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PubMed2001

Synthesis of novel gamma-aminobutyric acid (GABA) uptake inhibitors. 5.(1) Preparation and structure-activity studies of tricyclic analogues of known GABA uptake inhibitors.

On the basis of the SAR of a series of known gamma-aminobutyric acid (GABA) uptake inhibitors, including 4 (SKF 89976), new tricyclic analogues have been prepared. These novel compounds are derivatives of nipecotic acid, guvacine, and homo-beta-proline, substituted at the nitrogen of these amino acids by various lipophilic moieties such as (10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)alkoxyalkyl or (10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)alkoxyalkyl. The in vitro values for inhibition of [(3)H]-GABA uptake in rat synaptosomes was determined for each compound in this new series, and it was found that several of the novel compounds showed a high potency comparable with that of the reference compounds 4, 5 (tiagabine), and 6 (CI-966). Several of the novel compounds were also evaluated for their ability in vivo to inhibit clonic seizures induced by a 15 mg/kg (ip) dose of methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM). One compound, (R)-1-(2-(2-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)ethoxy)ethyl)-3-piperidinecarboxylic acid (23), was selected for further biological investigations and showed a protective index comparable to or slightly better than that of the recently launched anticonvulsant product 5 ((R)-1-(4,4-bis(3-methyl-2-thienyl)-3-butenyl)-3-piperidinecarboxylic acid).

Animals↗
PubMed2003

Failure of ischemic neuroprotection by potentiators of gamma-aminobutyric acid.

INTRODUCTION: Potentiators of inhibitory neurotransmission may provide a neuroprotective effect on cerebral tissue exposed to ischemia, without inducing toxic side effects. Topiramate and vigabatrin enhance the action of gamma-aminobutyric acid (GABA), and each has side effect profiles known to be well tolerated through their clinical use as anticonvulsant medications. We assessed the potential benefit through GABA activation by these drugs on infarct size and functional recovery following focal cerebral ischemia in mice. METHODS: Silicon-coated suture was advanced through the internal carotid artery of 89 halothane-anesthetized mice to temporarily occlude the right middle cerebral artery for either 45 minutes (topiramate), or 120 minutes (vigabatrin). Animals were treated either at the time of reperfusion with topiramate (100 mg/kg, 40 mg/kg, or saline control), or two hours before arterial occlusion with vigabatrin, (1000 mg/kg, 500 mg/kg, or saline control). Neurological outcome was measured 24 hours after ischemia using a 28-point functional examination score. Infarct volume was estimated by summing area maps of stained slices of infarcted hemispheres. RESULTS: Functional examination scores at 24 hours were similar between the high dose topiramate group, the low dose topiramate group, and the control group. Similarly, no differences were noted between examination scores of high dose vigabatrin, low dose vigabatrin, and control. Consistent sized right hemisphere infarcts were noted within each group on histological examination. Mean infarct volumes did not differ between groups treated with high dose topiramate, low dose topiramate, or control. Infarct volumes of animals treated with saline control were slightly larger than that of high dose vigabatrin and low dose vigabatrin groups, but the difference did not reach significance. CONCLUSION: Treatment with these two potentiators of GABA did not result in significant differences in outcome following focal cerebral ischemia, by either functional or histological measures. These results do not support a substantial neuroprotective role of GABA following ischemia in this mouse suture model.

Animals↗
PubMed1987

Potentiation of gamma-aminobutyric-acid-activated chloride conductance by a steroid anaesthetic in cultured rat spinal neurones.

