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PubMed2004

In vivo modulation of extracellular hippocampal glutamate and GABA levels and limbic seizures by group I and II metabotropic glutamate receptor ligands.

The effects of several metabotropic receptor (mGluR) ligands on baseline hippocampal glutamate and GABA overflow in conscious rats and the modulation of limbic seizure activity by these ligands were investigated. Intrahippocampal mGluR group I agonist perfusion via a microdialysis probe [1 mm (R,S)-3,5-dihydroxyphenylglycine] induced seizures and concomitant augmentations in amino acid dialysate levels. The mGlu1a receptor antagonist LY367385 (1 mm) decreased baseline glutamate but not GABA concentrations, suggesting that mGlu1a receptors, which regulate hippocampal glutamate levels, are tonically activated by endogenous glutamate. This decrease in glutamate may contribute to the reported LY367385-mediated anticonvulsant effect. The mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (50 mg/kg) also clearly abolished pilocarpine-induced seizures. Agonist-mediated actions at mGlu2/3 receptors by LY379268 (100 microm, 10 mg/kg intraperitoneally) decreased basal hippocampal GABA but not glutamate levels. This may partly explain the increased excitation following systemic LY379268 administration and the lack of complete anticonvulsant protection within our epilepsy model with the mGlu2/3 receptor agonist. Group II selective mGluR receptor blockade with LY341495 (1-10 microm) did not alter the rats' behaviour or hippocampal amino acid levels. These data provide a neurochemical basis for the full anticonvulsant effects of mGlu1a and mGlu5 antagonists and the partial effects observed with mGlu2/3 agonists in vivo.

Amino Acids↗
PubMed2006

Effects of some neurosteroids injected into some brain areas of WAG/Rij rats, an animal model of generalized absence epilepsy.

Neurosteroids are synthesized in the brain and have been demonstrated to modulate various cerebral functions. Allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one), a naturally occurring neurosteroid, and ganaxolone (3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one), a synthetic derivative, are two neurosteroids acting as positive allosteric modulators of the GABA(A) receptor complex acting on a specific steroid recognition site. Both agents antagonize generalized tonic-clonic seizures in various animal models of epilepsy. Pregnenolone sulphate (3beta-hydroxy-5alpha-pregnen-20-one 3-sulphate; PS) is a negative allosteric modulator of GABA(A) receptors and a positive modulator of the NMDA receptors. We have evaluated the effects of such compounds in a genetic animal model of absence epilepsy, the WAG/Rij rat. Animals were chronically implanted with five frontoparietal cortical electrodes for electrocorticogram (EEG) recordings and bilateral guide cannulae into specific brain areas of the cortico-thalamic circuit in order to evaluate the effects of these compounds on the number and duration of epileptic spike-wave discharges (SWDs). The focal and bilateral microinjection of the two GABA(A) positive modulators into some thalamic nuclei (nucleus ventralis posteromedialis, nucleus reticularis thalami, nucleus ventralis posterolateralis was usually able to significantly worsen the occurrence of SWDs in WAG/Rij rats. Whereas both compounds were able to reduce the number and duration of SWDs when microinjected into the peri-oral region of the primary somatosensory cortex. The effects of PS were more complex depending on both the dose and the site of administration, generally, at low doses in thalamic nuclei and cortex, PS induced an increase of absence activity and a reduction at higher doses. These findings suggest that neurosteroids might play a role in absence epilepsies and that it might depend on the involvement of specific neuronal areas.

Animals↗
PubMed1990

Synaptic interactions between GABAergic neurons and trigeminothalamic cells in the rat trigeminal nucleus caudalis.

Synaptic interactions between GABAergic neurons and thalamic projecting cells within the trigeminal nucleus caudalis were examined using a combined method of GABA immunohistochemistry and retrograde WGA-HRP labeling of the trigeminothalamic pathway. Results showed that GABA-positive neurons and projecting cells were separate but closely intermingled within the spinal trigeminal nucleus. GABAergic axon terminals formed symmetric synaptic connections with the cell bodies and dendrites of trigeminothalamic neurons. In turn, some WGA-HRP filled axon terminals, presumed to originate from axon collaterals of the projecting neurons, formed synaptic connections with GABA containing neurons. The results suggest that in the spinal trigeminal nucleus there is a reciprocal modulation between GABA neurons and trigeminothalamic cells.

