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1.
Synaptosomes and synaptoneurosomes were prepared from rat cerebral cortex. Comparison of the amino acid levels in the two types of organelles and of the effects of gabaculine thereon indicated that the neurosome portion of synaptoneurosomes constituted the major influencing component of the organelles. Administration to rats of inhibitors of gamma-aminobutyric acid (GABA) degradation, such as gabaculine and L-cycloserine, resulted in elevated GABA levels in synaptoneurosomes and a decrease in muscimol-stimulated Cl- up-take by the organelles. Addition of gabaculine directly to the incubation medium for the uptake assay had no effect on the Cl- transport. In contrast, administration to rats of isonicotinic acid hydrazide, an inhibitor of GABA synthesis, decreased the GABA level in synaptoneurosomes and increased the muscimol-stimulated Cl- uptake by the organelles. Although the evidence is not unequivocal, it does support the concept of GABA released from nerve endings being taken up by the postsynaptic cell, from where it exerts a regulatory influence on the functioning of the GABA receptor/ion channel complex. 相似文献
2.
Abstract: The possibility that γ-hydroxybutyrate (GHB), a metabolite of γ-aminobutyric acid (GABA), may play a role in the CNS has recently come to attention. We describe here a sensitive and specific mass fragmento-graphic technique that allows the measurement of picomole amounts of GHB in single rat brain areas. Moreover, we show that GHB can accumulate postmortem, an effect that is blocked by the use of microwave irradiation to kill the animals. To understand further the relationship between GABA and GHB formation, we treated rats with drugs known to inferfere with GABA metabolism at different levels and concomitantly measured GABA and GHB in cerebral cortex and cerebellum. Isoniazide, which blocks the formation of GABA, also decreases GHB. Blockers of the catabolism of GABA, such as aminooxyacetic acid and γ-acetylenic GABA, increase GABA levels and decrease those of GHB. Sodium dipropylacetate increases both GABA and GHB, supporting the hypothesis that this effective antiepileptic drug also blocks in vivo the enzyme that converts succinic semialdehyde to succinic acid. 相似文献
3.
The effect of pharmacological doses of two amino acids neurotransmitters, gamma-aminobutyric acid (GABA) and beta-alanine (beta-Ala), on thyrotrophin (TSH) secretion was studied in normal and hypothyroid (PTU-treated) male rats. Inhibition of TSH secretion was observed in normal rats treated with the drugs, 30 min after their administration. Hypothyroid animals responded only to GABA administration, decreasing their serum TSH at 30 min. Response to thyrotrophin-releasing hormone (TRH) after 15 min of drug administration was blunted in GABA injected animals, as compared to saline-injected controls. When TRH was injected at the same time as GABA and beta-Ala, the response was significantly lower than in controls. It is suggested that beta-Ala and GABA act at the pituitary by impairing the TSH response to TRH. The possibility that beta-Ala actions may be due to decreased GABA catabolism is considered, since beta-Ala administration increased GABA synaptosomal levels. 相似文献
4.
Gregory T. Payne David M. Soderlund 《Journal of biochemical and molecular toxicology》1991,6(4):283-292
The interaction of avermectin B1a (AVMB1a) with mouse brain chloride channels was characterized using a radiochloride efflux assay. The loss of intravesicular chloride from synaptoneurosomes preloaded with 36Cl involved an initial rapid phase followed by a slower phase that approached equilibrium within 10 min. AVMB1a stimulated a 30% loss of intravesicular chloride within the first 2 s of exposure; however, AVMB1a had no effect on the rate of the slower phase of chloride loss. Experiments with lysed synaptoneurosomes showed that both chloride loading and basal and AVMB1a-stimulated chloride release required the presence of intact vesicles. The efflux of 36Cl from mouse brain synaptosomes and the stimulation of efflux by AVMB1a were qualitatively similar to the results obtained with synaptoneurosomes but involved much lower overall levels of chloride loading and release. AVMB1a produced halfmaximal stimulation of chloride efflux from synaptoneurosomes at a concentration of 2.1 ± 0.3 μM and a 35.4 ± 1.4% maximal loss of intravesicular chloride at saturating concentrations. γ-Aminobutyric acid (GABA), bicuculline, or the chloride channel blockers picrotoxinin, t-butylbicyclophosphorothionate (TBPS) 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS), and anthracene 9-carboxylic acid (9-CA) had little or no effect on the loss of chloride from synaptoneurosomes either in the presence or the absence of AVMB1a. However, the chlorinated cycloalkane insecticides dieldrin and lindane were equally effective as inhibitors of GABA-dependent chloride uptake and AVMB1a-stimulated chloride efflux. These data demonstrate that AVMB1a-stimulated chloride efflux from mouse brain synaptic vesicles results from the activation of GABA-insensitive chloride channels and that this action is distinct from their previously documented effects on GABA-gated chloride channels in mouse brain preparations. Our findings imply that both GABA-gated and GABA-insensitive chloride channels may be toxicologically significant targets for the action of avermectins. 相似文献
5.