1. Intracellular recordings from cultured rat spinal cord neurones demonstrated that Cl(-)-dependent responses to GABA (gamma-aminobutyric acid) (but not glycine) were increased in amplitude and duration by the steroid anaesthetic alphaxalone (3 alpha-hydroxy-5 alpha-pregnane-11,20-dione) at submicromolar concentrations that produced little or no effect on passive electrical properties. The non-anaesthetic 3 beta-hydroxy analogue was without effect on GABA-evoked responses. 2. Under voltage clamp, membrane currents evoked by GABA were potentiated by alphaxalone without change in the reversal potential for the GABA-evoked response. Fluctuation analysis of GABA-evoked currents suggested that the mean open-time of GABA-activated channels was prolonged from 30 to 74 ms in the presence of the anaesthetic. 3. Higher concentrations of alphaxalone, similar to those reported during surgical anaesthesia, increased membrane conductance in the absence of exogenously applied GABA. Under voltage clamp, current responses to alphaxalone reversed at the same potential as did responses to GABA, suggesting that they result from increased Cl- conductance. 4. Alphaxalone responses were reduced by the GABA antagonist bicuculline. Fluctuation analysis of current responses to the anaesthetic suggest that they result from the activation of ion channels of long (100 ms) open-time and elementary conductance indistinguishable from that of channels activated by GABA (20 pS). Taken together, these findings indicate that the steroid anaesthetic is able to directly activate Cl- conductance normally activated by GABA in spinal neurones. 5. The actions of the steroid at GABA-receptor-Cl(-)-channel complexes are similar to those produced by the anaesthetic barbiturates (e.g. pentobarbitone), although obtained at 50-100-fold lower concentrations. These effects on the inhibitory Cl(-)-conductance mechanism may be partly responsible for the depressant actions of alphaxalone on the mammalian central nervous system.

Anesthetics↗
PubMed1986

Changes in gamma-aminobutyric acid high affinity binding to cerebral cortex membranes after pinealectomy or melatonin administration to rats.

In order to assess the effect of pinealectomy (Px) on the diurnal rhythmicity of gamma-aminobutyric acid (GABA) high affinity binding to cerebral cortex membranes, groups of intact, Px or sham Px rats (subjected to surgery 15 days earlier) were killed at six different time intervals during the 24-hour cycle. GABA binding was estimated by Scatchard analysis of 3H-GABA binding to cerebral cortex membranes prepared from individual brains; only one type of binding site with dissociation constant (KD) about 20-50 nM and site number (Bmax) about 200-500 fmol/mg protein was apparent in the assay conditions employed. In intact and sham Px rats Bmax attained minimal values at night and increased during daylight. Px increased generally Bmax and disrupted its normal diurnal rhythmicity, a peak in Bmax being observed at midnight. A significant decrease of GABA high affinity binding affinity was detected at morning hours in intact rats and at late scotophase and morning hours in Px and sham Px rats. Bmax of GABA high affinity binding in Px rats attained maximal values by 5-10 days after surgery and decreased somewhat 5 days later. Sham Px rats exhibited a transient increase in Bmax up to 10 days after surgery, returning to normal values by the 15th day. Superior cervical ganglionectomy increased binding affinity up to 15 days after surgery without affecting Bmax. The minimal melatonin effective dose to counteract Px-induced increase of GABA high affinity binding was 25 micrograms/kg body weight when given 3 h before sacrifice. Melatonin activity on GABA binding did not depend upon a direct effect on the binding sites, as shown in vitro. These results suggest a link between pineal function, melatonin secretion and GABA receptor activity in rats.

Animals↗
PubMed1996

Release of gamma-aminobutyric acid in the dorsal horn and suppression of tactile allodynia by spinal cord stimulation in mononeuropathic rats.

