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PubMed1996

Pre- and postsynaptic sites for serotonin modulation of GABA-containing neurons in the shell region of the rat nucleus accumbens.

The shell of the nucleus accumbens received a dense serotonergic innervation and contains abundant gamma-aminobutyric acid (GABA)-immunoreactive neurons. Moreover, serotonin (5-hydroxytryptamine: 5-HT) and GABA have been implicated in a variety of common motivational and motor-related functions partially ascribed in this brain area. We used immunoelectron microscopy of antisera directed against 5-HT and GABA in the same section of tissue to examine whether there were cellular substrates that might indicate more specific sites for functional interactions involving these transmitters in the shell region of the rat nucleus accumbens. Immunogold-silver labeling for GABA was localized to perikarya, dendrites, axons and axon terminals, whereas immunoperoxidase labeling for 5-HT was restricted to axons and axon terminals. Approximately half (187/366) of the 5-HT-immunoreactive axon terminals apposed or formed synaptic junctions with postsynaptic neurons. These junctions were mainly of the symmetric-type (83/187) characteristic of inhibitory transmitters, and were equally prevalent on dendrites with and without detectable gold-silver labeling for GABA. Of the 187 5-HT-labeled axon terminals with recognized synaptic contacts, 36% also showed convergence on a common dendrite with a GABA-labeled axon terminal. In addition, 5-HT- and GABA-immunoreactive axon terminals were commonly (83/366) identified in direct apposition to one another. Within a single plane of section, 41% of the apposed GABA-immunoreactive axon terminals formed symmetric-type junctions with dendrites or somata, whereas, the apposed 5-HT-labeled axon terminals rarely showed postsynaptic contacts. These results indicate that 5-HT-containing axon terminals may postsynaptically inhibit GABAergic neurons and their targets within the shell of the rat nucleus accumbens. Additionally, our results strongly suggest that, in this brain region, appositions between 5-HT and GABA axons and axon terminals may facilitate presynaptic interactions between these transmitter systems.

Animals↗
PubMed1998

Glutamate-modulated production of GABA in immortalized astrocytes transduced by a glutamic acid decarboxylase-expressing retrovirus.

Replication-defective Moloney murine leukemia virus expressing the GAD67 gene under the control of the GFAP promoter was produced using selected clones of a fibroblast-packaging cell line. A spontaneously immortalized astrocyte cell line was infected with this virus and cellular clones expressing GAD67 selected. Astrocyte and fibroblast clones expressed functional GAD (detected by glutamic acid decarboxylation), but only fibroblasts were able to also produce GABA in the extracellular medium. When exposed to 200 microM glutamate, despite an observed difference in the rates of glutamate accumulation in control and GAD67-expressing astrocytes, similar proportions of glutamate taken up were detected. In GAD67-expressing astrocytes, the glutamate was mainly converted into GABA, suggesting GAD transgene activity to be dominant over other glutamate metabolic pathways, such as glutamine synthetase and glutamate dehydrogenase. Moreover, rapid GABA release into the cell medium was also observed, suggesting the involvement of reverse GABA transporters. The use of the GFAP promoter might be able to take advantage of its activation in response to factors inducing reactive gliosis observed in pathological insults. GAD67-expressing astrocytes might therefore be used for future grafting in pathological situations in which an excess of glutamate results in neuronal dysfunction or cell death.

4-Aminobutyrate Transaminase↗
PubMed1998

Modulation of GABA-gated chloride ion influx in the brain by dehydroepiandrosterone and its metabolites.

Both DHEA and GABAA receptor agonists are known to reduce anxiety. Since GABAA receptor agonists are generally thought to elicit their anxiolytic effects by facilitating neuronal uptake of chloride ion, we set out to evaluate whether DHEA elicits its anxiolytic effects by a similar mechanism. The results of the studies show an uneven distribution of basal and GABA-stimulated chloride uptake in different regions (cerebellum, pons-medulla, striatum, hippocampus, mid-brain, hypothalamus and cortex) of rat brain. Contrary to our expectations, however, both DHEA and DHEAS inhibited GABA-mediated chloride uptake with DHEAS being more potent than DHEA. On the other hand, delta 4-androstenedione, another DHEA metabolite, did not have any effect on chloride uptake in any region of the brain. In conclusion, the data presented here, therefore, suggest that DHEA and DHEAS may elicit anxiolysis through mechanisms independent of GABAA receptor-mediated facilitation of neuronal chloride uptake.

Androstenedione↗
PubMed2002

A new antioxidant compound H-290/51 modulates glutamate and GABA immunoreactivity in the rat spinal cord following trauma.