The putative psychotropic effect of the anabolic-androgenic steroid, testosterone propionate (TP), was determined in intact adult male rats after 1 or 2 weeks of continued exposure via subcutaneously implanted capsules. Behavior was assessed in a novel open-field arena and in the elevated plus-maze. In addition, γ-aminobutyric acid (GABA)-stimulated 36 chloride (CI-) influx was determined in cerebral cortical synaptoneurosomes as a function of TP exposure. The weight of the prostate gland was taken and blood serum level of total testosterone (T) was assayed. One week of TP exposure (˜3.5-5.0 mg/kg per day) resulted in anxiolytic behavior, as evidenced by an increase in the exploration of the open arms of the elevated plus-maze. The behavioral effect in the elevated plus-maze was not observed in animals exposed to TP for a 2-week period. Ambulation scores in the novel open field did not change as a function of TP exposure. Blood T levels were increased 7-fold by 1 week of exposure, and increased 10-fold in animals with implants for a 2-week period. After 1 week of TP exposure, the concentration of GABA that elicited 50% of the maximal CI- influx in cortical synaptoneurosomes (i.e., EC50) was significantly decreased; this effect was not seen in animals exposed to TP for 2 weeks. The maximal efficacy of the GABAA receptor-gated CI- influx was not affected after 1 or 2 weeks of TP treatment. Thus, 1 week of treatment with TP resulted in anxiolytic behavior that was accompanied by an increase in the sensitivity of cortical GABAA receptors. However, the behavioral slid neurochemical changes were no longer present after 2 weeks of TP exposure. These results ate discussed in terms of the agonist effects of reduced androgen metabolites at the GABAA receptor and the possible development of tolerance to these effects. 相似文献
6.
To investigate the role of gamma aminobutyric acid (GABA) on prolactin secretion, castrated male rats were infused with aminooxyacetic acid (AOAA) or bicuculline, two drugs that affect GABA metabolism or its binding to the receptors, respectively. The infusion of AOAA or bicuculline for 2 hr did not significantly modify serum prolactin levels. A quick iv injection of sulpiride, a drug that induces hyperprolactinemia, brought about a significantly lower release of prolactin in rats infused with AOAA than in control rats, infused with saline. The response to sulpiride in rats infused with bicuculline was significantly greater, in terms of prolactin release, than in control rats. These results suggest that GABA may have an inhibitory role on the regulation of prolactin release. 相似文献
7.
Chronic antidepressants and GABA "B" receptors: a GABA hypothesis of antidepressant drug action 总被引:4,自引:0,他引:4
Amitryptyline (10 mg/kg), desipramine (5 mg/kg), citalopram (10 mg/kg) and viloxazine (10 mg/kg) were administered to rats either acutely (decapitation 1 hr after i.p. injection) or subacutely (by subcutaneous minipump implantation for 18 days followed by decapitation 24 hr after removal). After acute administration there was not any consistent alteration in GABA levels, GAD activity, 3H GABA "A" or 3H-GABA "B" receptor binding or 3H-nipecotic acid binding to the recognition site for GABA uptake in the frontal cortex or hippocampus. Upon subacute antidepressant drug infusion, GABA levels, GAD activity and 3H-GABA-"A" binding showed only scattered differences in drug treated animals as compared to saline treated rats. However, 3H-GABA "B" binding in the frontal cortex was consistently elevated after all drug treatments (in % of control: amitryptyline = 155%; desipramine = 151%; citalopram = 173%; viloxazine = 189%). Scatchard analysis showed that this was due to a Bmax increase without an effect in Kd. These findings were reproduced by subacute administration of pargyline, a MAO inhibitor. These data suggest that GABA "B" receptors may be involved in the mechanism of action of antidepressant drugs and provide a link between GABAergic and monoaminergic hypotheses of depression. 相似文献
8.
