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At least 865 records · Page 48Linked to original sources
PubMed1997

Electrophysiological evidence for agonist properties of flumazenil, a benzodiazepine receptor antagonist, in rat hippocampus slices.

The purpose of this study was to determine the ability of the putative benzodiazepine antagonist flumazenil to modulate the excitatory synaptic responses recorded from rat hippocampus slices. The benzodiazepine agonist clonazepam was demonstrated to depress the CA1 population spike. This effect was attributed to an enhancement of GABA efficacy after its electrically-elicited release from local inhibitory circuitry. As an unexpected effect, flumazenil failed to antagonize this depressing effect. Moreover, flumazemil was observed to significantly depress, on its own, the magnitude of the evoked response to the activation of the excitatory afferents. This intrinsic depressant activity of flumazenil suggests that flumazenil acts 'in vitro' as an agonist at the benzodiazepine receptors, and is consistent with some previously reported atypical effects of flumazenil 'in vivo'.

Animals↗
PubMed1997

Activation of picrotoxin-resistant GABA receptors by GABA and related compounds induces modulation of cockroach dorsal paired median (DPM) neuron firing.

Activation of gamma-aminobutyric acid (GABA) receptors in insect dorsal paired median (DPM) neurons induced two types of response which appeared to be mediated by two different GABA receptor subtypes. When activated by bath application of GABA, one receptor subtype, insensitive to picrotoxin (PTX), mediated a drastic reduction in the firing frequency, leading to a blockade of the spontaneous electrical activity. These effects were accompanied by decreases in the amplitude and duration of the plateau action potential (AP) and the spike after-hyperpolarization (AHP). In most cases, a slight depolarization of the resting membrane potential occurred. Bath application of the vertebrate GABA(B) receptor agonists 3-aminopropyl(methyl)phosphinic acid (SKF 97541) and 3-aminopropylphosphinic acid (CGA 147823/CGP 27492) induced similar responses. Another GABA receptor subtype, less sensitive to GABA, mediated a chloride dependent hyperpolarization that was suppressed by bath application of PTX. The approximate locations of these two GABA receptor subtypes were determined by local pressure microapplications of GABA and vertebrate GABAergic agonists. The PTX-sensitive receptors were located predominantly on the surface of the ganglion where the apical pole of the soma is situated, while the PTX-resistant receptors appeared to be located deeper within the ganglion.These results reveal the existence of two GABA receptor subtypes on the DPM neurons and provide evidence for a functional role for PTX-resistant GABA receptors in the regulation of spontaneous firing.

Journal Article↗
PubMed2005

GABA(B) receptor-mediated modulation of cutaneous input at the cuneate nucleus in anesthetized cats.

This study examined the modulatory influence exerted by GABA(B) receptors on the transmission of cutaneous afferent input to cuneate nucleus neurons in anesthetized cats. Electrical stimulation at the center of a receptive field activated cuneate nucleus cells at latencies of < or = 7 ms whereas stimulation at neighboring sites (receptive field edge) increased the response latency. Extracellular recording combined with microiontophoresis demonstrated that GABA(B) receptors are tonically active. Blockade of GABA(B) receptors prolonged sensory-evoked response durations and decreased times of occurrence of successive bursts whereas the agonist baclofen suppressed both these effects. Ejection of baclofen delayed the evoked response from the receptive field edge with respect to the receptive field center response and inhibited responses from the receptive field edge more effectively than responses from the receptive field center. From these results it is concluded that activation of GABA(B) receptors precludes cuneate cells from reaching firing threshold when afferent inputs are weak, spatially modulate cuneate nucleus excitability, play a major role in temporal pattern of discharges, and shape cutaneous receptive fields.

Anesthesia↗
PubMed1993

Sensitization of gamma-aminobutyric acid-induced depressions of cerebellar Purkinje neurons to the potentiative effects of ethanol by beta adrenergic mechanisms in rat brain.