Animals↗
PubMed1995

Direct and indirect effects of muscimol on medial vestibular nucleus neurones in guinea-pig brainstem slices.

Inhibitory amino acids are considered as major transmitters in the vestibular system. Using intracellular recordings in slices, we applied gamma-aminobutyric acid (GABA) and muscimol (a specific agonist of the GABAA receptor) to the two main types of medial vestibular nucleus neurones (A and B MVNn). In either a high Mg2+/low Ca2+ solution, or a solution containing tetrodotoxin, all MVNn were hyperpolarized by GABA and muscimol. This indicates that both types of MVNn are endowed with postsynaptic, hyperpolarising GABAA receptors. In a normal medium, about half of A and B MVNn were, in contrast, depolarised by GABA and muscimol, whereas the remaining cells were hyperpolarised. These results could be due to a modulation by GABA and muscimol of a tonic GABA release in the slice. Such a release was, indeed, suggested by results showing the depolarising effect of either tetrodotoxin (TTX) or bicuculline, when applied alone. The cells that were depolarised by GABA or muscimol in control conditions were always hyperpolarised in the presence of TTX. Our data therefore suggest that GABA acting at GABAA receptors in the medial vestibular nucleus can play a role either through a postsynaptic hyperpolarising action or indirectly by inhibiting a tonic GABA release, probably resulting from the spontaneous activity of local inhibitory interneurones. A GABAergic regulation of these interneurones could be important in processes of vestibular habituation and/or adaptation.

Animals↗
PubMed2004

Response to flumazenil in the late luteal phase and follicular phase of the menstrual cycle in healthy control females.

RATIONALE: Animal studies of short-term progesterone administration and withdrawal model the natural increase and abrupt decrease in progesterone levels which occur in the late luteal phase (LP) of the human menstrual cycle (MC). Previously, studies in animals have shown that abrupt cessation of chronic or short-term progesterone administration results in pharmacological changes at the GABAA receptor, resulting in altered sensitivity to GABAA receptor neuromodulators such as benzodiazepines and flumazenil, a GABAA receptor antagonist. OBJECTIVES: This study's goal was to compare the response to flumazenil in the follicular phase (FP) and late LP in female healthy controls (HCs). We postulated that HC females would exhibit a greater psychological and somatic response to flumazenil in the late LP, a period of progesterone withdrawal, compared to the FP. METHODS: Twelve healthy females, without history of psychiatric disorder, were randomized to receive two injections of a 2 mg bolus injection of flumazenil (one in the late LP and one in the FP) and two injections of placebo (one in the late LP and one in the FP). Following injection, subjects were asked to rate the occurrence and intensity of panic symptoms on the panic symptom scale (PSS). RESULTS: A main treatment effect was detected for the PSS score response after flumazenil injection (P=0.008). However, there was no significant treatment-by-phase interaction observed (P=0.449). CONCLUSIONS: These findings indicate that MC phase did not affect the response to flumazenil in HC females. This result is contrary to our hypothesis of altered sensitivity to flumazenil in the late LP.

Adult↗
PubMed2005

Effect of diazepam on anxiety, sexual motivation, and blood testosterone in anxious male mice.

The effects of diazepam on anxious behavior, sexual motivation, and blood level of testosterone in the presence of a female were studied in male mice with elevated anxiety. Diazepam produced an anxiolytic effect in novel environment, but was ineffective during social contacts. The drug potentiated the primary sexual interest, but failed to correct exhaustion of sexual motivation. The drug produced no effect on blood testosterone.

Animals↗
PubMed1988

A comparison of the effects of midazolam and pentobarbital on the dose-response of GABA-gated Cl- influx in rat brain microsacs.

gamma-Aminobutyric acid (GABA)-gated Cl- influx was studied in a rat brain 'microsac' preparation. Midazolam (a benzodiazepine), at 0.1-10 microM, increased GABA potency (maximum 2-fold) without affecting its efficacy or exerting GABA-mimetic effect. Pentobarbital (10-500 microM) increased GABA potency (maximum 12-fold) and efficacy (maximum 40%). Pentobarbital exhibited GABA-mimetic effect at concentrations above 200 microM. The differential effects of midazolam and pentobarbital in modulating GABA-mediated responses may account for some of the differences between these two classes of drugs.

