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PubMed1998

Towards a functional neuroanatomy of conscious perception and its modulation by volition: implications of human auditory neuroimaging studies.

Conscious sensory perception and its modulation by volition are integral to human mental life. Functional neuroimaging techniques provide a direct means of identifying and characterizing in vivo the systems-level patterns of brain activity associated with such mental functions. In a series of positron emission tomography activation experiments, we and our colleagues have examined a range of normal and abnormal auditory states that, when contrasted, provide dissociations relevant to the question of the neural substrates of sensory awareness. These dissociations include sensory awareness in the presence and absence of external sensory stimuli, the transition from sensory unawareness to awareness (or vice versa) in the presence of sensory stimuli, and sensory awareness with and without volition. The auditory states studied include hallucinations, mental imagery, cortical deafness modulated by attention, and hearing modulated by sedation. The results of these studies highlight the distributed nature of the functional neuroanatomy that is sufficient, if not necessary, for sensory awareness. The probable roles of unimodal association (as compared with primary) cortices, heteromodal cortices, limbic/paralimbic regions and subcortical structures (such as the thalamus) are discussed. In addition, interactions between pre- and post-rolandic regions are examined in the context of top-down, volitional modulation of sensory awareness.

Auditory Perception↗
PubMed2001

Suppression of neuronal hyperexcitability and associated delayed neuronal death by adenoviral expression of GABA(C) receptors.

The excessive neuronal excitation underlying several clinically important diseases is often treated with GABA allosteric modulators in an attempt to enhance inhibition. An alternative strategy would be to enhance directly the sensitivity of postsynaptic neurons to GABA. The GABA(C) receptor, normally found only in the retina, is more sensitive to GABA and demonstrates little desensitization compared with the GABA(A) receptor. We constructed an adenovirus vector that expressed cDNA for both the GABA(C) receptor rho(1) subunit and a green fluorescent protein (GFP) reporter and used it to transduce cultured hippocampal neurons. Transduced neurons were identified by fluorescence, double immunocytochemistry proved colocalization of the rho(1) protein and the reporter, Western blot verified the expected molecular masses, and electrophysiological and pharmacological properties confirmed the presence of functional GABA(C) receptors. rho(1)-GFP transduction resulted in an increased density of GABA(A) receptors as well as expression of novel GABA(C) receptors. This effect was not reproduced by addition of TTX or Mg(2+) to the culture medium to reduce action potentials or synaptic activity. In a model of neuronal hyperexcitability induced by chronic blockade of glutamate receptors, expression of GABA(C) receptors abolished the hyperactivity and the consequent delayed neuronal death. Adenovirus-mediated neuronal GABA(C) receptor engineering, via its dual mechanism of inhibition, may offer a way of inhibiting only those hyperexcitable neurons responsible for clinical problems, avoiding the generalized nervous system depression associated with pharmacological therapy.

Action Potentials↗
PubMed1993

Synaptic and non-synaptic immunolocalization of GABA and glutamate acid decarboxylase (GAD) in cerebellar cortex of rat.

The existence of a large number of GABA receptors in the cerebellar molecular layer, and the observation of numerous punctate immunoreactive deposits of GABA synthesizing enzyme (GAD) throughout this layer, could indicate the existence of numerous axon terminals that may be involved in neurotransmission modulated by GABA. These axon terminals may be different from those considered classically as cerebellar GABAergic axon terminals. Therefore, we have reinvestigated the localization of GABA- and GAD-immunoreactivities in the cerebellar cortex of the rat with the PAP method, using different antisera obtained from rabbits immunized with GABA, baclofen and GAD. The results observed in our investigation have demonstrated GABA- and GAD-immunoreactivities in the axon terminals considered classically as GABAergic, as well as in others which, until now, have not been considered GABAergic. This fact leads us to think that the distribution of GABA or molecules structurally similar to GABA is far more extended than previously thought in the cerebellum. We have also observed both GABA- and GAD-immunoreactivities within dendrites and glial cells. These facts suggest us a possible extrasynaptic release of GABA.