OBJECTIVE: The aim of the present study is to monitor the extracellular gamma-aminobutyric acid (GABA) levels in the lumbar dorsal horn of allodynic rats, which respond to spinal cord stimulation (SCS) with a normalization of the tactile withdrawal threshold. In addition, we monitored the GABA levels in nonresponding and sham-stimulated rats. METHODS: Partial constriction injury of the sciatic nerve was performed, and a permanent electrode for SCS was inserted into the spinal canal. The response to SCS was assessed with von Frey hairs in awake animals. Later, microdialysis was performed in the dorsal horn of the spinal cord under halothane anesthesia. The concentration of GABA in the microdialysate was assessed by high-performance liquid chromatography. RESULTS: Extracellular GABA levels in rats with sciatic nerve lesions and allodynia (2.3 +/- 0.5 nmol/L) were significantly lower (P < 0.001) than in control rats with intact sciatic nerves (8.1 +/- 1.0 nmol/L), whereas only slightly decreased GABA levels (5.7 +/- 1.1 nmol/L) were detected in nonallodynic rats with sciatic nerve lesions. In the allodynic rats, which respond to SCS by a normalization of the tactile withdrawal threshold, significantly (P < 0.001) increased GABA levels (6.7 +/- 2.3 nmol/L) were detected after SCS. In contrast, neither the allodynic rats, which did not respond to SCS, nor the sham-stimulated allodynic rats displayed increased GABA levels in response to stimulation. CONCLUSION: Our results indicate that the development of allodynia, a common symptom in neuropathic pain states, may be linked to a decreased spinal release of GABA. We suggest that an SCS-induced release of GABA could be important for the suppression of allodynia observed in rats after SCS. Similar mechanisms could also be involved in the SCS-induced alleviation of pain in patients with peripheral neuropathy.

Animals↗
PubMed2005

gamma-Aminobutyric acid inhibits cholangiocarcinoma growth by cyclic AMP-dependent regulation of the protein kinase A/extracellular signal-regulated kinase 1/2 pathway.

We studied the effect of the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), in the regulation of cholangiocarcinoma growth. We determined the in vitro effect of GABA on the proliferation of the cholangiocarcinoma cell lines (Mz-ChA-1, HuH-28, and TFK-1) and evaluated the intracellular pathways involved. The effect of GABA on migration of Mz-ChA-1 cells was also evaluated. In vivo, Mz-ChA-1 cells were s.c. injected in athymic mice, and the effects of GABA on tumor size, tumor cell proliferation, apoptosis, collagen quantity, and the expression of vascular endothelial growth factor-A (VEGF-A) and VEGF-C (cancer growth regulators) were measured after 82 days. GABA decreased in vitro cholangiocarcinoma growth in a time-dependent and dose-dependent manner, by both cyclic AMP/protein kinase A- and D-myo-inositol-1,4,5-thriphosphate/Ca(2+)-dependent pathways, leading to down-regulation of extracellular signal-regulated kinase 1/2 phosphorylation. Blocking of GABA(A), GABA(B), and GABA(C) receptors prevented GABA inhibition of cholangiocarcinoma proliferation. GABA inhibited Mz-ChA-1 cell migration and, in vivo, significantly decreased tumor volume, tumor cell proliferation, and VEGF-A/C expression whereas increasing apoptosis compared with controls. An increase in collagen was evident in GABA-treated tumors. GABA decreases biliary cancer proliferation and reduces the metastatic potential of cholangiocarcinoma. GABA may represent a therapeutic agent for patients affected by malignancies of the biliary tract.

Animals↗
PubMed1989

Co-release of acetylcholine and gamma-aminobutyric acid by a retinal neuron.

Rabbit retinas were vitally stained with 4',6-diamidino-2-phenylindole (DAPI), a fluorescent compound that selectively accumulates within the cholinergic amacrine cells. The retinas were then incubated in vitro in the presence of radioactive gamma-aminobutyric acid (GABA) and autoradiographed. The cells that accumulated DAPI were found to accumulate GABA, confirming immunohistochemical evidence that the cholinergic amacrine cells contain GABA. Incubation of retinas in the presence of elevated concentrations of K+ caused them to release acetylcholine and GABA, and autoradiography showed depletion of radioactive GABA from the cholinergic amacrine cells. This indicates that the cholinergic amacrine cells can secrete acetylcholine and GABA. Retinas were double-labeled with [14C]GABA and [3H]acetylcholine, allowing simultaneous measurement of their release. The release of [14C]GABA was found to be independent of extracellular Ca2+. Radioactive GABA synthesized endogenously from [14C]glutamate behaved the same way as radioactive GABA accumulated from the medium. In the same experiments the simultaneously measured release of [3H]acetylcholine was strongly Ca2+-dependent, indicating that the releases of acetylcholine and GABA are controlled by different mechanisms. Synaptic vesicles immunologically isolated from double-labeled retinas contained much [3H]acetylcholine and little or no [14C]GABA. These results suggest that the cholinergic amacrine cells release acetylcholine primarily by vesicle exocytosis and release GABA primarily by means of a carrier.