Animals↗
PubMed1996

Diazepam physical dependence and withdrawal in rats is associated with alteration in GABAA receptor function.

Alteration in the function of the GABAA receptor complex and its relation to changes in withdrawal signs in diazepam (DZP)-dependent rats were studied. Physical dependence on DZP was induced in male F344 rats by using the drug-admixed food method. After cessation of treatment, withdrawal signs such as spontaneous convulsions were observed and withdrawal scores were maximal at 39 approximately 45 hr after the DZP withdrawal. Furthermore, these withdrawal signs almost disappeared by 159 approximately 168 hr after the DZP withdrawal. GABA-stimulated 36Cl- influx into cerebral cortical membrane vesicles was significantly decreased in rats 0 hr after DZP withdrawal and significantly increased in rats 42 hr after DZP withdrawal compared with control rats Flunitrazepam (FZ)-induced potentiation and an antagonistic effect of Ro 15-1788 on GABA-stimulated 36Cl- influx were observed in control rats. No FZ-potentiated GABA-stimulated 36Cl- influx was observed in rats 0 hr after DZP withdrawal: however, such an effect of FZ was recognized in rats 42 hr and 162 hr after DZP withdrawal. No antagonistic effect of Ro15-1788 on the FZ-induced stimulation was recognized in rats 0 hr and 42 hr after DZP withdrawal but was recognized at 162 hr after DZP treatment, although it was not significant. In a [3H]FZ assay of binding to benzodiazepine (BZ) receptors. Bmax values were significantly decreased in rats 0 hr after DZP withdrawal, but increased at 42 hr after DZP withdrawal, compared with control rats Bmax had almost returned to the control level at 162 hr after DZP treatment rats. In conclusion, these results indicate that functional changes in the GABAA/BZ receptor/CI- channel complex, i.e. increased sensitivity in GABAA receptors and impairment in the functional coupling between BZ receptors and GABAA receptors, may possibly be involved in the biochemical mechanism of the severe withdrawal symptoms appearing after chronic treatment with DZP.

Animals↗
PubMed1993

Stable expression of cloned rat GABAA receptor subunits in a human kidney cell line.

A predominant form of the GABAA/benzodiazepine receptor-Cl- channel complex is believed to consist of three different 48-55 kDa subunits (alpha, beta, gamma) with unknown stoichiometry. Plasmids containing the rat GABAA receptor cDNAs coding for alpha 1, beta 2, and gamma 2 were co-transfected, along with a plasmid encoding G418 resistance, into human embryonic kidney cells previously transformed with Adenovirus 5 (HEK-293) [J. Gen. Virol., 36 (1977) 59-72]. Four percent of the G418 resistant colonies were found to express mRNA for all three of the GABAA subunits constitutively. A single cell clone derived from one of the alpha 1 beta 2 gamma 2 expressors has demonstrated stable electrophysiological characteristics over 25 passages. The GABA-activated Cl- current in this cell line is blocked by picrotoxin and bicuculline, and is modulated by a variety of agonist and inverse agonist ligands including diazepam, Ro 154513, zolpidem, and beta-CCE. The cell line has been used successfully over a 12-month period as a screen for novel drugs modulating GABA-mediated polarization of neuronal cells.

Autoradiography↗
PubMed2005

Biflavones from Rhus species with affinity for the GABA(A)/benzodiazepine receptor.