Animals↗
PubMed1998

Presynaptic GABAB autoreceptor modulation of P/Q-type calcium channels and GABA release in rat suprachiasmatic nucleus neurons.

GABA is the primary transmitter released by neurons of the suprachiasmatic nucleus (SCN), the circadian clock in the brain. Whereas GABAB receptor agonists exert a significant effect on circadian rhythms, the underlying mechanism by which GABAB receptors act in the SCN has remained a mystery. We found no GABAB receptor-mediated effect on slow potassium conductance, membrane potential, or input resistance in SCN neurons in vitro using whole-cell patch-clamp recording. In contrast, the GABAB receptor agonist baclofen (1-100 microM) exerted a large and dose-dependent inhibition (up to 100%) of evoked IPSCs. Baclofen reduced the frequency of spontaneous IPSCs but showed little effect on the frequency or amplitude of miniature IPSCs in the presence of tetrodotoxin. The activation of GABAB receptors did not modulate postsynaptic GABAA receptor responses. The depression of GABA release by GABAB autoreceptors appeared to be mediated primarily through a modulation of presynaptic calcium channels. The baclofen inhibition of both calcium currents and evoked IPSCs was greatly reduced (up to 100%) by the P/Q-type calcium channel blocker agatoxin IVB, suggesting that P/Q-type calcium channels are the major targets involved in the modulation of GABA release. To a lesser degree, N-type calcium channels were also involved. The inhibition of GABA release by baclofen was abolished by a pretreatment with pertussis toxin (PTX), whereas the inhibition of whole-cell calcium currents by baclofen was only partially depressed by PTX, suggesting that G-protein mechanisms involved in GABAB receptor modulation at the soma and axon terminal may not be identical. We conclude that GABAB receptor activation exerts a strong presynaptic inhibition of GABA release in SCN neurons, primarily by modulating P/Q-type calcium channels at axon terminals.

Animals↗
PubMed1995

A progesterone metabolite stimulates the release of gonadotropin-releasing hormone from GT1-1 hypothalamic neurons via the gamma-aminobutyric acid type A receptor.

The reduced progesterone metabolite tetrahydroprogesterone (3 alpha-hydroxy-5 alpha-pregnan-20-one; 3 alpha,5 alpha-THP) is a positive modulator of the gamma-aminobutyric acid type A (GABAA) receptor. Experiments performed in vitro with hypothalamic fragments have previously shown that GABA could modulate the release of gonadotropin-releasing hormone (GnRH). Using GT1-1 immortalized GnRH neurons, we investigated the role of GABAA receptor ligands, including 3 alpha,5 alpha-THP, on the release of GnRH. We first characterized the GABAA receptors expressed by these neurons. [3H]Muscimol, but not [3H]flunitrazepam, bound with high affinity to GT1-1 cell membranes (Kd = 10.9 +/- 0.3 nM; Bmax = 979 +/- 12 fmol/mg of protein), and [3H]muscimol binding was enhanced by 3 alpha,5 alpha-THP. mRNAs encoding the alpha 1 and beta 3 subunits of the GABAA receptor were detected by the reverse transcriptase polymerase chain reaction. In agreement with binding data, the benzodiazepine-binding gamma subunit mRNA was absent. GnRH release studies showed a dose-related stimulating action of muscimol. 3 alpha,5 alpha-THP not only modulated muscimol-induced secretion but also stimulated GnRH release when administered alone. Bicuculline and picrotoxin blocked the effects of 3 alpha,5 alpha-THP and muscimol. Finally, we observed that GT1-1 neurons convert progesterone to 3 alpha,5 alpha-THP. We propose that progesterone may increase the release of GnRH by a membrane mechanism, via its reduced metabolite 3 alpha,5 alpha-THP acting at the GABAA receptor.