Acetylcholine↗
PubMed1996

Embryonic and postnatal expression of four gamma-aminobutyric acid transporter mRNAs in the mouse brain and leptomeninges.

The distribution of gamma-aminobutyric acid (GABA) transporter mRNAs (mGATs) was studied in mouse brain during embryonic and postnatal development using in situ hybridization with radiolabeled oligonucleotide probes. Mouse GATs 1 and 4 were present in the ventricular and subventricular zones of the lateral ventricle from gestational day 13. During postnatal development, mGAT1 mRNA was distributed diffusely throughout the brain and spinal cord, with the highest expression present in the olfactory bulbs, hippocampus, and cerebellar cortex. The mGAT4 message was densely distributed throughout the central nervous system during postnatal week 1; however, the hybridization signal in the cerebral cortex and hippocampus decreased during postnatal weeks 2 and 3, and in adults, mGAT4 labeling was restricted largely to the olfactory bulbs, midbrain, deep cerebellar nuclei, medulla, and spinal cord. Mouse GAT2 mRNA was expressed only in proliferating and migrating cerebellar granule cells, whereas mGAT3 mRNA was absent from the brain and spinal cord throughout development. Each of the four mGATs was present to some degree in the leptomeninges. The expression of mGATs 2 and 3 was almost entirely restricted to the pia-arachnoid, whereas mGATs 1 and 4 were present only in specific regions of the membrane. Although mGATs 1 and 4 may subserve the classical purpose of terminating inhibitory GABAergic transmission through neuronal and glial uptake mechanisms, GABA transporters in the pia-arachnoid may help to regulate the amount of GABA available to proliferating and migrating neurons at the sub-pial surface during perinatal development.

Animals↗
PubMed1999

Regional distribution and cellular localization of gamma-aminobutyric acid subtype 1 receptor mRNA in the rat brain.

The distribution of gamma-aminobutyric acid (GABA) receptor subtype B1 (GABA(B1)) mRNA-containing cells in the brain of adult rats was determined with in situ hybridization histochemistry. The vast majority of neurons expressed GABA(B1) receptor mRNA. However, there were nuclei of relative high density, and, in some nuclei, the majority of neurons did not express detectable levels of GABA(B1) receptor transcripts. Areas where the majority of neurons expressed a high density of mRNA included the medial habenula; the septohippocampal, periventricular, suprachiasmatic, and supraoptic nuclei; Purkinje cells in the cerebellum; and pyramidal and granule cells of the hippocampus and dentate gyrus, respectively. Also, brainstem nuclei containing monoaminergic neurons and neurons in the thalamic motor nuclei contained relatively high levels of expression. mRNA was low or absent in neuronal populations in regions with well-developed cytoarchitecture, such as the stratum radiatum and stratum oriens of the hippocampus, the molecular and granular layers of the cerebellum, and the molecular layer of the cortex. Low expression was observed also in many extrapyramidal nuclei, such as the globus and ventral pallidum and the substantia nigra, pars reticulata. Expression also was low in the reticular thalamic nucleus and zona incerta. Neurons lacking detectable GABA(B1) receptor mRNA were generally in nuclei that contained largely GABAergic neurons.

Animals↗
PubMed1992

gamma-Aminobutyric acid receptor activation of outer hair cells in the guinea pig cochlea.

Gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter of the central nervous system, may also be released from olivocochlear efferent nerves reaching the outer hair cells of the cochlea. In the present study the cell potential of isolated outer hair cells of the third and fourth turns of the guinea pig cochlea was measured with patch-clamp electrodes. GABA-receptor agonists and antagonists were applied extracellularly. The cell membrane hyperpolarized in a reversible manner with increasing concentrations of extracellular GABA. Half-maximal hyperpolarization (2 mV) was achieved with approximately 10(-7) M GABA. Desensitization was not observed. The hyperpolarizing effect of GABA was potentiated by the benzodiazepine clorazepate and was blocked by picrotoxin.