We previously reported that both systemic administration and brief local application of ethanol potentiated gamma-aminobutyric acid (GABA)-induced depressions of cerebellar Purkinje neurons when the GABA responses were concomitantly facilitated (modulated) by catecholaminergic agonists. In the present study, we further investigated the effects of prolonged local applications of ethanol, which more closely mimic the systemic application of ethanol, and we characterized the pharmacological specificity of the catecholaminergic interaction with these ethanol effects. As has been previously observed, iontophoretic applications of isoproterenol (ISO), a beta adrenergic agonist, facilitated GABA-induced depressions of cerebellar Purkinje neurons. The prolonged local application of ethanol produced a long-lasting potentiation of the ISO-modulated GABA responses that was similar in duration to that caused by systemic ethanol administration. The ethanol-induced augmentation of the ISO-modulated GABA responses was diminished both by terminating the beta adrenergic agonist application as well as by administering the beta adrenergic antagonist timolol. The alpha adrenergic agonist phenylephrine, on the other hand, either attenuated or had no effects on the GABA-induced depressions of cerebellar Purkinje neurons, and a subsequent application of ethanol did not potentiate GABA responses in the presence of phenylephrine. We conclude that prolonged local application of ethanol mimics the interaction of systemic ethanol with GABA-induced depressions of cerebellar Purkinje neurons. Furthermore, the catecholaminergic sensitization of GABA responses to these potentiative effects of ethanol is mediated by a beta adrenergic mechanism.

Animals↗
PubMed1995

GABAergic and developmental influences on homosynaptic LTD and depotentiation in rat hippocampus.

Low-frequency (1 Hz) stimulation (LFS) was used to elicit long-term depression (LTD) or depotentiation of excitatory transmission of the Schaffer collateral pathway in the CA1 region of the rat hippocampus. Both LTD and depotentiation were found to be homosynaptic and NMDA receptor (NMDAR) dependent. As NMDAR activation can be modulated by the inhibitory GABAergic system, we tested the hypothesis that GABA plays a role in regulating these phenomena. The GABAB antagonist CGP 35348 significantly inhibited LTD, but not depotentiation, in slices from young animals (indicating that the GABAB-mediated contribution was altered following HFS). The ability to express LTD was found to be developmentally dependent, as young animals (16-22 d) consistently expressed LTD, whereas LTD was not expressed in naive slices taken from mature (5-10 weeks) animals. The GABAA antagonist bicuculline did not affect LTD in the young animals, but did enhance LTD expression in slices from mature animals. LFS was also effective in decreasing, or depotentiating, responses that had undergone long-term potentiation (LTP) by high-frequency stimulation (HFS). In contrast to LTD, depotentiation was consistently expressed in slices from both the young and mature groups. Moreover, following an HFS train, LTD (compared to initial baseline response) could be induced in mature slices previously unable to express LTD in the naive state. Thus, the role of GABA in modulating the effects of LFS varied with the prior synaptic activity in the slice as well as with the maturity of the animal. Our results suggest that the influence of both age and prior synaptic activity (i.e., HFS) on LTD induction can be explained by changes in GABAergic systems in young versus mature, and naive versus tetanized slices.

Aging↗
PubMed2003

Convergent control of synaptic GABA release from rat dorsal horn neurones by adenosine and GABA autoreceptors.

Perforated patch clamp recordings were performed on cultured superficial neonatal rat dorsal horn (DH) spinal cord neurones in order to study the presynaptic modulation of GABA release at unitary synaptic connections. Since ATP can be coreleased with GABA at about two-thirds of GABAergic synapses between DH neurones, and can be rapidly metabolized to adenosine in the extracellular space, we investigated the potential role of A1 adenosine receptors and GABAB receptors which might function as inhibitory autoreceptors. Adenosine and GABAB receptor agonists reduced the amplitude of electrically evoked GABAergic inhibitory postsynaptic currents (eIPSCs) as well as the frequency of GABAergic miniature IPSCs, suggesting a presynaptic action of these substances. The actions of adenosine were blocked by the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). The effects of adenosine and GABAB agonists were occlusive, indicating a functional convergence of the signalling pathways engaged by A1 and GABAB receptors. A1 and GABAB antagonists increased the amplitude of eIPSCs in a supra-additive manner, suggesting a tonic activation of these receptors by ambient adenosine and GABA. Moreover, using trains of electrical stimulations, we were able to unravel a phasic (activity-dependent) activation of presynaptic A1 and GABAB autoreceptors only in the case of neurones coreleasing ATP and GABA, despite the presence of functional presynaptic A1 and GABAB receptors on all GABAergic DH neurones. This selective, convergent and activity-dependent inhibition of GABA release by A1 and GABAB autoreceptors might modulate the integrative properties of postsynaptic DH neurones under physiological conditions and/or during the development of pathological pain states.