Animals↗
PubMed2004

GABA transporters as drug targets for modulation of GABAergic activity.

The identification and subsequent development of the GABA transport inhibitor tiagabine has confirmed the important role that GABA transporters play in the control of CNS excitability. Tiagabine was later demonstrated to be a selective inhibitor of the GABA transporter GAT1. Although selective for GAT1, tiagabine lacks cell type selectivity and is an equipotent inhibitor of neuronal and glial GAT1. To date, four GABA transporters have been cloned, i.e., GAT1-4. The finding that some of these display differential cellular and regional expression patterns suggests that drugs targeting GABA transporters other than GAT1 might offer some therapeutic advantage over GAT1 selective inhibitors. Furthermore, it is particularly interesting that several recently defined GABA transport inhibitors have been demonstrated to display a preferential selectivity for the astrocytic GAT1 transporter. That cellular heterogeneity of GAT1 plays a role in the control of CNS function is confirmed by the demonstration that inhibition of astrocytic GABA uptake is highly correlated to anticonvulsant activity. At the present time, a functional role for the other GABA transporters is less well defined. However, recent findings have suggested a role for the mouse GAT2 (homologous to the human betaine transporter) in the control of seizure activity. In these studies, the non-selective GAT1 and mouse GAT2 transport inhibitor EF1502 (N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-hydroxy-4-(methylamino)-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol) was found to exert a synergistic anticonvulsant action when tested in combination with the GAT1 selective inhibitors tiagabine and LU-32-176B (N-[4,4-bis(4-fluorophenyl)-butyl]-3-hydroxy-4-amino-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol). Additional studies will be required to define a role for the other GABA transporters and to further identify the functional importance of their demonstrated cellular and regional heterogeneity. A summary of these and other issues are discussed in this brief review.

Animals↗
PubMed2000

Differential control of GABA release at synapses from distinct interneurons in rat hippocampus.

1. Paired recordings from monosynaptically connected CA3 interneurons and pyramidal cells of rat hippocampal slice cultures were used to compare the modulation of GABA release at synapses from distinct interneurons. 2. The group II metabotropic glutamate receptor (mGluR) agonist (2S,2'R,3'R)-2-(2',3'-dicarboxylcyclopropyl) glycine (DCG-IV, 5 muM) reduced the amplitude of IPSPs originating from stratum radiatum but not stratum oriens interneurons. In contrast, the GABAB receptor agonist (-)baclofen (10 muM) reduced the amplitude of unitary IPSPs elicited by all interneurons. 3. IPSPs mediated by stratum oriens interneurons were unaffected by the N-type calcium channel blocker omega-conotoxin MVIIA (1 muM) but were suppressed by the P/Q-type blocker omega-agatoxin IVA (200 nM). In contrast, IPSPs mediated by stratum radiatum interneurons were abolished by omega-conotoxin MVIIA. 4. Transmission dynamics were different at synapses from the two groups of interneurons. IPSPs mediated by stratum oriens interneurons showed marked paired-pulse depression (PPD) at intervals of 50 400 ms. IPSPs mediated by stratum radiatum interneurons showed paired-pulse facilitation (PPF) at 50 ms and PPD at longer intervals. 5. The amplitude of unitary IPSPs from all interneurons was unaffected by the GABAB receptor antagonist CGP52432 (2 muM) as was PPD at both 50 and 400 ms intervals. However, CGP52432 did reduce PPD of extracellularly evoked IPSPs. 6. Our results show that two groups of inhibitory synapses impinging onto CA3 pyramidal cells can be distinguished according to their dynamic and modulatory properties.

Animals↗
PubMed2005

Chronic treatment with flumazenil enhances binding sites for convulsants at recombinant alpha(1)beta(2)gamma(2S) GABA(A) receptors.