The involvement of the excitatory amino acid glutamate and the inhibitory amino acid gamma-amino butyric acid (GABA) in the pathophysiology of spinal cord injury is not known in details. This investigation is focused on the role of glutamate and GABA in a rat model of spinal cord trauma using immunohistochemistry. Spinal cord injury produced by a longitudinal incision of the right dorsal horn of the T10-11 segments resulted in profound edema and cell damage in the adjacent T9 segment at 5 h. Pretreatment with H-290/51 (50 mg/kg, p.o.), a potent antioxidant compound, effectively reduced the blood-spinal cord barrier (BSCB) permeability, edema formation and cell injury following trauma. At this time, untreated traumatised rats exhibited a marked increase in glutamate immunoreactivity along with a distinct decrease in GABA immunostaining in the T9 segment. These changes in glutamate and GABA immunoreactivity in traumatised rats were considerably attenuated by pretreatment with H-290/51. These results suggest that (i). oxidative stress contributes to alterations in glutamate and GABA in spinal cord injury, (ii). glutamate and GABA are important factors in the breakdown of the BSCB, edema formation and cell changes, and (iii). the antioxidant compound H-290/51 has a potential therapeutic value in the treatment of spinal cord injuries.

Animals↗
PubMed1982

In vivo modulations by GABA-related drugs of met-enkephalin release in basal ganglia of the cat brain.

The influence of the intrapallidal application of GABA-related compounds on the release of Met-enkephalin in the globus pallidus and the caudate nucleus in the two hemispheres was investigated in vivo in the cat. For this purpose, the 4 structures were continuously superfused with an artificial CSF through implanted push-pull cannulae and Met-enkephalin released in superfusates was determined using a specific radioimmunoassay. GABA (10-500 microM) reduced the local release of Met-enkephalin during its application but once the amino acid was removed from the superfusing fluid, an increase in the peptide release was observed. Diazepam (10 microM) induced only an inhibitory effect whereas muscimol (1 microM) stimulated Met-enkephalin release. Opposite changes in Met-enkephalin release were also seen with the GABA antagonists, bicuculline methiodide (1 microM) and picrotoxin (10 microM), suggesting that the local regulation of Met-enkephalin release by GABA related compounds may be mediated by at least two types of GABA receptors. In several cases, the unilateral pallidal application of GABA agonists and antagonists induced significant changes in Met-enkephalin release at distant structures. The most striking effect was observed with diazepam which markedly reduced the peptide release in both caudate nuclei and pallida. These data suggest that GABAergic systems can contribute to some bilateral regulation of striato-pallidal enkephalinergic neurones.

Animals↗
PubMed1984

Modulation of the GABA receptor complex by a steroid anaesthetic.

The interactions of a steroid anaesthetic, alphaxalone, with the GABA receptor-ionophore complex were investigated by two different experimental approaches. In the rat cuneate nucleus slice, alphaxalone (0.1-10 microM) potentiated depolarizing responses to superfused GABA and muscimol, but not those to glycine. The potentiating effect of alphaxalone was unaltered by the benzodiazepine antagonist Ro 15-1788. Alphaxalone (0.1-30 microM) also enhanced [3H]muscimol binding to rat brain membranes in the presence of Cl-ions; the enhancing effect on [3H]muscimol binding was abolished by Triton X-100. Analysis of binding curves for [3H]muscimol indicated that the steroid anaesthetic increases the affinity for [3H]muscimol of low affinity binding sites; this property is shared by pentobarbitone. The physiologically inactive beta-hydroxy isomer of the steroid was without activity in either of the experimental situations at 30 microM. It is suggested that alphaxalone and pentobarbitone share a common mode of action on the GABA system, which may be relevant to the mechanisms by which these drugs produce anaesthesia.

Anesthetics↗
PubMed1990

Physiological modulation of the GABA receptor by convulsant and anticonvulsant barbiturates in cultured rat hippocampal neurons.

The actions of convulsant and sedative barbiturates on responses to gamma-aminobutyric acid (GABA) application and on inhibitory postsynaptic currents were compared using voltage-clamp techniques in cultured rat hippocampal neurons. The convulsant barbiturates, 5-ethyl-5-(3-methylbut-2-enyl) barbituric acid (3M2B), and (+)-5-ethyl-5-(1,3-dimethylbutyl) barbituric acid [+)-DMBB), and the sedative barbiturate, 5-ethyl-5-(3-methylbutyl) barbituric acid (3MB), all potentiated GABA-mediated chloride currents. In addition, these compounds prolonged the duration of GABAergic inhibitory postsynaptic currents. The similarity between the action of convulsant and sedative barbiturates suggests that the convulsant activity of 3M2B and (+)-DMBB are not mediated by their actions at GABAergic synapses.

