as wounding or senescence.
Anterior pituitary glands from chickens (Gallus domesticus) were incubated with or without single, mediobasal chicken hypothalami in medium containing histamine, alone or together with the antagonist diphenhydramine or in medium containing gamma-aminobutyric acid (GABA), alone or together with the antagonists bicuculline or picrotoxin. The release of prolactin (Prl) and growth hormone (GH) was measured by homologous radioimmunoassay. Histamine had no direct effect on the release of either hormone but stimulated Prl (in a dose-related way) and GH release when anterior pituitary glands were co-incubated with hypothalami. Diphenhydramine also had no direct effect on Prl or GH secretion but blocked the stimulatory effect of histamine on hypothalamus-induced Prl and GH release. When anterior pituitary glands were incubated without hypothalami, GABA, bicuculline and picrotoxin had no effect on the release of Prl or GH. However, GABA inhibited the release of both hormones in a concentration-related manner, when anterior pituitary glands were co-incubated with hypothalami. This inhibition was blocked by both bicuculline and picrotoxin. These results suggest that histamine and GABA may be involved in controlling the secretion of Prl and GH from the avian pituitary gland, possible by modifying the secretion of hypothalamic releasing and/or release-inhibiting hormones.
BACKGROUND: Reboxetine is a selective norepinephrine (NE) reuptake inhibitor that exerts significant antidepressant action. The current study assessed norepinephrine-gamma-aminobutyric acid (GABA)-ergic mechanisms in reboxetine action, examining glutamic acid decarboxylase (GAD) mRNA expression in limbic neurocircuits following reboxetine within the context of chronic stress. METHODS: Male rats received 25 mg/kg reboxetine/day, p.o. Reboxetine and vehicle animals were exposed to 1 week of variable stress exposure or handling. Behavioral responses to stress (open field) were tested on day 7, and animals were killed on day 8 to assess neuroendocrine stress responses and limbic GAD65/67 mRNA regulation (in situ hybridization). RESULTS: Reboxetine significantly decreased behavioral reactivity in the open field. Reboxetine administration did not affect expression of GAD65/67 mRNA in handled rats; however, administration to stressed animals reduced GAD67 (but not GAD65) mRNA in the medial amygdaloid nucleus, posteromedial bed nucleus of the stria terminalis, and dentate gyrus. In contrast, GAD65 mRNA expression was increased by reboxetine in the lateral septum of stressed animals. CONCLUSIONS: Norepinephrine pathways appear to modulate synthesis of GABA in central limbic stress circuits. Decreases in GABA synthetic capacity suggest reduced activation of stress-excitatory pathways and enhanced activation of stress-inhibitory circuits, and is consistent with a role for GABA in the antidepressant efficacy of NE reuptake inhibitors.
This study utilizes tritiated muscimol binding and electron microscope autoradiography (Ilford L4 emulsion and phenidone development) to localize gamma-aminobutyric acid (GABA) receptor sites in the cerebellum of the rat. In the cerebellar cortex, silver grains were associated with somata and dendrites of basket and stellate cells in the molecular layer, with somata and primary and secondary dendritic shafts of Purkinje cells, axons and terminals of basket cells in the pinceau or basket, initial axonal segments and myelinated axons of Purkinje cells, and dendrites of granule and Golgi cells in the granular layer, and with somata and dendritic shafts of large and small cells in the cerebellar nuclei. These data correspond well to the light-microscope-autoradiographic observations in the cerebellum previously reported [Chan-Palay, V. (1978) Proc. Natl. Acad. Sci. 75, 1024-1028]. Label over GABA receptor sites can be localized to the plasma membranes between pre- and postsynaptic elements at synaptic junctions, of which 88.9% of the samples are axodendritic and the remaining 11.1% are axosomatic. GABA receptor sites are also found along axonal membranes of the GABA-containing basket cell within the basket surrounding Purkinje cells, where true axo-axonal synapses are rare. It is speculated that GABA receptors in the basket may suggest a possibility of the basis for synchronization, either self-inhibition or facilitation within the basket formation, or presynaptic suppression of inhibitory action of basket cell on Purkinje cell.