In South Africa Rhus pyroides is traditionally used in the treatment of epilepsy. In the present study two biflavonoids with activity in the (3)H-Ro 15-1788 (flumazenil) binding assay were isolated by high pressure liquid chromatography (HPLC) fractionation of the ethanol extract of the leaves from Rhus pyroides. The structures of the two biflavonoids were elucidated by nuclear magnetic resonance spectroscopy (NMR) to be agathisflavone and amentoflavone. Agathisflavone and amentoflavone competitively inhibited the binding of (3)H-Ro 15-1788 with a K(i) of 28 and 37 nM, respectively. Extracts of Rhus dentata and Rhus pentheri were not as active as the extract from Rhus pyroides; both were found to contain apigenin and agathisflavone. The monomer apigenin, agathisflavone and amentoflavone were fitted into a pharmacophore model for ligands binding to the GABA(A) receptor benzodiazepine site. This reflected the affinities of the compounds in the [(3)H]-flumazenil binding assay.

Animals↗
PubMed1998

[3H]t-butylbicycloorthobenzoate binding to recombinant alpha1beta2gamma2s GABA(A) receptor.

The interaction of several selected compounds with the binding of the cage convulsant t-[3H]butylbicycloorthobenzoate ([3H]TBOB) to membranes isolated from human embryonic kidney (HEK) 293 cells stably transfected with alpha1beta2gamma2s subtype of GABA(A) receptors was studied. Scatchard analysis of binding data revealed the existence of a single type of binding site for [3H]TBOB with a Kd of 47.06+/-4.06 nM and a Bmax value of 6.72+/-0.52 pmol/mg protein. GABA, thiopental, TBOB, picrotoxin and the neurosteroid dehydroepiandrosterone sulfate displaced concentration-dependently the binding of [3H]TBOB to this recombinant receptor. Dehydroepiandrosterone sulfate reversed the 5 microM GABA-induced inhibition of specific [3H]TBOB binding. It is concluded that membranes isolated from HEK 293 cells stably transfected with alpha1beta2gamma2s subunits exhibit specific high-affinity [3H]TBOB binding. The potency of drugs to inhibit [3H]TBOB binding mainly corresponded to that observed for the inhibition of the binding of cage convulsants to the native receptors or to transiently transfected HEK 293 cells.

Binding, Competitive↗
PubMed1997

The interaction of general anaesthetics with recombinant GABAA and glycine receptors expressed in Xenopus laevis oocytes: a comparative study.

