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PubMed2003

Low doses of ethanol and a neuroactive steroid positively interact to modulate rat GABA(A) receptor function.

Fast inhibitory responses in the central nervous system are mediated by the GABA(A) receptor. The activation and function of the GABA(A) receptor can be modulated by a variety of compounds including benzodiazepines, barbiturates and neuroactive steroids. Modulation of the GABA(A) receptor function by ethanol has been observed in some but not all studies. We have studied the effect of ethanol at concentrations corresponding to light intoxication on the function of the recombinant GABA(A) receptor containing alpha1beta2gamma2 subunits. The experiments were performed both in the absence and presence of low, subthreshold concentrations of a neuroactive steroid. The results demonstrate that, in the presence of the steroid, 0.05 % (9 mM) ethanol potentiates the GABA(A) receptor function by increasing the channel mean open duration. No effect was observed on the channel closed time durations. The data suggest that ethanol influences channel closing with no effect on the affinity of the receptor for GABA or the channel opening rate constant.

Androstanols↗
PubMedDate not supplied

Modulation by GABA(B) and delta opioid receptors of neurally induced responses in isolated guinea-pig taenia coli and human colonic circular muscle.

The GABA-ergic and opioid modulation of neurally induced muscle responses was studied in isolated guinea-pig taenia coli and human colonic circular muscle, using identical field stimulation parameters (rectangular pulses of 0.5 ms duration, 9 V x cm(-1) intensity, trains of 3 pulses at 0.5 Hz, repeated every 1/3/5 min). The stimulation-induced contractions were inhibited in both preparations by GABA and baclofen; the IC50 values in human colonic circular muscle were approximately 100 and 31.0 microM, respectively. In guinea-pig taenia coli, the inhibition by 10(-4) M GABA was dose-dependently reversed by 10(-4)-10(-3) M of GABA(B) receptor antagonist CGP 35348; antagonism by phaclofen was less effective in the same concentration range. In human colonic circular muscle, inhibition by 3 x 10(-5) M baclofen was fully reversed by 10(-3) M CGP 35348. With the exception of caecum, the delta 2 opioid receptor agonist deltorphin II was a potent inhibitor in human colonic circular muscle. 10(-8) M Deltorphin caused a 74.4 +/- 9.6% (n = 4) inhibition which was reversed by 10(-6) M of delta receptor selective peptide antagonist BOC-Tyr-Pro-Gly-Phe-Leu-Thr(OtBu). Deltorphin II was ineffective in guinea-pig taenia coli even at 10(-6) M; the same concentration caused an 84.3 +/- 7.9 (n = 4) inhibition in human preparations. It is concluded that: 1) GABA-ergic modulatory mechanisms are present both in human colonic circular muscle and guinea-pig taenia coli; 2) the GABA receptors involved are of type B; and 3) delta opioid receptor-mediated modulation functions only in human colonic circular muscle in regions other than the caecum.

Adult↗
PubMed2003

Semisynthetic preparation of amentoflavone: A negative modulator at GABA(A) receptors.

Amentoflavone is found in a number of plants with medicinal properties, including Ginkgo biloba and Hypericum perforatum (St. John's Wort). We have developed a rapid and economic semi-synthetic preparation of amentoflavone from biflavones isolated from autumnal Ginkgo biloba leaves. Several studies have shown that amentoflavone binds to benzodiazepine receptors. Using two electrode voltage-clamp methodology, amentoflavone has been shown to be a negative modulator of GABA at GABA(A) alpha(1)beta(2)gamma(2L) receptors expressed in Xenopus laevis oocytes This action appears to be independent of the flumazenil-sensitive benzodiazepine modulatory sites on the GABA(A) receptor.

Animals↗
PubMed1998

GABA(B) modulation improves sequence disambiguation in computational models of hippocampal region CA3.