This study examined the effect of chronic exposure to ethanol and brain-derived neurotrophic factor (BDNF) on the responsiveness of cerebellar granule cells to gamma-aminobutyric acid (GABA). Cerebellar granule cell cultures were chronically exposed to ethanol (100 mM), BDNF (20 ng/ml), or the combination of ethanol and BDNF. Whole-cell current responses of granule cells to exogenously applied GABA were monitored following at least 5 days of chronic exposure. In the ethanol-treated cultures, granule cell responsiveness to GABA was attenuated. Concomitant exposure of cultures to ethanol and BDNF mitigated the ethanol-induced attenuation of GABA response, although BDNF, by itself, did not affect responsiveness to GABA. BDNF increased the expression of the GABA(A) receptor alpha6 subunit, whereas ethanol had no effect, in chronically treated granule cell cultures. In addition, concomitant treatment with BDNF and ethanol did not increase the expression of the GABA(A) receptor alpha6 subunit, so the subunit expression alone could not account for the mitigating effect of BDNF. We propose that different mechanisms regulating responsiveness to GABA underlie the effects induced by ethanol and BDNF, with the former influencing the expression of functional GABA(A) receptors and the latter involving the activation of the TrkB receptor and its downstream signaling pathways.
The effects of the amphetamine analog, 3,4-methylenedioxymethamphetamine (MDMA) were compared to the effects of d-amphetamine on the in vivo release of dopamine and gamma-aminobutyric acid (GABA) in the striatum and substantia nigra. The brain region-dependent role of the 5-HT2 receptors in the striatum and substantia nigra in regulating MDMA-induced dopamine and GABA release also was studied. Changes in the extracellular concentration of dopamine, 5-HT and GABA were measured simultaneously in the awake rat by in vivo microdialysis. The increase in striatal dopamine produced by systemic administration of MDMA was attenuated by infusion of TTX into the striatum. Infusion of the 5-HT2A/2C antagonist ritanserin into the striatum or the ipsilateral substantia nigra also significantly attenuated MDMA-induced dopamine release in the striatum. At the doses used in this study, MDMA but not d-amphetamine increased the extracellular concentrations of 5-HT and decreased GABA efflux in the substantia nigra. The ability of MDMA to decrease nigral GABA efflux also was blocked by the local infusion of ritanserin into either the substantia nigra or the striatum. Overall, these data provide evidence that MDMA increases dopamine release partly through an impulse-mediated mechanism. Furthermore, this increase in striatal dopamine efflux produced by MDMA is regulated, in part, by 5-HT2A/2C receptors in the striatum and the substantia nigra and ultimately by GABAergic input into the substantia nigra.
Neuropathologically, Huntington's disease is characterized by a profound reduction in neuronal cells originating in the corpus striatum and globus pallidus. Since one of these cell types utilizes gamma-aminobutyric acid (GABA) as a neurotransmitter, it may be possible to differentially diagnose this disorder on the basis of the CSF content of this amino acid. In order to determine the validity of this hypothesis, cerebrospinal fluid GABA was analyzed, using a recently developed radioreceptor assay procedure and was found to be significantly reduced in patients diagnosed as having Huntington's disease and also lower in patients with Alzheimer's disease, though no difference was noted between Parkinson patients and control subjects. The results suggest that analysis of cerebrospinal fluid GABA may have diagnostic, and perhaps predictive, value in certain neurological disorders.
(S,E)-4-Amino-5-fluoropent-2-enoic acid (6) is synthesized in six steps starting from the known gamma-aminobutyric acid aminotransferase (gamma-Abu-T) inactivator, (S)-4-amino-5-fluoropentanoic acid (1). Compound 6 is a mechanism-based inactivator of gamma-Abu-T: time-dependent inactivation is saturatable and protected by substrate; thiols do not protect the enzyme from inactivation; no enzyme activity returns upon dialysis. This compound (6) binds 50 times more tightly to gamma-Abu-T than does the saturated analogue (1). No transamination of 6 occurs prior to inactivation. However, five molecules of 6 are required to inactivate the enzyme with concomitant release of five fluoride ions. Therefore, four molecules are being converted to product for each inactivation event. (E)-3-(1-Aminocyclopropyl)-2-propenoic acid is synthesized in seven steps from 1-aminocyclopropanecarboxylic acid. It is prepared as a cyclopropyl derivative of the proposed intermediate in the inactivation of gamma-Abu-T by 6. The cyclopropyl derivative, however, is a noncompetitive inhibitor and does not inactivate the enzyme. This study shows the usefulness and hazards of incorporation of a trans double bond into potential gamma-Abu-T inactivators.