GABA(A) receptors mediate most of the fast inhibitory neurotransmission in the brain. Prolonged occupancy of these receptors by ligands leads to regulatory changes often resulting in reduction of receptor function. The mechanism of these changes is still unknown. In this study, stably transfected human embryonic kidney (HEK) 293 cells were used as a model to study the effects of prolonged flumazenil (antagonist of benzodiazepine binding sites at GABA(A) receptors) exposure on the recombinant alpha(1)beta(2)gamma(2S) GABA(A) receptors, the most common type of GABA(A) receptors found in the brain. Exposure (48 h) of HEK 293 cells stably expressing recombinant alpha(1)beta(2)gamma(2S) GABA(A) receptors to flumazenil (1 or 5 microM) in the presence of GABA (1 microM), enhanced the maximum number (B(max)) without affecting the affinity (K(d)) of [(3)H]TBOB labeled binding sites for convulsants. Diazepam (1 nM-1 mM) in the presence of GABA (1 microM) modulated [(3)H]TBOB binding to control and flumazenil pretreated cells according to a two-site model. No significant differences between the groups were observed in either the potency or efficacy of diazepam to modulate [(3)H]TBOB binding, as evidenced by a lack of significant changes between their IC(50) and I(max) values. The results suggest that chronic exposure of HEK 293 cells stably expressing recombinant alpha(1)beta(2)gamma(2S) GABA(A) receptors to flumazenil up-regulates the binding sites for convulsants, but it does not appear to affect the functional coupling between these sites and benzodiazepine binding sites. Along with our recent data, these results suggest that chronic treatment with flumazenil enhances the number of GABA(A) receptors.

Binding Sites↗
PubMed2000

Long-term changes of GABAergic function in the sensorimotor cortex of amputees. A combined magnetic stimulation and 11C-flumazenil PET study.

Primary sensory and motor areas of the cerebral cortex contain organised maps of the body. These maps appear to reorganise after damage to the peripheral parts of the sensory or motor systems, so that the cortical representation of undamaged structures expands at the expense of the damaged parts. Several studies in animals have suggested that decreased activity of the inhibitory GABAergic neurones is responsible for driving these changes. However, whether similar mechanisms sustain the effects in the longer term in humans is unknown. The present study addressed this question by examining reorganisation of sensorimotor areas of cortex in six unilateral upper limb amputees several years after the initial injury. We measured two independent indices of GABAergic function. Volumes of distribution of GABA(A) receptors were determined from 11C-flumazenil binding measured with positron emission tomography (PET). The strength of inhibition in the motor cortex was measured with paired-pulse transcranial magnetic stimulation. In the six amputees taken as a whole and compared with 24 normal subjects, there was a highly significant increase in 11C-flumazenil binding in the upper limb region of primary sensorimotor cortex bilaterally and in medial frontal cortex of the hemisphere contralateral to the amputation. Surprisingly, however, there was no change in the time course or strength of intra-cortical inhibition in the motor cortex of the amputees compared with matched control subjects. The increased 11C-flumazenil binding may reflect up-regulation of GABA(A) receptors to compensate for a decrease in the GABA content or activity of inhibitory neurones. Up-regulation of GABA(A) receptors may also indicate that long-term changes require stabilisation of cortical organisation.

Adult↗
PubMed1996

Receptor imaging technique with 11C-labeled receptor ligands in living brain slices: its application to time-resolved imaging and saturation analysis of benzodiazepine receptor using [11C]Ro15-1788.