Computational models of hippocampal region CA3 were used to study the role of theta rhythm in storage and retrieval of temporal sequences of neuronal activity patterns. Retrieval of multiple overlapping temporal sequences requires a mechanism for disambiguation, e.g., for choosing between two sequences with the same starting pattern but different final patterns (forked sequences). Modulatory input to the hippocampus from the medial septum may enhance the disambiguation of pattern sequences by causing phasic changes in the relative strength of afferent input and recurrent excitation. In the models, the strength of recurrent synaptic transmission is modulated by activation of GABA(B) receptors. Theta frequency inputs from the medial septum cause oscillations in the levels of GABA in the model, producing phasic changes in the strength of synaptic potentials during a theta cycle similar to those observed experimentally (Wyble et al., Soc Neurosci Abstr 1997;23: 197.7). These phasic changes in GABA(B) suppression improve sequence disambiguation in the simulations, as previously shown with analysis of a simpler model (Sohal and Hasselmo, Neural Comp 1998;10:889-902). In addition, tonic changes in levels of cholinergic modulation enhance the storage of forked sequences by preventing a strong influence of recurrent synapses during storage.

Animals↗
PubMed1999

Biphasic modulation of GABA(A) receptor binding by steroids suggests functional correlates.

Neuroactive steroids and other positive modulators of GABA(A) receptors showed regional variation in both the efficacy and potency for modulation of [35S]TBPS binding to rat brain membrane homogenates, with biphasic concentration-dependence. GABA present in the binding assays prevented the enhancement phase of the steroid concentration-dependence plot while the antagonists bicuculline and RU5135 prevented the inhibition phase. Using recombinant GABA(A) receptors, expressed in insect cell line Sf9 using baculovirus, enhancement by steroids of [35S]TBPS binding was sensitive to the presence of the gamma2 subunit and the nature of the alpha subunit (alpha1 beta2 gamma2S > alpha1 beta2, alpha6 beta2, alpha6 beta2 gamma2S, and alpha6 beta2 delta). As in cerebellum, addition of RU5135 reduced the inhibitory phase and revealed a small enhancement of TBPS binding by neuroactive steroids. The subunit-dependent interactions of steroid and GABA site ligands are consistent with a three-state model in which the receptor mono-liganded by GABA or steroid has a different affinity for TBPS than the resting state, and the receptor biliganded by GABA, steroid, or both has little affinity for TBPS.

Androstanes↗
PubMed1996

Effects of diazepam, baclofen and thiopental on the silent period evoked by transcranial magnetic stimulation in humans.

The cortical silent period evoked by magnetic transcranial stimulation and the peripheral silent period were studied in healthy subjects after intravenous injection of diazepam, baclofen or thiopental. None of the drugs tested changed the peripheral silent period. But, unexpectedly, diazepam significantly shortened the cortical silent period, the inhibitory effect lasting about 30 min. In experiments using paired transcranial stimuli, the conditioning shock inhibited the test response to a similar extent with and without diazepam. Although baclofen did not change the cortical silent period, it reduced the size of the H reflex in the forearm muscles. Thiopental also left the duration of the cortical silent period unchanged. These findings show that the cortical silent period can be modified pharmacologically. Diazepam possibly shortens the silent period by modulating GABA A receptors at a subcortical site.

Adult↗
PubMed2001

GABA receptors modulate trigeminovascular nociceptive neurotransmission in the trigeminocervical complex.