Adenosine↗
PubMed1999

Chronic ethanol exposure increases 3H-GABA release in rat hippocampus by presynaptic muscarinic receptor modulation.

BACKGROUND: Chronic ethanol treatment (CET) for 28 weeks significantly increases electrically-stimulated 3H-GABA release from hippocampal slices. This increase in GABA release may be one of the mechanisms by which CET decreases the magnitude of long-term potentiation (LTP) in the hippocampus. The present study examined whether CET increases GABA release via an alteration in heterologous presynaptic cholinergic regulation. METHODS: Animals were treated with ethanol or sucrose diet for 28 weeks followed by either no withdrawal or a 48-hr withdrawal period. The electrically-stimulated 3H-GABA release from preloaded superfused hippocampal slices of naive and CET rats was measured. RESULTS: Carbachol increased 3H-GABA release in a concentration-dependent manner, and atropine modulated 3H-GABA release in a biphasic concentration-dependent manner. Atropine (10 microM) significantly blocked the effects of carbachol. Oxotremorine, a selective muscarinic receptor agonist, also increased 3H-GABA release. Mecamylamine, a selective nicotinic antagonist, did not modulate 3H-GABA release and did not block the effects of carbachol. The effects of these agents were also tested in rats 0 or 48 hrs after withdrawal from CET. The biphasic effects of atropine were decreased, whereas the facilitating effects of carbachol were significantly increased. There were no changes in the effects of these agents on 3H-acetylcholine release from hippocampal slices of CET rats compared to sucrose-treated rats. CONCLUSION: These results suggest that presynaptic muscarinic receptors facilitate GABA release, whereas nicotinic receptors do not play a significant role in modulating GABA release in hippocampus. CET selectively alters presynaptic muscarinic regulation of GABA release in hippocampus and may help us to further understand the mechanism underlying the disruption of LTP by CET.

Animals↗
PubMed1998

The molecular mechanism of action of general anesthetics: structural aspects of interactions with GABA(A) receptors.

(1) Considerable evidence has accumulated that the molecular target of general anesthetics in the central nervous system is the GABA(A) receptor, the major mediator of inhibitory synaptic transmission. This receptor is actually a family of ligand-gated chloride channel proteins, each a heteropentameric membrane-spanning structure. (2) Regional variation in anesthetic actions on the central nervous system may parallel a corresponding regional variation in pharmacological subtypes of GABA(A) receptors. These result from differential regional expression of approximately 18 subunit genes. (3) Receptors of varying subunit composition show differential sensitivity to GABA, modulatory drugs, and biological regulatory mechanisms. Regional variation in allosteric modulation of GABA(A) receptor binding and function can be reconstituted in certain recombinant receptor subunit combinations expressed in heterologous cells. (5) Differential sensitivity to anesthetics for various GABA(A) receptor subunits also allows the use of the chimeric and site-directed mutagenesis approach in attempting to define domains of the protein which participate in the binding and actions of anesthetics.

Anesthetics, General↗
PubMed2006

A centrally acting, anxiolytic angiotensin II AT1 receptor antagonist prevents the isolation stress-induced decrease in cortical CRF1 receptor and benzodiazepine binding.