1. The effects of five structurally dissimilar general anaesthetics were examined in voltage-clamp recordings of agonist-evoked currents mediated by recombinant gamma-aminobutyric acid (GABA)A receptors composed of human alpha 1 beta 1 and gamma 2L subunits expressed in Xenopus laevis oocytes. A quantitative comparison of the effects of these agents was made upon recombinant glycine receptors expressed as a homo-oligomer of human alpha 1 subunits, or as a hetero-oligomer of human alpha 1 and rat beta subunits. 2. Complementary RNA-injected oocytes expressing GABAA receptors responded to bath applied GABA with an EC50 of 158 +/- 34 microM. Oocytes expressing alpha 1 and alpha 1 beta glycine receptors subsequent to cDNA injection displayed EC50 values of 76 +/- 2 microM and 66 +/- 2 microM, respectively, in response to bath applied glycine. 3. Picrotoxin antagonized responses mediated by homo-oligomeric alpha 1 glycine receptors with an IC50 of 4.2 +/- 0.8 microM. Hetero-oligomeric alpha 1 beta glycine receptors were at least 100-fold less sensitive to blockade by picrotoxin. 4. With the appropriate agonist EC10, propofol enhanced GABA and glycine-evoked currents to approximately the maximal response produced by a saturating concentration of either agonist (i.e. Imax). The calculated EC50 values were 2.3 +/- 0.2 microM, 16 +/- 3 microM and 27 +/- 2 microM, for GABAA alpha 1 beta 1 gamma 2L, glycine alpha 1 and alpha 1 beta receptors, respectively. At relatively high concentrations, propofol was observed to activate directly both GABAA and glycine receptors. 5. Pentobarbitone potentiated GABA-evoked currents to 117 +/- 8.5% of Imax with an EC50 of 65 +/- 3 microM. The barbiturate also produced a substantial enhancement of the glycine-evoked currents, Imax and EC50 values being 71 +/- 2% and 845 +/- 66 microM and 51 +/- 10% and 757 +/- 30 microM for homomeric alpha 1 and heteromeric alpha 1 beta glycine receptors respectively. At high concentrations, pentobarbitone directly activated GABAA, but not glycine, receptors. 6. The potentiation by propofol or pentobarbitone of currents mediated by alpha 1 homo-oligomeric glycine receptors was in both cases associated with a parallel sinistral shift of the glycine concentration-effect curve. The effects of binary combinations of pentobarbitone and propofol at maximally effective concentrations were mutually occlusive suggesting a common site, or mechanism, of action. 7. GABA-evoked currents were maximally potentiated by etomidate to 79 +/- 2% of Imax (EC50 of 8.1 +/- 0.9 microM). By contrast, glycine-induced currents mediated by alpha 1 and alpha 1 beta glycine receptor isoforms were enhanced only to 29 +/- 4% and 28 +/- 3% of Imax. Limited solubility precluded the calculation of EC50 values for the effect of etomidate at glycine receptors. None of the receptor isoforms examined were directly activated by etomidate. 8. The neurosteroid 5 alpha-pregnan-3 alpha-ol-20-one potentiated GABA-evoked currents to 69 +/- 4% of Imax, with an EC50 value of 89 +/- 6 nM. In contrast, both alpha 1 homo-oligomeric and alpha 1 beta hetero-oligomeric glycine receptors were insensitive to the action of this steroid. A direct agonist action of the steroid was discernible at GABAA, but not glycine, receptors. 9. Trichloroethanol, the active metabolite of the general anaesthetic chloral hydrate, enhanced glycine-evoked currents to 77 +/- 10% and 94 +/- 4% of Imax on alpha 1 and alpha 1 beta glycine receptors, with EC50 values of 3.5 +/- 0.1 mM and 5.9 +/- 0.3 mM respectively. On GABAA receptors, trichloroethanol had a lower maximum enhancement (52 +/- 5% of Imax), but a slightly higher potency (EC50 1.0 +/- 0.1 mM). Trichloroethanol activated neither GABAA, nor glycine, receptors. 10. The data demonstrate a variety of intravenous general anaesthetic agents, at clinically relevant concentrations, to augment preferentially GABA-evoked currents mediated by the alpha1beta1upsilon2L receptor subunit combination as compared to their effects on both alpha1 and alpha1beta glycine receptors. However, the presence on glycine receptors of lower affinity modulatory binding sites for pentobarbitone, propofol and trichloroethanol may aid in the identification of the molecular determinants of the CNS actions of these anaesthetics.

Anesthetics, Intravenous↗
PubMed2003

Actions and interactions of extracellular potassium and kainate on expression of 13 gamma-aminobutyric acid type A receptor subunits in cultured mouse cerebellar granule neurons.

Cerebellar granule neurons in culture are a popular model for studying neuronal signaling and development. Depolarizing concentrations of K(+) are routinely used to enhance cell survival, and kainate is sometimes added to eliminate GABAergic neurons. We have investigated the effect of these measures on expression of mRNA for gamma-aminobutyric acid type A (GABA(A)) receptor alpha1-6, beta1-3, gamma1-3, and delta subunits in cultures of mouse cerebellar granule neurons grown for 7 or 12 days in vitro (DIV) using semiquantitative reverse transcription-PCR. We detected mRNA for the alpha1, alpha2, alpha5, alpha6, beta2, beta3, gamma2, and delta subunits in all the cell cultures, but the expression levels of the alpha5-, alpha6-, and beta2-subunit mRNAs were significantly dependent on the composition of the culture medium. Both an increase of the extracellular K(+) concentration from 5 to 25 mm and the addition of 50 microm kainate immediately depolarized the neurons but prolonged exposure (7-8 DIV)-induced compensatory hyperpolarization. 25 mm K(+) caused a shift from alpha6 to alpha5 expression measured at 7 and 12 DIV, which was mimicked by kainate in 12 DIV cultures. The expression of beta2 was decreased by 25 mm K(+) in 7 DIV cultures and by kainate in 12 DIV cultures. The effects on beta2 expression could not be ascribed to depolarization. Alterations of alpha6 mRNA expression were reflected in altered sensitivity to GABA and furosemide of the resulting receptors. Our study has shown that a depolarizing K(+) concentration as well as kainate in the culture medium significantly disturbs maturation of GABA(A) receptor subunit expression.