1. GABA (gamma-aminobutyric acid) receptors involved in craniovascular nociceptive pathways were characterised by in vivo microiontophoresis of GABA receptor agonists and antagonists onto neurones in the trigeminocervical complex of the cat. 2. Extracellular recordings were made from neurones in the trigeminocervical complex activated by supramaximal electrical stimulation of superior sagittal sinus, which were subsequently stimulated with L-glutamate. 3. Cell firing evoked by microiontophoretic application of L-glutamate (n=30) was reversibly inhibited by GABA in every cell tested (n=19), the GABA(A) agonist muscimol (n=10) in all cells tested, or both where tested, but not by iontophoresis of either sodium or chloride ions at comparable ejection currents. Inhibited cells received wide dynamic range (WDR) or nociceptive specific input from cutaneous receptive fields on the face or forepaws. 4. The inhibition of trigeminal neurones by GABA or muscimol could be antagonized by the GABA(A) antagonist N-methylbicuculline, 1(S),9(R) in all but two cells tested (n=16), but not by the GABA(B) antagonist 2-hydroxysaclofen (n=11). 5. R(-)-baclofen, a GABA(B) agonist, inhibited the firing of three out of seven cells activated by L-glutamate. Where tested, this inhibition could be antagonized by 2-hydroxysaclofen. These baclofen-inhibited cells were characterized as having low threshold mechanoreceptor/WDR input. 6. GABA thus appears to modulate nociceptive input to the trigeminocervical complex mainly through GABA(A) receptors. GABA(A) receptors may therefore provide a target for the development of new therapeutic agents for primary headache disorders.

Animals↗
PubMed1997

Effects of PKC activation and receptor desensitization on neurosteroid modulation of GABA(A) receptors.

The effect of calcium-phospholipid-dependent protein kinase (PKC) activation on neurosteroid modulation of the GABA(A) receptor was examined in Xenopus oocytes expressing human recombinant alpha1beta2gamma2L GABA(A) receptors. GABA-gated chloride currents were measured using the two-electrode voltage-clamp technique. The peak amplitude of GABA-gated chloride currents was reduced by the PKC activator phorbol 12-myristate 13-acetate (PMA), but not by the inactive analog phorbol 12-mono-myristate (PMM). This effect of PMA was inhibited by the protein kinase inhibitor staurosporine. To investigate whether the activation of PKC could alter neurosteroid modulation of the GABA(A) receptor, the effect of PMA was studied on the positive allosteric modulatory steroid 3alpha,21-dihydroxy-5alpha-pregnan-20-one (THDOC) and the negative modulatory neurosteroid pregnenolone sulfate (PS). THDOC potentiation of GABA-gated chloride currents was found to be increased by approximately 120% following PMA treatment, while PS inhibition was not affected. The increase in THDOC potentiation by PMA was blocked by staurosporine. No change in THDOC potentiation was observed following PMM treatment. The enhancement of THDOC potentiation following PMA treatment was not due to a shift in the GABA EC50. In addition to inhibiting the peak amplitude of the GABA response, PMA treatment resulted in non-desensitizing GABA responses. Similarly, GABA responses of receptors which had been desensitized with prolonged GABA application also showed a reduction in peak amplitude and reduced desensitization. THDOC potentiation of desensitized receptors was enhanced approximately 70% with respect to non-desensitized receptors. The present results demonstrate that protein phosphorylation and receptor desensitization alter modulation of the GABA(A) receptor complex by some neurosteroids.

Animals↗
PubMed1990

GABA receptor modulation of tyrosine hydroxylase gene expression in the rat adrenal gland.

Chromaffin cell gamma-aminobutyric acid (GABA) receptors play a role in modulating catecholamine secretion. The present experiments examined the role of GABA receptors in modulation of tyrosine hydroxylase (TH) induction in rat adrenal gland. Administration of bicuculline, a GABA antagonist, had no effect on TH activity or TH mRNA. However, bicuculline potentiated reserpine's effect on TH activity and TH mRNA induction. These data suggest that GABA receptors modulate induction of TH and TH mRNA in the adrenal gland.

Adrenal Glands↗
PubMed1992

GABA-active steroids: endogenous modulators of GABA-gated chloride ion conductance.

