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PubMed2000

Enhanced GABA(A) inhibition enhances synchrony coding in human perception.

The benzodiazepine, lorazepam enhances the efficiency of local, inhibitory GABA(A) synapses in the cortex, which stabilize postsynaptic, excitatory activity by synchronizing their own discharges at around 40 Hz. Treatment with lorazepam has also been shown to adversely influence detection performance in perceptual tasks, suggesting a role for GABA(A)-mediated synchronization during visuo-perceptual organization. Consistent with these findings we report that reaction times to target stimuli were slower following lorazepam treatment. However, when targets followed presentation of a synchronized prime, presented within a flickering 40-Hz display matrix, the effects of priming were amplified relative to baseline and control conditions. We conclude that enhanced GABA(A)-induced inhibition enhances stimulus-evoked synchronization with differential effects upon mechanisms of perceptual segmentation and grouping.

Adult↗
PubMed1999

Altered in vitro and in vivo flumazenil binding in human epileptogenic neocortex.

In vitro and in vivo parameters of flumazenil (FMZ) binding were measured in spiking and nonspiking neocortex identified by intraoperative electrocorticography in epileptic patients who underwent cortical resection for seizure control. In vitro measures of receptor affinity (K(D)), number (Bmax) and laminar distribution for [3H]-FMZ binding in the epileptic focus (n = 38) were compared to nonspiking cortex from a subgroup of the patients (n = 12) and to tissue obtained from trauma patients (n = 5). The in vitro binding parameters were compared to in vivo [11C]-FMZ binding measured with positron emission tomography (PET) (n = 19). The Bmax was higher in the 38 spiking tissues as compared to the 12 nonspiking tissues (P = .012). Paired comparison of spiking versus nonspiking binding in the 12 patients from whom nonspiking tissue was available showed increases in both K(D) (P = .037) and Bmax (P = .0047) in spiking cortex. A positive correlation was found between K(D) and Bmax values for 38 patients (r = 0.55, P < .0001), the magnitude of the K(D) increase being twice that of the Bmax increase. In addition, there was a significant correlation between the asymmetry indices of the in vivo FMZ binding on PET and in vitro K(D) of spiking cortex (n = 19, r = 0.52, P = .02). The laminar distribution of [3H]-FMZ showed increased FMZ binding in cortical layers V-VI in spiking cortex compared to nonspiking and control cortex. The increased receptor number in spiking cortical layers V-VI may be a compensatory mechanism to decreased GABAergic input. The increased Bmax in spiking cortex was accompanied by a larger decrease in the affinity of FMZ for the receptor suggesting that decreased FMZ binding in the epileptic focus measured with PET is due to a decrease in the affinity of the tracer for the receptor.

Adolescent↗
PubMed1999

Blood-brain barrier transport and protein binding of flumazenil and iomazenil in the rat: implications for neuroreceptor studies.

The calculated fraction of receptor ligands available for blood-brain barrier passage in vivo (f(avail)) may differ from in vitro (f(eq)) measurements. This study evaluates the protein-ligand interaction for iomazenil and flumazenil in rats by comparing f(eq) and f(avail). Repeated measurements of blood-brain barrier permeability for two benzodiazepine antagonists were performed in 44 rats by the double-indicator technique. Cerebral blood flow was measured by intracarotid Xe-injection. The apparent permeability-surface product (PSapp) was measured while CBF or bolus composition was changed. Comparison of PSapp obtained in the absence and presence of 5% albumin in the injectate yielded f(avail), whereas f(eq) was measured by equilibrium dialysis. Iomazenil and flumazenil f(avail) was 62% and 82%, respectively, whereas f(eq) was significantly lower, 42% and 61%. The PSapp for iomazenil and flumazenil increased significantly by 89% and 161% after relative CBF increases of 259% and 201%, respectively. The results demonstrate that application of f(eq) in neuroreceptor studies underestimates the plasma input function to the brain. Model simulations render possible that the differences between f(avail) and f(eq) as well as the effect of CBF on PSapp can be caused by capillary heterogeneity.