《Neurochemistry international》1987,11(3):339-346
Dipyridamole (DPR) and nitrobenzylthioinosine (NBI) inhibition of adenosine accumulation in synaptoneurosomes derived from rat cerebral cortex, rat cerebellum, guinea pig cerebral cortex and guinea pig cerebellum was investigated. The inhibition of adenosine accumulation by NBI was observed to be distinctly biphasic in both guinea pig and rat synaptoneurosomes. Such biphasic inhibition consisted of a nM potency component to inhibition, accounting for 20–30% of the maximum inhibition, and a μM potency component, accounting for the remaining 70–80% maximum inhibition. Such an inhibitory profile contrasts sharply with that of DPR which appears monophasic, with a mean IC50 of between 10−7 M and 10−6 M, in all rat and guinea pig synaptoneurosomes preparations studied.Further differences between the potency of NBI and DPR in inhibiting [3H]adenosine accumulation were also noted. DPR was more potent in inhibiting [3H]adenosine accumulation in guinea pig cerebellar synaptoneurosomes than in cerebral cortex synaptoneurosomes. In rat synaptoneurosomes, the reverse selectivity was observed. DPR was also 2–6 fold (depending on brain region of comparison) more potent in inhibiting adenosine accumulation in guinea pig synaptoneurosomes than in inhibiting such accumulation in rat synaptoneurosomes. In contrast, NBI was approximately equipotent in inhibiting adenosine accumulation in rat and guinea pig synaptoneurosomes. Additional binding studies using [3H]NBI are also reported. The data presented are entirely consistent with the hypotheses that (1) NBI and DPR bind to functionally relevant sites and (2) there are different populations of nucleoside transporters in mammalian brain. 相似文献
9.
Male albino rats were administered daily with haloperidol, clozapine or L-DOPA and sacrificed 18 hours after the last dose of the drug. Acutely haloperidol (5mg/kg, i.p.) greatly lowered nigral GABA levels whereas after 167 daily doses the nigral GABA levels were not significantly different from controls, but were significantly increased as compared with the acutely treated animals. In contrast, acute L-DOPA (2 × 100mg, p.o.) greatly raised nigral GABA levels whereas after chronic L-DOPA (167 days) nigral GABA levels were not significantly different from controls and were significantly lower as compared with the animals receiving the acute treatment. Clozapine (20 mg/kg, i.p. either acutely or chronically) did not have as marked an effect on nigral GABA levels as did haloperidol. Of these various drug regimens only chronic L-DOPA significantly affected nigral GAD activity, producing a moderate decrease. 相似文献
10.
Gamma-aminobutyric acid (GABA) is involved in the mechanism of action of many drugs affecting different functions in the central nervous system. The present study has investigated the effect of diazepam, a positive allosteric GABAA receptor modulator, and sodium valproate, a GABA transaminase inhibitor, on thermoregulation in rats. The experiments were designed into two main parts: (1) in vivo experiments on body temperature of conscious rats; (2) in vitro experiments on temperature sensitivity (temperature coefficient, TC) of rat PO/AH neurons in slice preparations. Central (i.c.v.) or systemic (i.p.) administration of diazepam, as well as sodium valproate produced dose-dependent hypothermia in rats. Both GABAergic drugs diazepam and sodium valproate increased temperature sensitivity (TC) in warm-sensitive rat PO/AH neurons. These results are in agreement with the neuronal model of temperature regulation and confirm the involvement of GABAergic mechanisms in thermoregulation. 相似文献
11.