Long-term pretreatment with an angiotensin II AT1 antagonist blocks angiotensin II effects in brain and peripheral organs and abolishes the sympathoadrenal and hypothalamic-pituitary-adrenal responses to isolation stress. We determined whether AT1 receptors were also important for the stress response of higher regulatory centers. We studied angiotensin II and corticotropin-releasing factor (CRF) receptors and benzodiazepine binding sites in brains of Wistar Hannover rats. Animals were pretreated for 13 days with vehicle or a central and peripheral AT1 antagonist (candesartan, 0.5 mg/kg/day) via osmotic minipumps followed by 24 h of isolation in metabolic cages, or kept grouped throughout the study (grouped controls). In another study, we determined the influence of a similar treatment with candesartan on performance in an elevated plus-maze. AT1 receptor blockade prevented the isolation-induced increase in brain AT1 receptors and decrease in AT2 binding in the locus coeruleus. AT1 receptor antagonism also prevented the increase in tyrosine hydroxylase mRNA in the locus coeruleus. Pretreatment with the AT1 receptor antagonist completely prevented the decrease in cortical CRF1 receptor and benzodiazepine binding produced by isolation stress. In addition, pretreatment with candesartan increased the time spent in and the number of entries to open arms of the elevated plus-maze, measure of decreased anxiety. Our results implicate a modulation of upstream neurotransmission processes regulating cortical CRF1 receptors and the GABA(A) complex as molecular mechanisms responsible for the anti-anxiety effect of centrally acting AT1 receptor antagonists. We propose that AT1 receptor antagonists can be considered as compounds with possible therapeutic anti-stress and anti-anxiety properties.

Amphibian Proteins↗
PubMed1984

GABA induces functionally active low-affinity GABA receptors on cultured cerebellar granule cells.

The effect of gamma-aminobutyric acid (GABA) and its agonists muscimol and 4,5,6,7-tetrahydroisoxazolo[5-4-c]pyridin-3-ol (THIP) on the development of GABA receptors on cerebellar granule cells was studied by cultivation of the cells in media containing these substances. It was found that the presence of 50 microM GABA in the culture media led to the induction of low-affinity GABA receptors (KD 546 +/- 117 nM) in addition to the high-affinity receptors (KD 7 +/- 0.5 nM) which were present regardless of the presence of GABA in the culture media. The functional activity of the GABA receptors was tested by investigating the ability of GABA to modulate evoked glutamate release from the cells. It was found that GABA could inhibit evoked glutamate release (ED50 10 +/- 3 microM) only when the cells had been cultured in the presence of 50 microM GABA, 50 microM muscimol, or 150 microM THIP, i.e., under conditions where low-affinity GABA receptors were present on the cells. This inhibitory effect of GABA could be blocked by 120 microM bicuculline and mimicked by 50 microM muscimol or 150 microM THIP whereas 150 microM (-)-baclofen had no effect. It is concluded that GABA acting extracellularly induces formation of low-affinity receptors on cerebellar granule cells and that these receptors are necessary for mediating an inhibitory effect of GABA on evoked glutamate release. The pharmacological properties of these GABA receptors indicate that they belong to the so-called GABAA receptors.

Animals↗
PubMed1994

A single amino acid of the human gamma-aminobutyric acid type A receptor gamma 2 subunit determines benzodiazepine efficacy.

Incorporation of the gamma 2 subunit into gamma-aminobutyric acid type A (GABAA) receptors is required for the expression of benzodiazepine pharmacology, but the regions of the subunit responsible for benzodiazepine actions have not been defined. Using mutagenesis, we identified a single amino acid of the gamma 2 subunit of the human GABAA receptor that profoundly alters the nature of this pharmacology. When threonine 142 was mutated to serine, the benzodiazepine receptor antagonist, flumazenil, and the weak inverse agonist, Ro 15-4513, both acted as potent partial agonists. Further, potentiation of GABA responses by diazepam, alprazolam, clonazepam, or flunitrazepam doubled in receptors containing the Ser-142 gamma 2 subunit. In contrast, responses to the Type I benzodiazepine receptor selective ligands, zolpidem, alpidem, and CL218,872, were roughly halved. This change in pharmacology appears to occur at a stage following ligand binding, i.e. the mutation affects benzodiazepine efficacy. There was no effect on GABA affinity or efficacy or pentobarbital, Ro 5-4864, or alphaxalone modulation of GABA responses. These findings demonstrate that very minor changes in receptor structure can profoundly affect the efficacy of receptor ligands. Thus, agonism is determined not only by the structure of the drug, but also by the structure of the receptor, or protein complex, with which it interacts.

Animals↗
PubMed2002

GABA(A) and GABA(B) receptors in the anterior piriform cortex modulate feeding in rats.