Animals↗
PubMed1987

Autoradiographic localization of gamma-aminobutyric acid receptors in mouse barrel field.

The distribution of high-affinity gamma-aminobutyric acid (GABA) receptors in mouse posteromedial barrel subfield (PMBSF) in layer IV of the somatosensory (SI) cortex was studied using [3H]muscimol autoradiography in vitro. A qualitative study revealed a heterogeneous distribution in the density of [3H]muscimol binding in the barrel field. In the barrel sides and septum between the barrels [3H]muscimol binding exhibits the lowest level of labelling in the entire tissue. In comparison, [3H]muscimol binding in the hollows is considerably higher than in the barrel sides although the level is not homogeneous. These findings suggest that the barrel hollows are much richer in GABA receptors than the surrounding barrel sides and septa.

Animals↗
PubMed1997

Tigabine hydrochloride, an inhibitor of gamma-aminobutyric acid (GABA) uptake, induces cortical depolarizations in vitro.

The effect of the gamma-aminobutyric acid uptake inhibitor tiagabine hydrochloride was studied on electrical responses in cortical wedges prepared from 20-30 day-old, audiogenic seizure-prone DBA/2 mice. Perfusion of tiagabine (50 microM) for 15 min, evoked large, slow depolarizations with a frequency of 6-8/h which persisted for 4-5 h. The GABA(A) receptor antagonists, bicuculline (10 microM) and picrotoxin (100 microM), inhibited established depolarizations. These depolarizations were also calcium-dependent and blocked by tetrodotoxin. The non-opioid antitussive, dextromethorphan, which has been shown to inhibit glutamate release, irreversibly blocked the depolarizations. Conversely, 4-aminopyridine (50 microM), a potassium channel antagonist, markedly potentiated the responses. The NMDA receptor antagonist, 3-((R)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid, had no effect on the depolarizations at concentrations up to 100 microM but the AMPA/kainate receptor antagonist, 6,7-dinitroquinoxaline-2.3-dione at high concentrations (100 and 200 microM), reversibly decreased the frequency without affecting the amplitude. It is concluded that the tiagabine-induced depolarizations in this in vitro preparation were initiated through GABA(A) receptors leading, possibly, to a release of excitatory amino acids.

Acoustic Stimulation↗
PubMed2001

Bicarbonate and thiocyanate ions affect the gating of gamma-aminobutyric acid(A) receptors in cultured rat cortical cells.

The ionophore function of gamma-aminobutyric acid(A) (GABA(A)) receptors was studied by whole-cell patch clamp electrophysiology in primary cultures of rat cerebral cortex. Chloride ions were replaced for SCN(-) (thiocyanate) and HCO(-3) (bicarbonate) ions. The EC(50) values of the GABA(A) agonist muscimol (HCO(-3)>Cl(-)>SCN(-)) varied parallel with the free energies of dehydration of the anions, while the inhibition constants of the GABA(A) antagonist bicuculline methiodide were not affected. These findings might be relevant in the interpretation of the contribution of HCO(-3) versus Cl(-) currents to the pharmacological differences between depolarizing and hyperpolarizing GABA responses.

Animals↗
PubMed1998

Modulation of gamma-aminobutyric acid (GABA) receptors and the feeding response by neurosteroids in Hydra vulgaris.