Recently we developed a novel imaging technique using positron emitter-labeled compounds as probes and a storage phosphor screen as a detector. This approach makes it possible to follow a variety of biochemical processes with spatial information in living brain slices. Further technical development is reported here in terms of time-resolved imaging and receptor characterization in a real equilibrium state. The method was validated by use of [11C]Ro15-1788, a benzodiazepine receptor antagonist. Fresh brain slices were incubated with [11C]Ro15-1788 in oxygenated Krebs-Ringer solution at 37 degrees C, in a specially designed chamber. By placing the chamber on a storage phosphor screen, we could obtain two-dimensional images of radioactivity in the slices. Time-resolved imaging was made at 5 min intervals, revealing that it took 60 min to reach equilibrium binding. The dissociation process was observed by adding an excess amount of unlabeled Ro15-1788 to the chamber, 25 min was required for the full dissociation. In the equilibrium state, i.e. in the presence of free radio-ligand, Scatchard plot analysis was performed on the cerebral cortex (Kd = 7.4 nM, Bmax = 146 fmol/mg tissue) and striatum (Kd = 7.5 nM, Bmax = 107 fmol/mg tissue), suggesting the presence of a single component of binding site in these two regions. The present method, for the first time, made it possible to study a ligand-receptor interaction in living brain slices with temporal and spatial resolutions. This technique should prove useful for studies of receptor function under physiological conditions.

Animals↗
PubMed2005

Two flavonoids from Artemisia herba-alba Asso with in vitro GABAA-benzodiazepine receptor activity.

An ethyl acetate extract of Artemisia herba-alba was partitioned by HPLC in 10 fractions that were tested in the [(3)H]-flumazenil radioligand assay, for affinity to the GABA(A)-benzodiazepine receptor. Two fractions showed activity from which hispidulin and cirsilineol were isolated. The structures were confirmed by (1)H NMR. The IC(50) values were 8 microM for hispidulin and 100 microM for cirsilineol.

Artemisia↗
PubMed2006

Pharmacological evaluation of an [(123)I] labelled imidazopyridine-3-acetamide for the study of benzodiazepine receptors.

In vitro binding of the iodinated imidazopyridine, N',N'-dimethyl-6-methyl-(4'-[(123)I]iodophenyl)imidazo[1,2-a]pyridine-3-acetamide [(123)I]IZOL to benzodiazepine binding sites on brain cortex, adrenal and kidney membranes is reported. Saturation experiments showed that [(123)I]IZOL, bound to a single class of binding site (n(H)=0.99) on adrenal and kidney mitochondrial membranes with a moderate affinity (K(d)=30 nM). The density of binding sites was 22+/-6 and 1.2+/-0.4 pmol/mg protein on adrenal and kidney membranes, respectively. No specific binding was observed in mitochondrial-synaptosomal membranes of brain cortex. In biodistribution studies in rats, the highest uptake of [(123)I]IZOL was found 30 min post injection in adrenals (7.5% ID/g), followed by heart, kidney, lung (1% ID/g) and brain (0.12% ID/g), consistent with the distribution of peripheral benzodiazepine binding sites. Pre-administration of unlabelled IZOL and the specific PBBS drugs, PK 11195 and Ro 5-4864 significantly reduced the uptake of [(123)I]IZOL by 30% (p<0.05) in olfactory bulbs and by 51-86% (p<0.01) in kidney, lungs, heart and adrenals, while it increased by 30% to 50% (p<0.01) in the rest of the brain and the blood. Diazepam, a mixed CBR-PBBS drug, inhibited the uptake in kidney, lungs, heart, adrenals and olfactory bulbs by 32% to 44% (p<0.01) but with no effect on brain uptake and in blood concentration. Flumazenil, a central benzodiazepine drug and haloperidol (dopamine antagonist/sigma receptor drug) displayed no effect in [(123)I]IZOL in peripheral organs and in the brain. [(123)I]IZOL may deserve further development for imaging selectively peripheral benzodiazepine binding sites.

Adrenal Glands↗
PubMed2005

Differential effects of ammonia on the benzodiazepine modulatory site on the GABA-A receptor complex of human brain.