Animals↗
PubMed1991

Mercury modulation of GABA-activated chloride channels and non-specific cation channels in rat dorsal root ganglion neurons.

The effects of mercuric chloride and methylmercury chloride on the rat dorsal root ganglion neurons in primary culture were studied by the whole-cell patch clamp technique. gamma-Aminobutyric acid-induced chloride currents were augmented by mercuric chloride in a potent and efficacious manner; at concentrations of 1 and 10 microM, the current amplitude was increased to 130% and 200% of the control. Methylmercury even at 100 microM did not augment but rather decreased the GABA-induced chloride current. Both mercuric chloride and methylmercury generated slow inward currents by themselves. These currents are not mediated by the GABA-activated chloride channels or by voltage-activated sodium, potassium or calcium channels, and are likely to be due to non-specific cation channels.

Animals↗
PubMed1991

Mechanism of modulation of GABA-activated current by internal calcium in rat central neurons.

GABA-activated currents in Purkinje cells isolated from rat cerebellum were investigated. Increase of intracellular Ca2+ in the physiological range of concentrations caused a decrease in GABA-activated chloride currents. This effect resulted from a decrease of both the maximal values of GABA-activated currents and possibly from the affinity of GABAA receptors. Therefore, the mechanism of Ca2+ effect on GABAA receptors in central rat neurons differs from that in bullfrog sensory neurons.

Animals↗
PubMed1987

Benzodiazepine and beta-carboline modulation of GABA-stimulated 36Cl-influx in cultured spinal cord neurons.

GABAA agonists stimulate 36Cl-influx in spinal cord cultured neurons in a concentration-dependent manner. This effect of GABAA receptor stimulation is enhanced by benzodiazepines like clonazepam, diazepam and flurazepam and attenuated by (+)bicuculline and picrotoxinin. The beta-carbolines, methyl-6, 7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) and propyl-beta-carboline-3-carboxylate (beta-CCPr) exhibited opposite effects, with DMCM attenuating, while beta-CCPr potentiating GABA's effect. These results are consistent with the behavioral and electrophysiological effect of benzodiazepines and beta-carbolines with GABA receptor complex.

Animals↗
PubMed1989

5 alpha-pregnan-3 alpha,20 alpha-diol behaves like a partial agonist in the modulation of GABA-stimulated chloride ion uptake by synaptoneurosomes.

In rat cortical synaptoneurosomes, the maximum potentiation of GABA-stimulated 36Cl uptake produced by 5 alpha-pregnan-3 alpha,20 alpha-diol (5 alpha-pregnanediol) is significantly less than that elicited by 5 alpha-pregnan-3 alpha-ol-20-one (3 alpha-OH-DHP). This observation suggests that 5 alpha-pregnanediol may be a partial agonist whereas 3 alpha-OH-DHP acts as a full agonist at a common site on or near the GABAA/benzodiazepine receptor-chloride ionophore complex (GBRC). This hypothesis is supported by the finding that 5 alpha-pregnanediol will antagonize in a dose-dependent manner the enhancement of GABA-stimulated 36Cl uptake produced by 3 alpha-OH-DHP under certain conditions. Collectively, these findings support the hypothesis that GBRC-active progesterone metabolites with varying degrees of efficacy exist as reflected by their differential ability to potentiate 36Cl uptake in brain synaptoneurosomes.

Animals↗
PubMed1988

Modulation of GABA-stimulated chloride influx into membrane vesicles from rat cerebral cortex by triazolobenzodiazepines.

The effects of triazolobenzodiazepines on GABA-stimulated 36Cl- uptake by membrane vesicles from rat cerebral cortex were examined. Triazolam and alprazolam showed a significant enhancement of GABA-stimulated 36Cl- uptake at 0.01-10 microM. On the other hand, adinazolam showed a small enhancement at 0.1-1 microM followed by a significant inhibition of GABA-stimulated 36Cl- uptake at 100 microM. The enhancement of GABA-stimulated 36Cl- uptake by 1 microM alprazolam was antagonized by Ro15-1788, a benzodiazepine antagonist, but the inhibition of this response by 30 microM adinazolam was not antagonized by Ro15-1788. These results indicate that triazolobenzodiazepines enhanced GABA-stimulated 36Cl- uptake through benzodiazepine receptors. High concentrations of adinazolam inhibit GABA-stimulated 36Cl- uptake which may be due to the direct blockade of GABA-gated chloride channel.

Alprazolam↗
PubMed1987

Intracellular effectors and modulators of GABA-A and GABA-B receptors: a commentary.