Animals↗
PubMed2000

Behavioural effects of a benzodiazepine receptor partial agonist, Ro 19-8022, in the social conflict test in mice.

The study examined the effects of the benzodiazepine receptor partial agonist, Ro 19-8022, on anxiety-like, aggressive, social and locomotor behaviours in timid ('anxious') and aggressive mice in the social conflict test. To test the hypothesis that Ro 19-8022 acts as a partial agonist in this model, i.e. it reduces anxiety-like and aggressive behaviours without affecting motor coordination, its effects were compared to those of the full agonist, nitrazepam. Both Ro 19-8022 and nitrazepam decreased anxiety-like behaviour in timid mice and aggressive behaviour in aggressive mice. The effect of the full agonist, nitrazepam, was dose-dependent while the effect of the partial agonist, Ro 19-8022, was lower in magnitude and reflected its partial agonistic properties. Both drugs stimulated social behaviour in both groups of mice, presumably due to disinhibition of anxiety or aggression. The marked difference was in their effects on motor coordination, as nitrazepam, but not Ro 19-8022, produced motor impairment at higher doses. Thus, Ro 19-8022 produces anxiolytic-like and potent anti-aggressive effects without causing muscle relaxation or ataxia in the present model. Our data confirm that the main behavioural differences between partial and full benzodiazepine receptor agonists are in their side-effect profiles.

Aggression↗
PubMed1995

Pharmacology of flumazenil.

Flumazenil, an imidazobenzodiazepine, is the first benzodiazepine antagonist available for clinical use. It is a specific competitive antagonist at benzodiazepine receptors, which are associated with receptors for gamma-aminobutyric acid, the most important inhibitory neurotransmitter in the central nervous system. Administered orally, it has a low bioavailability and the preferred route is intravenous. Its usual clinical role is to reverse the effects of benzodiazepine sedation; however, administered before, or with, other benzodiazepines, it modifies their effects, the extent of such modification depending on the dose, duration of effect and relative receptor affinity of the agonist. Flumazenil also reverses adverse physiological effects of benzodiazepines. Its indications include reversal of benzodiazepine-induced sedation, termination of benzodiazepine-induced anaesthesia, return of spontaneous respiration and consciousness in intensive care patients and the treatment of paradoxical reactions to benzodiazepines. Other potential indications include its use in hepatic encephalopathy, alcohol intoxication and coma; however, these claims still require substantiation. Following sedation reversed with flumazenil, minimal residual effects of the agonist can sometimes be detected using psychomotor tests and are due to the relatively short half-life of flumazenil, but are of no clinical consequence. There is concern that flumazenil could precipitate an acute withdrawal syndrome following long-term benzodiazepine administration; however, the available evidence suggests otherwise and that it could be useful in the treatment of benzodiazepine tolerance. The existence of flumazenil is important, with implications for future research and the development of minimally invasive therapy and day-case surgery. With increasing pressures on non-anaesthetically trained practitioners to perform sedation, flumazenil has important implications for safety.

Administration, Oral↗
PubMed1997

Frequency-dependent actions of benzodiazepines on GABAA receptors in cultured murine cerebellar granule cells.

1. Miniature IPSCs recorded from cultured murine cerebellar granule cells increased in half-width and amplitude following application of the benzodiazepine (BDZ) Flunitrazepam (Flu, 1 microM). The increase in the half-width was much greater than that in the amplitude. 2. Five-millisecond applications of 1 mM GABA to nucleated outside-out patches elicited rapidly rising biexponentially decaying responses that resembled IPSCs. Flu had no effect on the amplitude of such responses, but consistently slowed their deactivation by approximately 50%. This effect was reversed by Flu washout or application of the BDZ antagonist Ro15-1788. The partial inverse agonist. Ro15-4513 speeded deactivation and depressed peak current amplitude by 23 +/- 12%. 3. The EC50 for GABA was between 45 and 50 microM. At submaximally effective agonist concentrations, Flu increased response amplitude and slowed response deactivation. Both effects were present in all cells taken from young cultures (4-7 days in vitro) but the latter was absent in 55% of the neurones obtained from older cultures (14-27 days in vitro). 4. With 120 ms applications of 20 microM GABA, responses activated monoexponentially (time constant, 39.8 +/- 2.8 ms) and deactivated biexponentially (time constants, 40.4 +/- 2.1 and 251 +/- 15 ms). Application of Flu slowed both activation and deactivation. The latter effect arose from an increased contribution of the slower component of decay. 5. Desensitization of responses to 1 mM GABA was biexponential, with time constants of 47 +/- 11 and 479 +/- 49 ms. Flu speeded desensitization by decreasing both fast and slow time constants. GABAA receptor desensitization consistently slowed subsequent deactivation. No significant relationship between the level of desensitization and the amount of slowing of deactivation produced by Flu was found. 6. Responses to paired 5 ms applications of 1 mM GABA indicated that the slowing of deactivation and the speeding of desensitization produced by Flu combine to generate a marked frequency dependence in the actions of this BDZ. Thus when compared with control responses, GABA-induced charge transfer was only enhanced by Flu during the first of two successive agonist applications.