Naturally occurring 3-alpha-hydroxy ring A-reduced metabolites of progesterone and deoxycorticosterone and their synthetic analogues bind to specific sites within the hydrophobic channel domain of the GABAA receptor complex. Acting at these sites, these ligands function as positive allosteric effectors of the complex; they potentiate GABA-stimulated membrane chloride ion conductance, enhance the binding of [3H]muscimol and [3H]flunitrazepam, and displace the binding of [35S]t-butylbicyclophosphorothionate ([35S]TBPS), a channel ligand that is a specific marker of the GABA-associated chloride ionophore. Moreover, steroid metabolites (namely pregnenolone sulfate and dehydroepiandrosterone sulfate) have been identified that display properties of GABA-negative allosteric effectors. The identification of this membrane-associated steroid binding should stimulate development of new classes of anxiolytic, sedative-hypnotic, anticonvulsant, anesthetic, and muscle-relaxant medications that may be devoid of many of the side effects associated with benzodiazepines and barbiturates. Also, elucidation of the physiologic role of this binding site should contribute both to our understanding of endogenous mechanisms for modulating inhibitory neurotransmission, and the pathophysiologic role of the GABAA receptor complex in a variety of neuropsychiatric disorders.

Animals↗
PubMed2002

Acute hypoxic hypoxia alters GABA(A) receptor modulation by allopregnanolone and pentobarbital in embryonic chick optic lobe.

Using a previously developed model of acute normobaric hypoxic hypoxia on chick embryos, here we studied at embryonic day 12 the in vitro effect of two positive allosteric modulators of GABA binding, the barbiturate sodium pentobarbital and the neurosteroid allopregnanolone. In both cases an increase in E(max) values in membranes obtained from hypoxic embryos was observed. Studies of GABA-gated chloride influx showed that there were no differences in maximal chloride uptake between hypoxic and control membranes. We have already demonstrated that maximal density of GABA binding sites was decreased after hypoxia, suggesting that each of the remaining GABA(A) receptors display a greater chloride flux than controls. To further characterize GABA(A) receptor alterations, GABA-gated chloride influx modulated by the above barbiturate and neurosteroid was determined, finding that E(max) values were increased 60% and 42%, respectively. The increase in Cl(-) influx per receptor subsequent to hypoxic trauma, and the enhancement in the modulatory properties studied, may mediate neuronal damage by potential changes in subunit interaction at the GABA(A) receptor level.

Anesthetics↗
PubMed2003

Glutamate modulation of GABA transport in retinal horizontal cells of the skate.

Transport of the amino acid GABA into neurons and glia plays a key role in regulating the effects of GABA in the vertebrate retina. We have examined the modulation of GABA-elicited transport currents of retinal horizontal cells by glutamate, the likely neurotransmitter of vertebrate photoreceptors. Enzymatically isolated external horizontal cells of skate were examined using whole-cell voltage-clamp techniques. GABA (1 mM ) elicited an inward current that was completely suppressed by the GABA transport inhibitors tiagabine (10 microM) and SKF89976-A (100 microM), but was unaffected by 100 microM picrotoxin. Prior application of 100 microM glutamate significantly reduced the GABA-elicited current. Glutamate depressed the GABA dose-response curve without shifting the curve laterally or altering the voltage dependence of the current. The ionotropic glutamate receptor agonists kainate and AMPA also reduced the GABA-elicited current, and the effects of glutamate and kainate were abolished by the ionotropic glutamate receptor antagonist 6-cyano-7-nitroquinoxaline. NMDA neither elicited a current nor modified the GABA-induced current, and metabotropic glutamate analogues were also without effect. Inhibition of the GABA-elicited current by glutamate and kainate was reduced when extracellular calcium was removed and when recording pipettes contained high concentrations of the calcium chelator BAPTA. Caffeine (5 mM) and thapsigargin (2 nM), agents known to alter intracellular calcium levels, also reduced the GABA-elicited current, but increases in calcium induced by depolarization alone did not. Our data suggest that glutamate regulates GABA transport in retinal horizontal cells through a calcium-dependent process, and imply a close physical relationship between calcium-permeable glutamate receptors and GABA transporters in these cells.

Animals↗
PubMed2003

Effects of positive GABA(A) modulators on a multiple-component, repeated-acquisition test of spatial learning.