Animals↗
PubMed1997

Computer model of clonazepam's effect in thalamic slice.

In the thalamus, paradoxical changes in response to augmentation of inhibition can occur as a result of either cellular or network effects. Clonazepam, a GABA(A) agonist, produces a paradoxical reduction in evoked thalamocortical neuron inhibitory postsynaptic potential (IPSP) in thalamic slice. This has been hypothesized to be a result of augmentation in inhibitory to inhibitory connections. In a computer model, orthodromic simulation produced an increase in initial IPSP, a result contrary to that found experimentally. This failure was traced to the inability of orthodromic activation to produce fast enough recurrent inhibition to alter initial reticularis neuron firing. Simulated antidromic stimulation was able to reduce this initial spike train and reproduced the experimental finding.

Animals↗
PubMed2000

Similarity and robustness of PET and SPECT binding parameters for benzodiazepine receptors.

The single photon emission computed tomography (SPECT) radiotracer [123I]iomazenil is used to assess benzodiazepine receptor binding parameters. These measurements are relative indices of benzodiazepine receptor concentration (B'max). To evaluate the ability of such indices in accurately accessing the B'max the authors compared them with absolute values of B'max, measured using positron emission tomography (PET). The authors performed SPECT, PET, and magnetic resonance imaging (MRI) studies on a group composed of seven subjects. For SPECT studies, the authors administered a single injection of [123I]iomazenil and estimated the total and specific distribution volumes (DV(T SPECT), DV(S SPECT)) and the binding potential (BP) using unconstrained (BP(SPECT)) and constrained (BP(C SPECT)) compartmental models. For PET studies, the authors used a multiinjection approach with [11C]flumazenil and unlabeled flumazenil to estimate absolute values of receptor concentration, B'max, and some other binding parameters. The authors studied the correlation of different binding parameters with B'max. To study the robustness of the binding parameter measurements at the pixel level, the authors applied a wavelet-based filter to improve signal-to-noise ratio of time-concentration curves, and the calculated kinetic parameters were used to build up parametric images. For PET data, the B'max and the DV(PET) were highly correlated (r = 0.988). This confirms that it is possible to use the DV(PET) to access benzodiazepine receptor density. For SPECT data, the correlation between DV(SPECT) estimated using a two- and three-compartment model was also high (r = 0.999). The DV(T SPECT) and BP(C SPECT) parameters estimated with a constrained three-compartment model or the DV(T''SPECT) parameter estimated with a two-compartment model were also highly correlated to the B'max parameter estimated with PET. Finally, the robustness of the binding parameters allowed the authors to build pixel-by-pixel parametric images using SPECT data.

Adult↗
PubMed1996

Effect of diazepam on plasma gamma-aminobutyric acid in sons of alcoholic fathers.

A subgroup of abstinent alcoholics, display low levels of plasma gamma-aminobutyric acid (GABA). Two previous studies of plasma GABA in sons of alcoholic fathers (SOAs) have yielded conflicting results. The aim of the current study was to measure plasma GABA both at baseline and after challenge with diazepam, a GABAA receptor agonist, in a group of SOAs already shown to display decreased eye movement, memory, and sedative effects of diazepam. Twenty-seven SOAs and 23 male control subjects received four logarithmically increasing doses of diazepam or placebo in randomized order on 2 days at least 1 week apart. Plasma GABA was measured at baseline and after the last dose. There were no significant differences between SOAs and controls in baseline plasma GABA levels. In the whole sample, there were significant correlations between baseline plasma GABA and both high novelty-seeking and low-harm avoidance scores on the Tridimensional Personality Questionnaire. Both SOAs and controls displayed decreases in plasma GABA over time on both testing days, but there was no effect of diazepam on plasma GABA and no significant difference between groups in plasma GABA response to diazepam. These results suggest that neither low plasma GABA at baseline nor altered plasma GABA response to diazepam is associated with increased genetic risk for alcoholism.

Adolescent↗