Ammonia is a key factor in the pathogenesis of encephalopathies associated with liver failure. A direct effect of ammonia on GABAergic neurotransmission was proposed as a mechanism that may explain its neurotoxic effect on the basis of electrophysiological and biochemical studies performed in animal models of liver failure. In the present study, we investigated using a radiometric assay the effect of ammonia on the binding of GABA-A receptor ligands to membranes from normal human brains. Ammonium tartrate significantly decreased the maximal binding of [3H]flunitrazepam to well-washed frontal cortical membranes (366+/-63 fmol/mg protein in absence of ammonia versus 294.1+/-51 fmol/mg protein in presence of 2 mM ammonia; p<0.05). The efficacy of the effects of ammonia was within the millimolar range (IC50=4.8 mM). This effect was not seen in cerebellum or hippocampus. Ammonia exposure decreased the maximal binding of [3H]flumazenil (284.9+/-24.2 fmol/mg protein in absence of ammonia versus 146.4+/-15.6 fmol/mg protein in presence of 2 mM ammonia; p<0.01). This effect was seen with a greater potency (Imax=32.4%) and a lower IC50 (0.1 mM). Inhibition of [3H]flumazenil binding was significant in all brain regions. The apparent ammonia-induced decrease of [3H]flunitrazepam and [3H]flumazenil binding was due to a decrease in the binding affinities of these ligands for the benzodiazepine site. In contrast, ammonium tartrate exposure did not cause significant changes to the binding of [3H]muscimol in any brain region. These findings demonstrate that ammonia interacts negatively with components of the benzodiazepine-associated site at the GABA-A receptor complex in human brain in contrast to previous reports in the rat, and thus, does not support the notion that ammonia directly activates the GABA-A receptor complex resulting in increased GABAergic neurotransmission in human hepatic encephalopathy. These findings also suggest that positron emission tomography studies in cirrhotic patients using [11C]flumazenil may be underestimating GABA-A receptor sites depending upon the degree of hyperammonemia of the patient.

Ammonia↗
PubMed2004

Modafinil prevents the MPTP-induced increase in GABAA receptor binding in the internal globus pallidus of MPTP-treated common marmosets.

The psychostimulant drug modafinil induces a reversal of motor deficits in MPTP treated primates and prevents MPTP toxicity to substantia nigra but its mechanism of action is not clear. In common marmosets acutely treated with MPTP in the presence or absence of modafinil, we have studied changes in GABA(A) receptor binding in the basal ganglia. MPTP treatment had no effect on [(3)H]-flunitrazepam (FNZ) binding density in the striatum or external globus pallidus (GPe) but increased [(3)H]-FNZ binding density in the internal globus pallidus (GPi). Administration of modafinil (10-100 mg/kg) with MPTP did not alter [(3)H]-FNZ binding density in the striatum or GPe. Low doses of modafinil (10 and 30 mg/kg) had no effect on the increased [(3)H]-FNZ binding density in the GPi but high dose modafinil (100 mg/kg) significantly decreased [(3)H]-FNZ binding density in GPi. These findings suggest that modafinil can selectively alter GABA binding density in the GPi either by preventing MPTP-induced toxicity or through an action on striatal output pathway related to its antiparkinsonian activity and its ability to inhibit MPTP toxicity.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1996

Chronic treatment with diazepam or abecarnil differently affects the expression of GABAA receptor subunit mRNAs in the rat cortex.

Diazepam and abecarnil produce their overt effects by interaction with the GABAA receptor. Chronic treatment with abecarnil, however, does not induce diazepam-like tolerance. This study investigates the effects of chronic diazepam and abecarnil treatment on expression of GABAA receptor alpha 1-6 beta 1-3 and gamma 1-3 subunit isoform mRNAs in rat cortex. Male Sprague-Dawley rats were injected subcutaneously once daily for 7 or 14 days with 15 mg/kg diazepam or 6 mg/kg abecarnil in sesame-oil vehicle, and steady-state levels of GABAA receptor subunit mRNAs were quantified by solution hybridization. The levels of alpha 4- and alpha-, beta 1- and gamma 3-subunit mRNAs were significantly increased after 7 days of diazepam treatment, and this effect was maintained at 14 days. A significant increase in alpha 3-subunit mRNA was apparent only after 14 days of diazepam treatment and a significant decrease in beta 2-subunit mRNA was seen only after 14 days of abecarnil treatment. Gamma 2-Subunit mRNA was significantly decreased after 14 days of either diazepam or abecarnil exposure. A degree of association between a particular drug treatment and changes in the levels of mRNAs arising from a given gene cluster was noted. Our results are consistent with a model of diazepam dependence based on GABAA receptor subunit isoform switching.