The purpose of this study was to determine the effects of the benzodiazepines, midazolam and chlordiazepoxide, and the barbiturate, pentobarbital, on spatial learning, in a within-subject, repeated-acquisition and performance procedure adapted to the Morris Swim Task. In the presence of one stimulus arrangement, rats learned to swim to a hidden escape platform that was always in the same location in a swimming pool (performance component). In the presence of a second stimulus arrangement, the platform moved to a different place in the pool for each daily session (acquisition component). All subjects completed six training trials in both components during each daily training session, alternating between the two components within each session. Relatively direct paths to the platform and short escape latencies in the performance component, and steep within-session learning curves in the acquisition component, demonstrated that behavior under each component was controlled by the discriminative stimuli. All three GABA(A) modulators increased swim distances, escape latencies, and slowed swim speed in a dose-dependent manner. Midazolam and chlordiazepoxide, but not pentobarbital, produced selective impairments of swim distances and escape latencies in the acquisition component. Benzodiazepines disrupted acquisition at doses that did not disrupt steady-state performance. Pentobarbital impaired acquisition only at doses that also disrupted behavior during the performance component and reduced swimming speeds.

Animals↗
PubMed1998

Pharmacological modulation of GABA(A) receptor-mediated postsynaptic potentials in the CA1 region of the rat hippocampus.

It is unclear whether GABA(A) receptor-mediated hyperpolarizing and depolarizing synaptic potentials (IPSP(A)s and DPSP(A)s, respectively) are evoked by (a) the same populations of GABAergic interneurones and (b) exhibit similar regulation by allosteric modulators of GABA(A) receptor function. We have attempted to address these questions by investigating the effects of (a) known agonists for presynaptic receptors on GABAergic terminals, and (b) a range of GABA(A) receptor ligands, on each response. The GABA uptake inhibitor NNC 05-711 (10 microM) enhanced whereas bicuculline (10 microM) inhibited both IPSP(A)s and DPSP(A)s. (-)-Baclofen (5 microM), [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAGO; 0.5 microM), and carbachol (10 microM) caused substantial depressions (up to 99%) of DPSP(A)s that were reversed by CGP 55845A (1 microM), naloxone (10 microM) and atropine (5 microM), respectively. In contrast, 2-chloroadenosine (CADO; 10 microM) only slightly depressed DPSP(A)s. Quantitatively, the effect of each agonist was similar to that reported for IPSP(A)s. The neurosteroid ORG 21465 (1 - 10 microM), the anaesthetic propofol (50-500 microM), the barbiturate pentobarbitone (100-300 microM) and zinc (50 microM) all enhanced DPSP(A)s and IPSP(A)s. The benzodiazepine (BZ) agonist flunitrazepam (10-50 microM) and inverse agonist DMCM (1 microM) caused a respective enhancement and inhibition of both IPSP(A)s and DPSP(A)s. The BZomega1 site agonist zolpidem (10-30 microM) produced similar effects to flunitrazepam. The anticonvulsant loreclezole (1-100 microM) did not affect either response. These data demonstrate that similar populations of inhibitory interneurones can generate both IPSP(A)s and DPSP(A)s by activating GABA(A) receptors that are subject to similar allosteric modulation.

Animals↗
PubMed1999

Differential alcohol modulation of GABA(A) and NMDA receptors.

NMDA and GABA(A) receptors are believed to be important CNS targets of alcohol action. In mouse hippocampal neurons, n-alcohols from ethanol to dodecanol enhanced GABA-activated ion current, whereas higher alcohols had no effect. Alcohols below pentanol affected NMDA receptors more potently than GABA(A) receptors. Increasing alcohol carbon chain length produced a greater average change in apparent binding energy and potency for modulation of GABA(A) than of NMDA receptor-channels, with the result that alcohols above pentanol affected GABA(A) receptors more potently than NMDA receptors. The anesthetic potency of n-alcohols in rats more closely reflected NMDA receptor modulatory potency for lower alcohols and GABA(A) receptor modulatory potency for higher alcohols. The results suggest that there may be fundamental differences in the sites through which alcohols affect NMDA and GABA(A) receptor function.