The endogenous γ-aminobutyric acid (GABA) content of the rat pineal gland and superior cervical ganglion (SCG) was measured by high pressure liquid chromatography. It was found that GABA levels in both tissues increased after decapitation of the animals. The GABA content of tissues frozen within 20 seconds after decapitation was the same as that of tissues removed from animals killed by microwave irradiation. Amino-oxyacetic acid, a GABA-transaminase inhibitor, increased the endogenous GABA content of both of these tissues. Dimethylphenylpiperizinium or isoniazid administration did not alter GABA levels in these tissues. Isoproterenol increased the GABA content of the SCG but did not change the pineal gland GABA levels. The ability of the pineal gland to take up and accumulate 3H-GABA was significantly reduced in rats that had been ganglionectomized. A fluctuation in endogenous GABA levels in the pineal gland was seen to occur when measures were taken at different times of the day. These results tend to suggest that GABA may have some functional role in the pineal gland and the superior cervical ganglion. 相似文献
12.
Wolfgang Löscher Gerhard Böhme Frank Müller Sonia Pagliusi 《Journal of neurochemistry》1985,45(3):879-889
A procedure is described for the rapid preparation of nerve ending particles (synaptosomes) from 11 regions of one rat brain. The synaptosomal fractions have been characterized by electron microscopy and determination of four marker enzymes, i.e., glutamate decarboxylase (GAD), acetylcholinesterase, succinate dehydrogenase, and glycerol 3-phosphate dehydrogenase. Comparison with a much lengthier standard (Ficoll-sucrose) preparation showed that the synaptosomal yield of the new procedure was substantially better as judged by both morphological evaluation and protein recovery. The improved synaptosome preparation was used for determination of regional gamma-aminobutyric acid (GABA) levels in synaptosomal fractions. The postmortem increase in GABA level during removal and dissection of brain tissue and homogenization and fractionation procedures could be minimized by rapid processing of the tissue at low temperatures and inclusion of the GAD inhibitor 3-mercaptopropionic acid (3-MP; 1 mM) in the homogenizing medium. The addition of GABA (0.2 mM) to the homogenizing medium did not alter the GABA levels in the synaptosomes, indicating that no significant redistribution of GABA occurred during subcellular fractionation in sodium-free media. Synaptosomal GABA levels determined in the 11 rat brain areas showed the same regional distribution as the GABA-synthesizing enzyme GAD. On the basis of these findings, it was suggested that the synaptosome preparation could be used to evaluate the in vivo effects of drugs on nerve terminal GABA. Treatment of rats with a convulsant dose of 3-MP (50 mg/kg i.p.) 3 min before decapitation significantly lowered synaptosomal GABA levels in olfactory bulb, hippocampus, thalamus, tectum, and cerebellum. The 3-MP-induced seizures and reduction of GABA levels could be prevented by administration of valproic acid (200 mg/kg i.p.) 15 min before the 3-MP injection. The data indicate that the improved synaptosome preparation offers a convenient method of preparing highly purified synaptosomes from a large number of small tissue samples and can provide useful information on the in vivo effects of drugs on regional GABA levels in nerve terminals. 相似文献
13.
W. Lscher 《Neurochemistry international》1981,3(6):397-404
The time course of the effects of aminooxyacetic acid, γ-vinyl GABA, γ-acetylenic GABA, gabaculine, ethanolamine-O-sulphate (EOS) and valproic acid (VPA) on brain GABA content and the activities of glutamic acid decarboxylase (GAD) and GABA aminotransferase (GABA-T), the enzymes involved in biosynthesis and degradation of GABA, was re-determined and compared with the action on the electroconvulsive threshold in mice. All drugs caused significant increases in the seizure threshold, and the temporal pattern of this effect correlated rather well with the induced elevation of brain GABA. However, no clear relationship was found between the extent of GABA increase and the relative increase of seizure threshold. Except for VPA, the time course of the increment in brain GABA followed closely the inhibition of GABA-T. The activity of GAD was gradually decreased by γ-acetylenic GABA and a slow decline of GAD activity was also observed after γ-vinyl GABA. EOS and gabaculine suggesting a feedback repression of GAD synthesis by highly elevated GABA concentrations. Concomitant with significant reduction of GAD activity, a decrease in seizure threshold occurred though brain GABA levels remained markedly elevated. On the other hand, following administration of VPA the effect of GABA levels was paralleled by an increase in GAD activity indicating that the GABA-elevating action of this drug can be attributed at least in part to an activation of GABA synthesis. The data suggest that reduction of GAD activity may be an inevitable consequence of increasing brain GABA concentrations over a certain extent and this effect seems to limit the anticonvulsant efficacy of GABA-T inhibitors. 相似文献
14.