The inhibitory neurotransmitter GABA activates two receptor subtypes that can be distinguished by their pharmacology. The GABA-A site is competitively antagonized by bicuculline and exclusively coupled to a chloride channel. The GABA-B receptor, for which baclofen is the only specific agonist, is resistant to bicuculline inhibition and, depending upon its localization, will activate K currents and/or inhibit Ca currents. Both electrophysiological and biochemical approaches have been applied to the study of each receptor. The membrane and intracellular components that to date have been implicated in GABA-B activation are discussed: G proteins, adenylate cyclase and intracellular calcium levels. This latter factor is also discussed with respect to GABA-A receptor action.

Calcium↗
PubMed1991

Modulation of GABA-mediated inhibition in rat cerebellar slices by benzodiazepine receptor ligands.

1. Extracellular recordings were made from the Purkinje cell layer of rat cerebellar slices. Compounds were perfused over the slice and bipolar stimulating electrodes placed in the external layer of the slice close to the recording electrode. 2. Stimulus-evoked inhibition of Purkinje layer cell activity was sensitive to bicuculline methiodide and picrotoxin, suggesting it was gamma-aminobutyric acid (GABA) mediated. The benzodiazepine ligands RU 32007 and Ro 19-0528 reversibly increased the period of inhibition, as did pentobarbital. This benzodiazepine effect was antagonised by Ro 15-1788. 3. Five inverse agonists all reduced the period of stimulated inhibition and this effect was reversed by Ro 15-1788, suggesting the involvement of benzodiazepine receptors. 4. It is concluded that this system provides a convenient physiological and possibly quantitative model for studying the action of benzodiazepine receptor ligands.

Animals↗
PubMed1999

Behavioral effects of diazepam in the murine plus-maze: flumazenil antagonism of enhanced head dipping but not the disinhibition of open-arm avoidance.

Although it is widely believed that benzodiazepines reduce anxiety through positive allosteric modulation of the GABA(A)-chloride channel complex, this is not the only mechanism through which agents of this class can modify CNS function. Furthermore, a significant number of reports of apparent flumazenil blockade of diazepam anxiolysis in animal models have paid limited attention to possible intrinsic behavioral actions of the antagonist per se. In the present study, ethological methods were employed to assess in detail the effects of diazepam, flumazenil, and their combination on the behavior of male DBA/2 mice in the elevated plus-maze paradigm. In two experiments, diazepam (1.5 mg/kg) alone reduced open-arm avoidance and increased head dipping, whereas flumazenil (10-40 mg/kg) alone was without significant behavioral effect. However, with the sole exception of head dipping, prior administration of flumazenil (10 and 40 mg/kg) failed to block the behavioral effects of diazepam under present test conditions. These findings imply that the anxiolytic effects of diazepam in the mouse plus-maze are not mediated through flumazenil-sensitive benzodiazepine receptors and that alternate mechanisms must be considered.

Animals↗
PubMed1999

The effects of neurosteroids on rat behavior and 3H-muscimol binding in the brain.

The effects of ICV administration of metabolites of progesterone and deoxycorticosterone [i.e., neurosteroids: AP (3alpha-hydroxy-5alpha-pregnan-20-one, allopregnanolone), 5alpha(-THDOC (3alphat-21-dihydroxy-5alpha-pregnan-20-one, 5alpha-tetrahydrodeoxycorticosterone), 5beta-THDOC (3alpha-21-dihydroxy-5beta-pregnan-20-one, 5beta-tetrahydrodeoxycorticosterone), and PS (3beta-hydroxy-5-pregnen-20-one sulfate, pregnenolone sulfate] were studied in the open-field test of neophobia and Vogel's test of conflict behavior in rats. The influence of in vivo administered 5beta-THDOC, a positive allosteric modulator of the GABA(A) receptor complex, on 3H-muscimol binding in different brain structures, was also studied with the help of quantitative autoradiography. The presented data did not reveal any anxioselective effects for a range of centrally active neurosteroids, in the ethologically orientated and conflict models of anxiety, after intracerebral drug administration. Their central effects appeared secondary to changes in rat gross behavior. It is possible that high local concentration of neurosteroids after ICV injection and production of a narrower range of behavioral effects than that of benzodiazepines, precluded manifestation of the antianxiety effects of AP, 5alpha-THDOC and 5beta-THDOC. Autoradiography did not reveal any significant changes in the specific binding of 3H-muscimol in brain structures after in vivo ICV administration of 5beta-THDOC at the behaviorally active dose. Thus, the possibility that neuroactive neurosteroids may provide a novel potential site for therapeutic interventions in anxiety disorders is not supported. The part of the experiment with 5beta-THDOC is interpreted as contributing to other results, suggesting the existence of a new category of neurosteroids acting as partial agonists of the GABA(A) receptor.

Animals↗