Gamma-Aminobutyric acid (GABA) receptors are present in membrane preparations from Hydra vulgaris, one of the most primitive organisms with a nervous system. These receptors are sensitive to muscimol and benzodiazepines and appear to be important in the regulation of the feeding response. The effects of neurosteroids, general anaesthetics, and GABA antagonists on GABA(A) receptors in membranes prepared from Hydra and on the feeding response have now been investigated. The neurosteroids tetrahydroprogesterone and tetrahydrodeoxycorticosterone increased [3H]GABA binding to hydra membranes with nanomolar potency (EC50, 141+/-11 and 623+/-36 nM, respectively) and high efficacy (maximal increase 79+/-6.5 and 62+/-4%, respectively), whereas the 3beta-hydroxy epimer of tetrahydroprogesterone was ineffective. The benzodiazepine receptor ligands diazepam (100 microM), clonazepam (100 microM) and abecarnil (30 microM) enhanced [3H]GABA binding to Hydra membranes by 22, 20 and 24%, respectively; effects abolished by the specific benzodiazepine antagonist flumazenil (100 microM). On the contrary, the peripheral benzodiazepine receptor ligand 4'chlorodiazepam failed to affect [3H]GABA binding to Hydra membranes. The general anaesthetics propofol and alphaxalone similarly increased (+38% and +30% respectively) [3H]GABA binding. Moreover, [3H]GABA binding to Hydra membranes was completely inhibited by the GABA(A) receptor antagonist SR 95531, whereas bicuculline was without effect. The modulation of GABA(A) receptors in vitro by these various drugs correlated with their effects on the glutathione-induced feeding response in the living animals. Tetrahydroprogesterone and tetrahydrodeoxy-corticosterone (1 to 10 microM) prolonged, in a dose-dependent manner, the duration of mouth opening induced by 10 microM glutathione, with maximal effects of +33 and +29%, respectively, apparent at 10 microM neurosteroid. Alphaxalone (10 microM) similarly increased (+33%) the effect of glutathione. The effects of steroids on the feeding response were inhibited by SR 95531 in a dose-dependent manner; t-butylbyclophosphorothyonate (1 microM), a specific Cl- channel blocker, which per se, like picrotoxin but not bicuculline, shortened the duration of the response, also counteracted the steroids effects at 1 microM. These results suggest that the modulation of GABA(A) receptors by steroids is an ancient characteristic of the animal kingdom and that the pharmacological properties of these receptors have been highly conserved through evolution.

Anesthetics↗
PubMed1987

Minimal model to account for the membrane conductance increase and desensitization of gamma-aminobutyric acid receptors synthesized in the Xenopus oocytes injected with rat brain mRNA.

gamma-Aminobutyric acid (GABA) receptors, which translocate chloride anion with binding GABA, were synthesized in Xenopus oocytes by injecting rat brain mRNA. GABA-elicited responses in the oocytes were measured electrophysiologically by the current-clamped method. Five different measurements were made to establish the relationship between GABA concentration and the electrical responses: (1) the GABA-elicited conductance increase before desensitization; (2) the rate of desensitization of GABA receptors; (3) the rate of recovery of desensitized receptors upon removal of GABA; (4) the GABA-elicited conductance increase after desensitization equilibrium; (5) the fraction of the active form of GABA receptors after desensitization equilibrium. These results were interpreted on the basis of the minimal model proposed for nicotinic acetylcholine receptor in Electrophorus electricus electroplax [Hess, G. P., Cash, D. J., & Aoshima, H. (1983) Annu. Rev. Biophys. Bioeng. 12, 443-473]. Estimated equilibrium and rate constants in the model for GABA receptors could successfully explain the results of the five above measurements.

Animals↗
PubMed2005

Picrotoxin inhibition mechanism of a gamma-aminobutyric acid A receptor investigated by a laser-pulse photolysis technique.

The gamma-aminobutyric acid(A) (GABA(A)) receptor, a major inhibitory neurotransmitter receptor, belongs to a family of membrane-bound proteins that regulate signal transmission between approximately 10(12) cells of the nervous system. It plays a major role in many neurological disorders, including epilepsy. It is the target of many pharmacological agents, including the convulsant picrotoxin. Here, we present the mechanism of inhibition by picrotoxin of the rat alpha1beta2gamma2L GABA(A) receptor investigated using rapid kinetic techniques in combination with whole-cell current recordings. The following new results were obtained by using transient kinetic techniques, the cell-flow method and the laser-pulse photolysis (LaPP) technique with a microsecond to millisecond time resolution. (i) The apparent dissociation constant of picrotoxin for the open-channel form of the receptor was approximately 5 times higher than that of the closed-channel form. (ii) Picrotoxin increased the channel-closing rate constant (k(cl)) approximately 4-fold, while the rate constant for channel opening (k(op)) remained essentially unaffected. (iii) The mechanism indicates that picrotoxin binds to an allosteric site of the receptor with higher affinity for the closed-channel form than for the open-channel form and thereby inhibits the receptor by decreasing 4-fold its channel-opening equilibrium constant [Phi(I)(-)(1) = k(op(I))/k(cl(I))]. (iv) The mechanism further indicates that compounds that bind with equal affinity to the picrotoxin-binding site on the open-channel form of the receptor and the closed-channel form will not affect the channel-opening equilibrium and can, therefore, displace picrotoxin and prevent inhibition of the GABA(A) receptor by picrotoxin. Such compounds may be therapeutically useful in counteracting the effects of compounds and diseases that unfavorably affect the channel-opening equilibrium of the receptor channel.