Leontino Battistin Mary Varotto Giorgio Berlese Giovanni Roman 《Neurochemical research》1984,9(2):225-231
The effect of anticonvulsant drugs was examined on brain GABA levels and GAD and GABA-T activities. The level of GABA was increased by the treatment with diphenylhydantoin. The drug had no effect on GABA-T activity, whereas GAD activity was inhibited. Carbamazepine increased the GABA level but did not effect GAD and GABA-T activities. Diazepam had no effect on GABA level and GAD activity, whereas it caused a slight inhibition of GABA-T activity. Phenobarbital administration decreased GABA level only at the higher concentration. Clonazepam effected only GAD activity. Some anticonvulsant drugs generally increase brain GABA level; however the lack of correlation with an effect on the GAD and GABA-T activities indicate that other factors than metabolism, such as membrane transport processes, are involved in the mechanism of action of anticonvulsant drugs. 相似文献
15.
Victoria A. L. Seymour Andrea B. Everitt M. Louise Tierney 《The Journal of membrane biology》2009,227(3):111-122
Hippocampal pyramidal neurons potentially express multiple subtypes of GABAA receptors at extrasynaptic locations that could therefore respond to different drugs. We activated extrasynaptic GABAA receptors in cultured rat hippocampal pyramidal neurons and measured single-channel currents in order to compare the actions
of two drugs that potentially target different GABAA receptor subtypes. Despite the possible difference in receptor targets of etomidate and diazepam, the two drugs were similar
in their actions on native extrasynaptic GABAA receptors. Each drug produced three distinct responses that differed significantly in current magnitude, implying heterogeneous
GABAA receptor populations. In the majority of patches, drug application increased both the single-channel conductance (>40 pS)
and the open probability of the channels. By contrast, in the minority of patches, drug application caused an increase in
open probability only. In the third group high-conductance channels were observed upon GABA activation and drug application
increased their open probability only. The currents potentiated by etomidate or diazepam were substantially larger in patches
displaying high-conductance GABA channels compared to those displaying only low-conductance channels. Factors contributing
to the large magnitude of these currents were the long mean open time of high-conductance channels and the presence of multiple
channels in these patches. In conclusion, we suggest that the local density of extrasynaptic GABAA receptors may influence their single-channel properties and may be an additional regulating factor for tonic inhibition and,
importantly, differential drug modulation.
This work is dedicated to the memory of Professor P. W. Gage. 相似文献
16.
Effects of GABAergic Drugs In Vivo on High-Affinity Choline Uptake In Vitro in Mouse Hippocampal Synaptosomes 总被引:3,自引:1,他引:2
The effects of several gamma-aminobutyric acid (GABA)-ergic drugs on sodium-dependent high-affinity choline uptake (HACU) were investigated in the hippocampus. HACU was measured in vitro after in vivo administration of the drug to mice. HACU was inhibited by those drugs that enhance GABA transmission. The convulsant 3-mercaptopropionic acid, which decreases GABA levels, stimulated HACU. From these results and previous findings, it appears that GABA mediates a tonic inhibitory effect on the septal-hippocampal cholinergic system. 相似文献
17.
The gamma aminobutyric acid (GABA) antagonists picrotoxin and bicuculline were injected into the striatum of rats via chronic cannulae. Dyskinesias were produced by these drugs which could be blocked by their injection combined with GABA. The intrastriatal (i.s.) injection of a cholinergic drug, carbachol, also produced dyskinesias which were blocked by GABA. The use of i.s. injection of GABA antagonists to produce an animal model of Huntington's chorea is discussed. 相似文献
18.