Animals↗
PubMed1987

GABA-benzodiazepine modulation of aversion in the medial hypothalamus of the rat.

Earlier results indicate that the neurons of the midbrain central gray (CG) responsible for the elaboration and/or expression of aversive states are tonically inhibited by the GABA-benzodiazepine system. In the present study, chemitrodes were implanted in the medial hypothalamus (MH) of the rat, another aversive area of the brain deeply interrelated with the dorsal CG. Microinjection of the benzodiazepine receptor agonist midazolam raised the aversive threshold of electrical stimulation of the MH in a dose-dependent way, though in only about half of the animals tested. In the remaining rats, midazolam was ineffective. Similar antiaversive effects were caused by the GABA-A receptor agonist THIP. In contrast, microinjection of the GABA-A receptor blocker bicuculline induced aversive-like behavioral and autonomic changes. The effects of bicuculline were antagonized by pretreatment with either THIP or midazolam, the latter being counteracted by the competitive benzodiazepine receptor blocker Ro 15-1788. These results extend to the MH, the hypothesis of GABA-benzodiazepine modulation of neurons integrating aversive motivational states.

Animals↗
PubMed1988

'GABA shift' in vivo: enhancement of benzodiazepine binding in vivo by modulation of endogenous GABA.

The enhancement of benzodiazepine binding by gamma-aminobutyric acid (GABA) and its analogues has been described in detail in brain membrane preparations, but results in in vivo preparations such as tissue slices or animals treated with GABA modulators are conflicting. This 'GABA shift' in vitro has been reported for compounds with agonist effects at the benzodiazepine receptor but not for antagonists. We examined the effects of modulators of endogenous GABA on benzodiazepine receptor binding in vivo as determined by specific uptake of the benzodiazepine antagonist [3H]Ro 15-1788. Enhancement of radioligand uptake was observed in cortex, hypothalamus, hippocampus and pons-medulla 4 h after treatment with aminooxyacetic acid (AOAA), in cortex, cerebellum, hypothalamus, hippocampus and pons-medulla 0.5 h after treatment with valproic acid, and in cortex, cerebellum, hypothalamus and hippocampus 6 h after treatment with gamma-vinyl-GABA. GABA concentrations were increased at each of these points, as were synaptosomal GABA concentrations in prior studies. In contrast, no changes in radioligand uptake or GABA concentrations were observed 12 and 24 h after gamma-vinyl-GABA treatment. Increases in binding appeared to be due to increased apparent affinity at the receptor rather than a change in receptor number. These data indicate that binding of a benzodiazepine antagonist undergoes a GABA shift in vivo analogous to that observed with agonists in vitro.

Aminooxyacetic Acid↗
PubMed1999

Modulation of GABA release by dopamine in the substantia nigra.

The role of specific dopamine receptor subtypes in the regulation of GABA release in the substantia nigra was investigated using microdialysis in the awake rat. Both basal and potassium-stimulated changes in the extracellular concentrations of GABA were examined in response to the local perfusion of tetrodotoxin (TTX), the D1 agonist SKF 38393, or the D2 agonist LY 171555 through the microdialysis probe in the substantia nigra. Although TTX (1 microM) did not alter the basal extracellular concentrations of GABA in the substantia nigra, it attenuated the potassium-stimulated (80 mM K+) release of GABA. SKF 38393 had no effect on basal extracellular concentrations of GABA, but did potentiate K+ -stimulated release of GABA in a concentration-dependent manner. The potentiated response at the highest concentration of SKF 38393 (100 microM) was blocked by the D1 antagonist SCH 23390. In contrast to the effect of the D1 agonist, the D2 agonist LY 171555 attenuated the stimulated release of GABA. These data indicate that although basal extracellular concentrations of GABA in the substantia nigra may not be derived from neuronal pools, K+ -stimulated release of GABA is impulse-mediated and is modulated by the D1 and the D2 receptors. Local interactions between dopamine and GABA in the substantia nigra may have important implications for the direct regulation of basal ganglia efferent activity and motor behavior.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