Allosteric Regulation↗
PubMed2004

Tonic inhibition in mouse hippocampal CA1 pyramidal neurons is mediated by alpha5 subunit-containing gamma-aminobutyric acid type A receptors.

The principal inhibitory neurotransmitter in the mammalian brain, gamma-aminobutyric acid (GABA), is thought to regulate memory processes by activating transient inhibitory postsynaptic currents. Here we describe a nonsynaptic, tonic form of inhibition in mouse CA1 pyramidal neurons that is generated by a distinct subpopulation of GABA type A receptors (GABA(A)Rs). This tonic inhibitory conductance is predominantly mediated by alpha5 subunit-containing GABA(A)Rs (alpha5GABA(A)Rs) that have different pharmacological and kinetic properties compared to postsynaptic receptors. GABA(A)Rs that mediate the tonic conductance are well suited to detect low, persistent, ambient concentrations of GABA in the extracellular space because they are highly sensitive to GABA and desensitize slowly. Moreover, the tonic current is highly sensitive to enhancement by amnestic drugs. Given the restricted expression of alpha5GABA(A)Rs to the hippocampus and the association between reduced alpha5GABA(A)R function and improved memory performance in behavioral studies, our results suggest that tonic inhibition mediated by alpha5GABA(A)Rs in hippocampal pyramidal neurons plays a key role in cognitive processes.

Animals↗
PubMed2004

Phosphatase inhibitors remove the run-down of gamma-aminobutyric acid type A receptors in the human epileptic brain.

The properties of gamma-aminobutyric acid (GABA) type A receptors (GABA(A) receptors) microtransplanted from the human epileptic brain to the plasma membrane of Xenopus oocytes were compared with those recorded directly from neurons, or glial cells, in human brains slices. Cell membranes isolated from brain specimens, surgically obtained from six patients afflicted with drug-resistant temporal lobe epilepsy (TLE) were injected into frog oocytes. Within a few hours, these oocytes acquired GABA(A) receptors that generated GABA currents with an unusual run-down, which was inhibited by orthovanadate and okadaic acid. In contrast, receptors derived from membranes of a nonepileptic hippocampal uncus, membranes from mouse brain, or recombinant rat alpha 1 beta 2 gamma 2-GABA receptors exhibited a much less pronounced GABA-current run-down. Moreover, the GABA(A) receptors of pyramidal neurons in temporal neocortex slices from the same six epileptic patients exhibited a stronger run-down than the receptors of rat pyramidal neurons. Interestingly, the GABA(A) receptors of neighboring glial cells remained substantially stable after repetitive activation. Therefore, the excessive GABA-current run-down observed in the membrane-injected oocytes recapitulates essentially what occurs in neurons, rather than in glial cells. Quantitative RT-PCR analyses from the same TLE neocortex specimens revealed that GABA(A)-receptor beta 1, beta 2, beta 3, and gamma 2 subunit mRNAs were significantly overexpressed (8- to 33-fold) compared with control autopsy tissues. Our results suggest that an abnormal GABA-receptor subunit transcription in the TLE brain leads to the expression of run-down-enhanced GABA(A) receptors. Blockage of phosphatases stabilizes the TLE GABA(A) receptors and strengthens GABAergic inhibition. It may be that this process can be targeted to develop new treatments for intractable epilepsy.

Adult↗