TheB
max of the [3H]muscimol binding in the cerebellum of ethanol-naive alcohol-sensitive ANT (Alcohol Non-Tolerant) rats was only about 70% of that in the alcohol-insensitive AT (Alcohol Tolerant) rats. There were no line differences in the muscimol binding to cerebrocortical and hippocampal membranes. In the alcohol-sensitive rats, the cerebellar [3H]muscimol binding (5 nM) negatively correlated with the ethanol-induced motor-impairment measured in the tilting plane test. Muscimol stimulated the flux of36Cl– in cerebellar synaptoneurosomes and non-filtered microsacs to the same extent in both rat lines. Ethanol produced only a small, although statistically significant, enhancement of the muscimol-stimulated chloride flux in both rat lines. The present data confirms our earlier finding of a low level of muscimol binding in the cerebellar membranes of alcohol-sensitive rats as compared to alcohol-insensitive rats. Further studies are needed to determine the relationship between the Cl– flux stimulation by muscimol and the differential muscimol binding in the cerebellum of these rat lines, and its importance for alcohol sensitivity. 相似文献
19.
An abamectin-resistant strain of Tetranychus cinnabarinus (Boisduval) (Rf = 25.3) was selected in laboratory. We compared the γ-aminobutyric acid (GABA) content in abamectin-susceptible T. cinnabarinus individuals with that in resistant individuals and investigated its relationship to abamectin resistance. High performance liquid chromatography (HPLC) was used to ascertain GABA content in abamectin-susceptible (SS) and resistant (AR) strains of T. cinnabarinus. The results indicate that GABA content in the AR was significantly higher than that in the SS (1.39-fold). AR individuals treated with a sublethal dose of abamectin did not show significant differences in GABA levels compared with AR individuals that were not treated with abamectin. However in the SS, abamectin treated individuals had a significantly higher GABA content than those that were untreated (1.52-fold). Individuals in the SS that survived from selection with LC95 of abamectin (SS-AR) showed significantly higher GABA levels compared to SS (1.41-fold). Similarly, progenies of the SS-AR parental generation (SS-ARF1) also showed increased GABA levels (1.51-fold) compared to SS. In addition, behavioral observations have shown that all individuals from the AR, SS-AR and SS-ARF1, which had more GABA content than the SS, demonstrated a significant decrease in crawling speed compared with SS individuals. This observation is consistent with excessive GABA levels had inhibitory effect on the central nervous system. Thus, we postulate that increasing GABA content in T. cinnabarinus is associated with resistance against abamectin. 相似文献
20.
The interaction of avermectin B1a (AVMB1a) with mouse brain chloride channels was characterized using a radiochloride efflux assay. The loss of intravesicular chloride from synaptoneurosomes preloaded with 36Cl involved an initial rapid phase followed by a slower phase that approached equilibrium within 10 min. AVMB1a stimulated a 30% loss of intravesicular chloride within the first 2 s of exposure; however, AVMB1a had no effect on the rate of the slower phase of chloride loss. Experiments with lysed synaptoneurosomes showed that both chloride loading and basal and AVMB1a-stimulated chloride release required the presence of intact vesicles. The efflux of 36Cl from mouse brain synaptosomes and the stimulation of efflux by AVMB1a were qualitatively similar to the results obtained with synaptoneurosomes but involved much lower overall levels of chloride loading and release. AVMB1a produced half-maximal stimulation of chloride efflux from synaptoneurosomes at a concentration of 2.1 +/- 0.3 microM and a 35.4 +/- 1.4% maximal loss of intravesicular chloride at saturating concentrations. gamma-Aminobutyric acid (GABA), bicuculline, or the chloride channel blockers picrotoxinin, t-butylbicyclophosphorothionate (TBPS) 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), and anthracene 9-carboxylic acid (9-CA) had little or no effect on the loss of chloride from synaptoneurosomes either in the presence or the absence of AVMB1a. However, the chlorinated cycloalkane insecticides dieldrin and lindane were equally effective as inhibitors of GABA-dependent chloride uptake and AVMB1a-stimulated chloride efflux. These data demonstrate that AVMB1a-stimulated chloride efflux from mouse brain synaptic vesicles results from the activation of GABA-insensitive chloride channels and that this action is distinct from their previously documented effects on GABA-gated chloride channels in mouse brain preparations. Our findings imply that both GABA-gated and GABA-insensitive chloride channels may be toxicologically significant targets for the action of avermectins. 相似文献