Animals↗
PubMed2000

The influence of an endogenous beta3 subunit on recombinant GABA(A) receptor assembly and pharmacology in WSS-1 cells and transiently transfected HEK293 cells.

Cell lines are commonly used for studying recombinant heterooligomeric ion channels with defined subunit composition. Such studies often ignore the contribution of endogenous proteins in the assembly of mature channels. We examined whether an endogenous subunit was required for the functional expression of gamma-aminobutyric acid type A (GABA(A)) receptors in WSS-1 cells, HEK293 cells stably expressing recombinant alpha1 and gamma2 subunits. Our pharmacological and RT-PCR analyses of GABA(A) receptors and their mRNAs in WSS-1 cells confirm the presence of alpha1 and gamma2 subunits and suggest the existence of an endogenous beta3 subunit. Whole-cell GABA-evoked currents recorded from untransfected WSS-1 cells were blocked by bicuculline methiodide and enhanced by anesthetics and anticonvulsants including the subunit-selective compounds diazepam and loreclezole. These data suggest that, in addition to the gamma2 subunit, WSS-1 cell receptors also contain beta2/3 subunits. RT-PCR revealed that WSS-1 cells and parental HEK293 cells contain beta3 mRNA. We examined the contribution of the beta3 subunit in the function of receptors formed by expression of alpha1 and gamma2S subunits. Untransfected HEK293 cells were unresponsive to GABA. Cells transfected with alpha1 and gamma2S cDNAs displayed small diazepam and loreclezole responsive GABA-activated currents. By contrast, the expression of alpha1 and gamma2S cDNAs in the neuroblastoma NB41A3 cell line, that lacks beta subunit mRNAs, failed to produce functional receptors. These data reaffirm that alpha1 and gamma2S subunits alone do not form functional GABA(A) receptors and that receptors of WSS-1 cells contain alpha1, beta3 and gamma2S subunits.

Animals↗
PubMed1999

Sex differences in long-term consequences of prenatal diazepam exposure: possible underlying mechanisms.

Prenatal exposure to diazepam, a benzodiazepine (BZD) compound, leads to pronounced effects on responses to stressors in exposed animals when they reach adulthood. Many of the responses are sex specific. The mechanisms mediating the effects of the exposure on the organism have not been elucidated; however, the time course for the appearance of altered function following in utero drug exposure indicates that the exposure interfered with neural organization of mechanisms mediating responses to stressors. The article discusses possible mechanisms that relate to sites of action of the drug in the developing brain: the GABA(A) receptor, and the mitochondrial BZD receptor. The mechanisms mediating the sex-specific impact of diazepam on the developing brain appear to be complex and interactive.

Animals↗
PubMed1997

Potentiation by ethanol of GABA-induced current and facilitation of its desensitization in cultured rat cortical neurons.

1. Patch-clamp whole cell recording was performed to elucidate whether or not ethanol, at low concentration, has an effect on the GABAA receptor in cultured rat cortical neurons as compared with flunitrazepam. 2. Bath application of ethanol (0.01%) or flunitrazepam (1 mM) potentiated the peak amplitude of GABA-induced (10 microM) current without affecting the equilibrium potential. 3. The decay time constant and time to peak of GABA-induced current were shortened in the presence of ethanol or flunitrazepam. 4. These findings indicate that a low concentration of ethanol and flunitrazepam potentiates the GABA-induced current concomitantly with acceleration of desensitization to the drug.

Animals↗