The effects of GABA(A) and GABA(B) receptors in the anterior piriform cortex (APC) on intake of an amino acid imbalanced diet and a basal diet were evaluated in rats. Administration of muscimol (GABA(A) receptor agonist) to the APC immediately suppressed ingestion of both amino acid imbalanced and basal diets. Central administration of bicuculline (a GABA(A) receptor antagonist) stimulated feeding of the amino acid imbalanced diet but had no effect on intake of the basal diet. The GABA(B) receptor antagonist phaclofen decreased consumption of the basal diet but did not affect consumption of the amino acid imbalanced diet. These findings demonstrate that manipulation of GABA-sensitive cells in the APC can have a pronounced effect on feeding behavior that is not selective to aminoprivic feeding. However, these data suggest that GABA(A) and GABA(B) receptors may function as regulators that are activated by monoaminergic systems and neuropeptides in response to amino acid imbalanced diet intake. Inhibitory effects of GABA(A) and GABA(B) receptors may modulate the pyramidal cells, contributing to the reduced feeding response to the amino acid imbalanced diet. Also, transcription of mRNA for both GABA receptors and the GABA reuptake transporter was affected by a threonine deficient but not a corrected diet, compared to the basal diet. Taken together, these results support the involvement of GABA receptors in the APC in feeding in general and the responses to amino acid deprivation in vivo.

Amino Acids↗
PubMed1996

A behavioural and neurochemical study in rats of the pharmacology of loreclezole, a novel allosteric modulator of the GABAA receptor.

Loreclezole is an anticonvulsant and anxiolytic compound which has been reported to potentiate GABA via a novel allosteric site on the beta-subunit of the receptor. We have now studied in rats both the in vivo and in vitro pharmacology of the compound. The dose of loreclezole required to increase by 50% the dose of intravenous pentylenetetrazol eliciting a seizure was comparable to that of barbiturates and chlormethiazole (in mg/kg): diazepam, 1.3; pentobarbitone, 16; chlormethiazole, 22; loreclezole, 25; pentobarbitone, 36. Loreclezole dose-dependently decreased locomotion (dose to decrease locomotion by 50% (in mg/kg): chlormethiazole, 9; pentobarbitone, 16; loreclezole, 25). Loreclezole, chlormethiazole and pentobarbitone all failed to displace [3H]muscimol and [3H]flunitrazepam binding from a rat cortical membrane preparation. All three compounds fully displaced [35S]TBPS binding (IC50 values: loreclezole, 4.34 +/- 0.68 microM; pentobarbitone, 37.39 +/- 3.24 microM; chlormethiazole, 82.10 +/- 8.52 microM). Addition of bicuculline (10 microM) produced a major rightward shift in the loreclezole and pentobarbitone displacement curves, increasing IC50 values for [35S]TBPS binding by 25 times (loreclezole), 6 times (pentobarbitone) and 2.7 times (chlormethiazole), suggesting a greater involvement of GABA in the interaction of loreclezole with the chloride channel than in the case of chlormethiazole. Anticonvulsant activity of the compounds did not appear to relate to [35S]TBPS binding activity. Other binding data suggested that although the evidence of others indicates that loreclezole interacts with a specific allosteric site on the beta-subunit, it nevertheless also alters the binding characteristics of other modulatory sites.

Allosteric Regulation↗
PubMed2006

A single point mutation of the GABA(A) receptor alpha5-subunit confers fluoxetine sensitivity.

Fluoxetine has been reported to be a novel allosteric modulator of GABA(A) receptors with the notable exception of receptors that contain the alpha5-subunit isoform [Robinson, R.T., Drafts, B.C., Fisher, J.L., 2003. Fluoxetine increases GABA(A) receptor activity through a novel modulatory site. J. Pharmacol. Exp. Ther. 304, 978-984]. A mutagenic strategy has been used to investigate the structural basis for the insensitivity of this subunit. An alpha1/alpha5-subunit chimeragenesis approach first demonstrated the importance of the alpha1-subunit N-terminal sequence E165-D183 (corresponding to alpha5 E169-D187) in fluoxetine modulation. Specific amino acid substitutions in this domain subsequently revealed that a single mutation in the alpha5-subunit to the equivalent residue in alpha1 (T179A) was sufficient to confer fluoxetine sensitivity to the alpha5-containing receptor. However, the reciprocal mutation in the alpha1-subunit (A175T) did not result in a loss in sensitivity, suggesting the involvement of additional determinants for fluoxetine modulation. A comparative modeling approach was used to probe amino acids that may lie in close proximity to alpha1A175. This led serendipitously to the identification of a specific residue, alpha1F45, which, when mutated to an alanine, resulted in a significant decrease in potency for activation of the receptor by GABA and also reduced the efficacies of the partial agonists, THIP and P4S.

