GABA(A) receptors mediate synaptic and tonic inhibition in many neurons of the central nervous system. These receptors can be constructed from a range of different subunits deriving from seven identified families. Among these subunits, ?(5) has been shown to mediate GABAergic tonic inhibitory currents in neurons from supraspinal nuclei. Likewise, immunohistochemical and in ...

Temporal lobe epilepsy (TLE), characterized by spontaneous recurrent seizures, learning and memory impairments is associated with neurodegeneration, abnormal reorganization of the circuitry and loss of functional inhibition in hippocampus. In adult hippocampus, the GABAergic cells mediate the major inhibitory function of the principal neurons, promoting the Cl(-) entry through the ...

GABAA (γ-aminobutyric acid type A) receptors are ligand-gated ion channels composed of five subunits, generally two αs, two βs, and a γ2. Recent research in which sets of subunits containing α1 or α6 subunits were artificially linked has revealed the importance of subunit ...

Zolpidem is an imidazopyridine hypnotic that is believed to act selectively at alpha(1) subunit-containing gamma-aminobutyric acid type A (GABA(A)) receptors and thus to have minimal abuse and dependence potential. We present three cases of zolpidem abuse and dependence in which the drug was used not for sedation but for stimulation and anxiolysis. All of ...

We show that in na�ve mice, tonic currents mediated by ? subunit-containing GABA(A) receptors in fast spiking interneurons are larger in females than in males while in regular spiking neurons such a difference was not observed. Moreover, in fast spiking interneurons, associative learning induced a larger reduction of these currents in females than in ...

The potent sedative-hypnotic zolpidem and the convulsant methyl-6,7-dimethoxy-4-ethyl-?-carboline-3-carboxylate (DMCM) act primarily by binding to the benzodiazepine site of the main inhibitory neurotransmitter receptor, the pentameric ?-aminobutyric acid type A receptor (GABA(A)). This binding depends critically on the wild-type F77 residue of the GABA(A) ...

Zolpidem, a widely used hypnotic drug which acts through benzodiazepine binding sites, is a positive allosteric modulator of gamma-aminobutyric acid (GABA) action with preferential affinity for GABA(A) receptors containing alpha1 subunit. The pharmacological profile of zolpidem is different from that of classical benzodiazepines. The aim of this study was to find out whether ...

Prolonged ethanol exposure causes central nervous system hyperexcitability that involves a loss of GABAergic inhibition. We previously demonstrated that long-term ethanol exposure enhances the internalization of synaptic GABA(A) receptors composed of alpha1beta2/3gamma2 subunits. However, the mechanisms of ethanol-mediated internalization are unknown. This study explored the ...

Histamine is an important wake-promoting neurotransmitter that activates seven-transmembrane G-protein coupled histamine receptors. However, histamine demonstrates target promiscuity, including direct interaction with the structurally unrelated glutamate (NMDA) and GABA(A) receptor channels. Previous work showed that histamine enhances the activity of recombinant ...

The rodent ventrobasal (VB) thalamus contains a relatively uniform population of thalamocortical (TC) neurons that receive glutamatergic input from the vibrissae and the somatosensory cortex, and inhibitory input from the nucleus reticularis thalami (nRT). In this study we describe ?-aminobutyric acid (GABA)(A) receptor-dependent slow outward currents (SOCs) in TC neurons that ...

?-aminobutyric acid type A (GABA(A)) receptors are heteropentameric glycoproteins. Based on consensus sequences, the GABA(A) receptor ?2 subunit contains three potential N-linked glycosylation sites, Asn-32, Asn-104, and Asn-173. Homology modeling indicates that Asn-32 and Asn-104 are located before the ?1 helix ...

We have established that there is a considerable amount of common genetic influence on physiological dependence and associated withdrawal from sedative-hypnotic drugs including alcohol, benzodiazepines, barbiturates and inhalants. We previously mapped two loci responsible for 12 and 9% of the genetic variance in acute alcohol and pentobarbital withdrawal convulsion liability in mice, respectively, ...

1-Bromopropane (1-BP) has been widely used as a cleaning agent and a solvent in industries, but the central neurotoxicity of 1-BP remains to be clarified. In the present study, we investigated the effects of subchronic inhalation exposure to 1-BP vapor on the function of the inhibitory neurotransmitter system mediated by gamma-aminobutyric acid (GABA) in the rat brain. Male Wistar rats were ...

Pairing tactile stimulation of whiskers with a tail shock is known to result in expansion of cortical representation of stimulated vibrissae and in the increase in synaptic GABAergic transmission. However, the impact of such sensory learning in classical conditioning paradigm on GABAergic tonic currents has not been addressed. To this end, we performed whole cell patch-clamp slice recordings of ...

The antinociceptive effects of intrathecally administered 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a potent 5-HT receptor agonist, were studied in three behavioral tests in mice: the tail-flick test and the intrathecal substance P and N-methyl-D-aspartic acid (NMDA) assays. Intrathecal administration of 5-MeO-DMT (4.6-92 nmol/mouse) produced a significant prolongation of the tail-flick ...