Animals↗
PubMed1998

The dynamics of synchronized neurotransmitter release determined from compound spontaneous IPSCs in rat dentate granule neurones in vitro.

1. The properties of GABAA receptor-mediated spontaneous IPSCs generated in hippocampal dentate granule neurones were analysed using whole-cell voltage-clamp techniques in order to explore the functional consequences of the low number (6-12) and close proximity of synaptic contacts made by single GABAergic interneurones. 2. Spontaneous IPSCs (sIPSCs) occurred with a frequency of 14.0 +/- 9.1 Hz (n = 31) and revealed a multi-modal positively skewed amplitude distribution (39.0 +/- 19.8 pA, median values). 3. The variance of 10-90% rise times and decay kinetics between IPSCs decreased with increasing peak amplitude. Larger amplitude events had significantly faster rise times, consistent with their site of generation being proximal to the soma. The decay kinetics of sIPSCs did not significantly change with amplitude. 4. Large amplitude sIPSCs occurred singularly or in discrete bursts, repeated regularly at low frequency. The rising phase of such sIPSCs were multi-phasic, composed of clear step-like inflections that were not a product of noise. The variability between the rising phase of individual sIPSCs was quantified by calculating their standard deviation, which produced fast rising (0.22 +/- 0.05 ms time to peak, n = 16) functions with half-widths of 0.38 +/- 0.10 ms, which declined to plateaux. 5. Computer simulations demonstrated that IPSCs with properties similar to those recorded experimentally could be generated by the linear summation of groups of temporally dispersed component events. Standard deviation functions of the rising phase of simulated IPSCs accurately described distributions of the temporal dispersion of unitary components. 6. The GABA uptake inhibitor (R)-N[4,4-bis(3-methyl-2-thienyl)but-3-enl-yl] nipecotic acid (tiagabine) (10 microM, n = 12) significantly prolonged the decay of mIPSCs (6.5 +/- 0.8 to 8.7 +/- 1.0 ms, median values) and sIPSCs (6.2 +/- 0.4 to 7.3 +/- 1.2 ms, median values), but failed to alter the frequency of occurrence, 10-90% rise times or peak amplitude of events. The application of flurazepam (30 microM, n = 7; 50 microM, n = 4) prolonged the decay of sIPSCs regardless of their amplitude. 7. These data indicate that sIPSCs are formed by the summation of unitary components that occur asynchronously and that GABA released from multiple sites has independent post-synaptic actions.

Animals↗
PubMedDate not supplied

Pregnenolone sulphate and Zn2+ inhibit recombinant rat GABA(A) receptor through different channel property.