Amino Acid Substitution↗
PubMed2006

Neurosteroid modulation of recombinant rat alpha5beta2gamma2L and alpha1beta2gamma2L GABA(A) receptors in Xenopus oocyte.

GABA(A) receptors containing alpha(5)-subunit have an important role in cognitive function. As the agonistic effect of 3alpha-hydroxy ring-A reduced steroids depends on subunit combinations of the GABA(A) receptor, the antagonistic effect of pregnenolone sulfate and 3beta-hydroxypregnane steroids may vary between alpha(5)-subunit and alpha(1)-subunit containing receptors. We investigated the effect of agonist and antagonist steroids in the recombinant rat alpha(1)beta(2)gamma(2L) and alpha(5)beta(2)gamma(2L) receptors expressed in Xenopus oocytes using a two electrodes voltage-clamp technique. We did not find any significant difference in potency and efficacy of GABA response between alpha(1)beta(2)gamma(2L) and alpha(5)beta(2)gamma(2L) receptors. Compared to the alpha(1)beta(2)gamma(2L) receptor, a significantly lower degree of desensitization was observed in the alpha(5)beta(2)gamma(2L) receptor. In addition, the potencies of 3alpha-OH-5alpha-pregnan-20-one (3alpha5alphaP), 5alpha-pregnan-3alpha,21-diol-20-one (3alpha5alphaTHDOC) and 5alpha-androstane-3alpha,17beta-diol (3alpha5alphaADL) to enhance GABA response were significantly higher in the alpha(5)beta(2)gamma(2L) receptor, whereas their efficacies remained unchanged between two receptors. In either receptor, the efficacy of 3alpha5alphaTHDOC was significantly higher than 3alpha5alphaP and 3alpha5alphaADL. The efficacies of 5beta-pregnan-3beta,21-diol-20-one(UC1015) and 5alpha-pregnan-3beta,20alpha-diol(UC1019) to inhibit 30 microM GABA response, and the efficacies of 3beta-OH-5beta-pregnan-20-one (UC1014) and 5beta-pregnan-3beta, 20beta-diol (UC1020) to inhibit 3 microM 3alpha5alphaTHDOC+3 microM GABA response were higher in the alpha(5)beta(2)gamma(2L) receptor compared to the alpha(1)beta(2)gamma(2L) receptor. The potencies of pregnenolone sulfate and 3beta-hydroxypregnane steroids to inhibit the GABA response and the 3alpha5alphaTHDOC+GABA response did not vary between two receptors. Interestingly, the potencies and efficacies of pregnenolone sulfate and 3beta-hydroxypregnane steroids to inhibit the GABA response were positively correlated to their potencies and efficacies to inhibit the 3alpha5alphaTHDOC+GABA response. Results from the current study revealed a different modulation pattern by neurosteroids between the alpha(1)beta(2)gamma(2L) and alpha(5)beta(2)gamma(2L) receptor.

Androstane-3,17-diol↗
PubMed2004

GABAA receptor modulation of trigeminovascular nociceptive neurotransmission by midazolam is antagonized by flumazenil.

Studies of the pharmacology of trigeminocervical neurons with input from intracranial pain-producing structures have enhanced the understanding of the basic neurobiology of primary headache, such as migraine. Clinical observations of the treatment of migraine with medicines acting at the gamma-aminobutyric acid (GABA) GABAA receptor have lead to studies of their effects on models of trigeminovascular nociception. Extracellular recordings were made from neurons in the trigeminocervical complex activated by supramaximal electrical stimulation of superior sagittal sinus (SSS) in the cat. Intravenous administration of the benzodiazepine receptor agonist midazolam, resulted in a dose-dependent inhibition of superior sagittal sinus evoked trigeminocervical nucleus activity. The inhibition at 50 microg/kg midazolam was 65+/-11% compared to the baseline response (n=11). Intravenous administration of the benzodiazepine receptor antagonist flumazenil, resulted in a dose-dependent recovery of superior sagittal sinus evoked trigeminocervical nucleus activity. At a dose of 50 microg/kg, there was a 64+/-5% recovery (n=6). The data demonstrate a potent, reproducible effect of facilitation of GABA transmission at the GABAA receptor that results in inhibition of trigeminovascular nociceptive transmission. These data are consistent with the useful clinical effects reported with compounds that can augment GABAergic transmission in the central nervous system (CNS).