Clinical studies have shown that negative symptoms of schizophrenia unresponsive to antipsychotic given alone can improve after augmentation with SSRI antidepressant. Laboratory investigations into the mechanism of this synergism showed that co-administration of SSRI and antipsychotic produces changes in GABA(A) receptor and related systems, which differ from the effects of ...

Adaptive changes in hypothalamic neural circuitry occur in response to alterations in nutritional status. This plasticity at hypothalamic synapses contributes to the control of food intake and body weight. Here we show that genetic ablation of leptin receptor gene expression in pro-opiomelanocortin (POMC) neurons (POMC: Lepr(-/-) GFP) induces alterations at synapses on POMC neurons in the arcuate ...

Robust GABA-mediated inhibitory postsynaptic currents (IPSCs) in neurons of the thalamic relay (TC) nuclei are important in sustaining oscillatory activity within thalamic and thalamocortical circuits. The biophysical properties and pharmacological sensitivities of these IPSCs both depend on the subunit combination of postsynaptic gamma-aminobutyric acid-A (GABA(A)) receptors. ...

Although cholinergic drugs are known to modulate nociception, the role of endogenous acetylcholine in nociceptive processing remains unclear. In the current study, we evaluated the role of cholinergic transmission through spinal ?(2)-subunit-containing nicotinic acetylcholine receptors in the control of nociceptive thresholds. We show that mechanical and thermal nociceptive ...

GABA(A) receptors that contain the alpha5 subunit (alpha5GABA(A)Rs) are highly expressed in the hippocampus, and have been implicated in learning and memory processes. They generate a tonic form of inhibition that regulates neuronal excitability. Recently it was shown that alpha5GABA(A)Rs also contribute to slow phasic inhibition of CA1 pyramidal neurons following local ...

Zolpidem is a short-acting imidazopyridine hypnotic that is an agonist at the gamma-aminobutyric acid A type (GABAA) receptor. It has been suggested that it acts selectively on alpha1 subunit-containing GABAA benzodiazepine (BZ1) receptors presenting (contrary to classic benzodiazepines) low or no affinity for other subtypes. ...

Tonic inhibition has emerged as a key regulator of neuronal excitability in the CNS. Thalamic relay neurons of the dorsal lateral geniculate nucleus (dLGN) exhibit a tonic GABA(A) receptor (GABA(A)R)-mediated conductance that is correlated with delta-subunit expression. Indeed, consistent with the absence of delta-subunit expression, no tonic conductance is found in the ...

During hibernation in the 13-lined ground squirrel, Ictidomys tridecemlineatus, the cerebral cortex is electrically silent, yet the brainstem continues to regulate cardiorespiratory function. Previous work showed that neurons in slices through the medullary ventral respiratory column (VRC) but not the cortex are insensitive to high doses of pentobarbital during hibernation, leading to the ...

Neuroligins (NLGs) are postsynaptic cell adhesion molecules that are thought to function in synaptogenesis. To investigate the role of NLGs on synaptic transmission once the synapse is formed, we transfected neuroligin-2 (NLG-2) in cultured mouse cerebellar granule cells (CGCs), and recorded GABA(A) (gamma-aminobutyric acid) receptor mediated miniature postsynaptic currents ...

Traumatic brain injury (TBI) can result in altered inhibitory neurotransmission, hippocampal dysfunction, and cognitive impairments. GABAergic spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs) and tonic (extrasynaptic) whole cell currents were recorded in control rat hippocampal dentate granule cells (DGCs) and at 90days after controlled cortical impact (CCI). At 34 ...

Cajal-Retzius (CR) cells are principal cells of layer I in the developing neocortex. They are able to generate action potentials, make synaptic contacts in layer I and receive excitatory GABAergic inputs before birth. Although CR cells participate in neuronal network activity in layer I, the properties of their synaptic inputs are not yet characterized. We recorded miniature (mIPSCs) and evoked ...

As three-dimensional (3D) structure of the GABA(A) ?5 was not determined, the crystal structure of 2Vl0E at 3.3?� resolution which is a ligand-gated K(+) channel was used as a template in homology modeling, and the result was used in molecular dynamic simulation for obtaining its conformation in a water sphere. The resulted conformation of the receptor ...

Previous research suggests that intrinsic efficacy of benzodiazepines is an important determinant of their behavioral effects. We evaluated the reinforcing effects of the benzodiazepine partial agonist bretazenil using behavioral economic models referred to as "consumer demand" and "labor supply". Four rhesus monkeys were trained under a progressive-ratio (PR) schedule of i.v. midazolam injection. ...