Animals↗
PubMed2002

1-Methyl-4-phenylpridinium (MPP+)-induced functional run-down of GABA(A) receptor-mediated currents in acutely dissociated dopaminergic neurons.

We have evaluated GABA(A)receptor function during treatment of 1-methyl-4-phenylpridinium (MPP+) using patch-clamp perforated whole-cell recording techniques in acutely dissociated dopaminergic (DAergic) neurons from rat substantia nigra compacta (SNc). Gamma-aminobutyric acid (GABA), glutamate or glycine induced inward currents (I(GABA), I(Glu), I(Gly)) at a holding potential (VH) of -45 mV. The I(GABA) was reversibly blocked by the GABA(A) receptor antagonist, bicuculline, suggesting that I(GABA) is mediated through the activation of GABA(A) receptors. During extracellular perfusion of MPP+ (1-10 microm), I(GABA) , but neither I(Glu) nor I(Gly), declined (termed run-down) with repetitive agonist applications, indicating that the MPP+-induced I(GABA) run-down occurred earlier than I(Gly) or I(Glu) under our experimental conditions. The MPP+-induced I(GABA) run-down can be prevented by a DA transporter inhibitor, mazindol, and can be mimicked by a metabolic inhibitor, rotenone. Using conventional whole-cell recording with different concentrations of ATP in the pipette solution, I(GABA) run-down can be induced by decreasing intracellular ATP concentrations, or prevented by supplying intracellular ATP, indicating that I(GABA) run-down is dependent on intracellular ATP concentrations. A GABA(A) receptor positive modulator, pentobarbital (PB), potentiated the declined I(GABA) and eliminated I(GABA) run-down. Corresponding to these patch-clamp data, tyrosine hydroxylase (TH) immunohistochemical staining showed that TH-positive cell loss was protected by PB during MPP+ perfusion. It is concluded that extracellular perfusion of MPP+ induces a functional run-down of GABA(A) receptors, which may cause an imbalance of excitation and inhibition of DAergic neurons.

1-Methyl-4-phenylpyridinium↗
PubMed1997

Muscimol and midazolam do not potentiate each other's effects on sleep EEG in the rat.

The interaction of a gamma-aminobutyric acid-A (GABAA) receptor agonist and a benzodiazepine-type modulator of GABAA receptors on sleep was investigated. Low doses of muscimol (0.3 mg/kg) and the benzodiazepine midazolam (1.5 mg/kg) were administered alone and in combination, in random order, to eight rats. All injections were given intraperitoneally at light onset. Electroencephalogram (EEG) and electromyogram were recorded during the first 6 h post injection. Compared with vehicle, muscimol hardly affected the time spent in non-rapid eye movement sleep (non-REMS) and REMS, but significantly enhanced EEG activity in the frequency range between 2 and 6 Hz during non-REMS. Midazolam significantly increased the time spent in non-REMS, reduced EEG activity at frequencies < 12 Hz, and elevated EEG activity in most higher frequencies during this state. The combined administration of muscimol and midazolam affected non-REMS-specific EEG activity in an unexpected fashion: the effects were intermediate between those of muscimol and midazolam. These results indicate that muscimol and midazolam have dissimilar effects on EEG within non-REMS and demonstrate that midazolam does not augment but attenuates the muscimol-induced changes in sleep EEG. Our data are at variance with established mechanisms, according to which agonistic modulators would have similar effects and should potentiate the effects of GABAA agonists. The present data suggest that application of agonists and agonistic modulators of GABAA receptors causes differential net effects on sleep parameters.

Animals↗