GABAergic neurons in the reticular thalamic nucleus (RTN) synapse onto thalamocortical neurons in the ventrobasal (VB) thalamus, and this reticulo-thalamocortical pathway is considered an anatomic target for general anesthetic-induced unconsciousness. A mutant mouse was engineered to harbor two amino acid substitutions (S270H, L277A) in the GABA(A) receptor (GABA(A)-R) alpha1 ...

In the present study, we established receptor binding assays to evaluate the water extracts of ten central nervous system (CNS)-active Chinese herbal drugs. These ten herbal drugs are Chaihu (Radix Bupleuri), Chuanxiong (Rhizoma Chuanxiong), Danggui (Radix Angelicae sinensis), Danshen (Radix Salviae miltiorrhizae), Duhuo (Radix Angelicae pubescentis), Hangqin (Radix Scutellariae), Qinjiao (Radix ...

1. The GABA transaminase inhibitor and activator of glutamic acid decarboxylase, valproic acid is being used for the treatment of migraine. Its mechanism of action is unknown. We tested the effects of sodium valproate and GABAA-agonist muscimol on dural plasma protein ([125I]-bovine serum albumin) extravasation evoked by either unilateral trigeminal ganglion stimulation (0.6 ...

Background?-aminobutyric acid type A (GABAA) receptor-mediated inhibition in the central nervous system exists in two forms: phasic (inhibitory postsynaptic currents, IPSCs) and tonic (non-synaptic). Phasic inhibition is further subdivided into fast (GABAA, fast) and slow (GABAA, slow) IPSCs. By virtue of its dendritic location and ...

1-Bromopropane (1-BP), an alternative to ozone-depleting solvents, exhibits neurotoxicity and reproductive toxicity in animals and humans. The present study investigated the effects of exposure to 1-BP on expression of neurotransmitter receptor genes in the rat brain to explore possible biomarkers for central neurotoxicity and find brain regions sensitive for microarray analysis. Thirty-six F344 ...

IPSCs are modulated differentially by furosemide, a subtype-specific GABAA antagonist. Furosemide blocks fast IPSCs and pharmacologically distinct postsynaptic receptors. Key words: hippocampus; GABAA receptors; furosemide; IPSC furosemide is a subtype- specific blocker of GABAA receptors (Tia et al., 1996; Wafford et al., 1996

Effects of the Volatile Anesthetic Enflurane on Spontaneous Discharge Rate and GABAA butyric acid-A (GABAA )-mediated synaptic inhibition. anesthetic enflurane on spontaneous discharge rate and GABAA- There is growing evidence that volatile anesthetics affect mediated inhibition of Purkinje cells

Channel Opening by Anesthetics and GABA Induces Similar Changes in the GABAA Receptor M2 Segment general anesthetics, their molecular basis of action involves interactions with GABAA receptors. Anesthetics produce concentration-dependent effects on GABAA receptors. Low concentrations potentiate

Synchronization of neuronal activity in the visual cortex at low (30-70 Hz) and high gamma band frequencies (> 70 Hz) has been associated with distinct visual processes, but mechanisms underlying high-frequency gamma oscillations remain unknown. In rat visual cortex slices, kainate and carbachol induce high-frequency gamma oscillations (fast-gamma; peak frequency approximately 80 Hz at 37 ...

Positive modulators at the benzodiazepine site of ?2- and ?3-containing GABA(A) receptors are believed to be anxiolytic. Through oocyte voltage clamp studies, we have discovered two series of compounds that are positive modulators at ?2-/?3-containing GABA(A) receptors and that show no functional activity at ?1-containing GABA(A) ...

1. The effects of progesterone, its A-ring-reduced metabolites, allopregnanolone, tetrahydroxydeoxycorticosterone and the synthetic neuroactive steroid alphaxalone were evaluated in a rat model of plasma extravasation within the meninges following unilateral electrical stimulation (ES) of the trigeminal ganglion (0.6 mA, 5 ms, 5 min) or substance P ...

Gamma-aminobutyric acid A (GABA_A) receptors are the principal mediators of synaptic inhibition, and yet when intensely activated, dendritic GABA_A receptors excite rather than inhibit neurons. The membrane depolarization mediated by GABA_A receptors is a result of the differential, activity-dependent collapse of the opposing ...

Gamma-Aminobutyric acid (GABA) is a key inhibitory neurotransmitter in the mammalian central nervous system. Two major categories of receptors, termed GABA(A) and GABA(B) are activated by the amino acid. Whereas GABA(A) receptors appear to be directly inv...

Previous work by the principal investigators and others has shown that the major type of synaptic receptor for the major inhibitory neurotransmitter, the GABA-A receptor/chloride channel complex, is the target of numerous drugs and toxins. The GABA-A rece...

BEHAVIORAL SENSITIZATION TO ETHANOL IS MODULATED BY ENVIRONMENTAL CONDITIONS, BUT IS NOT ASSOCIATED, OR 97239, USA Abstract--Rationale: The ability of ethanol to facilitate GABAA receptor-mediated transmission may result in GABAA receptor alterations during repeated ethanol administration, and lead