AIMS: We compared the antagonistic effects of state-dependent gamma-aminobutyric acid A (GABA(A)) receptor blockers picrotoxin, Zn(2+) and pregnenolone sulphate (PS) on GABA- and pentobarbital-activated currents in recombinant rat GABA(A) receptors in Xenopus oocytes. METHODS: Experiments were performed with wild type rat alpha1 beta2 gamma2L and alpha1beta2 receptors, mutants alpha1V256S beta2 gamma2L and alpha1beta2A252Sgamma2L receptors by the two-electrode voltage-clamp technique. RESULTS: In contrast to respective 3840- and 56-fold increases in Zn(2+) potencies to inhibit GABA- and pentobarbital-activated currents in the alpha1beta2 receptor, the corresponding potencies of PS remained unchanged in comparison with the alpha1 beta2 gamma2L receptor. A homologous mutation of the residue at 2' position closest to the cytoplasmic end of the M(2) helix to serine on both alpha1 and beta2 subunit, alpha1V256S and beta2A252S, abolished the inhibition of GABA(A) receptor by PS. In comparison with the wild type alpha1beta2gamma2L receptor, mutants alpha1V256S beta2 gamma2L and alpha1beta2 A252S gamma2L receptors did not affect the Zn(2+) inhibition. Furthermore, a significant increase in GABA potency was observed in the mutant alpha1V256S beta2 gamma2L receptor (P < 0.05), but not the mutant alpha1beta2 A252S gamma2L receptor compared with the wild type receptor. CONCLUSIONS: Pregnenolone sulphate was a gamma2-subunit independent inhibitor in the GABA(A) receptor, whereas the Zn(2+) antagonism was profoundly influenced by the gamma2-subunit. It is likely that the 2' residue closest to the N-terminus of the protein at M(2) helix on both alpha1 and beta2 subunit are critical to the inhibitory actions of PS and the function of Cl(-) channels. These results are consistent with the hypothesis that PS behaves as a Cl(-) channel blocker that does not share with Zn(2+), the coincident channel property in the GABA(A) receptors.

Animals↗
PubMed2002

Short-interval paired-pulse inhibition and facilitation of human motor cortex: the dimension of stimulus intensity.

Paired transcranial magnetic stimulation has greatly advanced our understanding of the mechanisms which control excitability in human motor cortex. While it is clear that paired-pulse excitability depends on the exact interstimulus interval (ISI) between the first (S1) and second stimulus (S2), relatively little is known about the effects of the intensities of S1 and S2, and the effects of manipulating neurotransmission through the GABA(A) receptor. When recording the motor evoked potential (MEP) from the resting abductor digiti minimi (ADM) muscle, using a fixed ISI of 1.5 ms, and expressing the interaction between S1 and S2 as MEP(S1+S2)/(MEP(S1) + MEP(S2)), then a systematic variation of the intensities of S1 and S2 revealed short-interval intracortical facilitation (SICF) if S1 and S2 were approximately equal to MEP threshold (RMT), or if S1 > RMT and S2 < RMT. In contrast, short-interval intracortical inhibition (SICI) occurred if S1 < RMT and S2 > RMT. Contraction of the ADM left SICI unchanged but reduced SICF. The GABA(A) receptor agonist diazepam increased SICI and reduced SICF in the resting ADM while diazepam had no effect during ADM contraction. Surface EMG and single motor unit recordings revealed that during ADM contraction SICI onset was at the I3-wave latency of S2, whereas SICF typically "jumped up" by one I-wave and started with the I2-wave latency of S2. Findings suggest that SICI is mediated through a low-threshold GABA(A) receptor-dependent inhibitory pathway and summation of IPSP from S1 and EPSP from S2 at the corticospinal neurone. In contrast, SICF originates through non-synaptic facilitation at the initial axon segment of interneurones along a high-threshold excitatory pathway.

Adult↗
PubMed2003

The role of GABAB receptors in the discriminative stimulus effects of gamma-hydroxybutyrate in rats: time course and antagonism studies.

gamma-Hydroxybutyrate (GHB) is a neurotransmitter in brain and an emerging drug of abuse, although its mechanism of action is poorly understood. This study characterized the role of GABA(A), GABA(B), and other receptors in the discriminative stimulus effects of GHB. Eight rats reliably discriminated 200 mg/kg GHB from saline after a median of 35 (range: 23-41) training sessions. GHB, a metabolic precursor 1,4-butanediol (1,4-BDL), and the GABA(B) agonist (+/-)baclofen all occasioned greater than 83% responding on the GHB lever. The onset of action was similar for GHB and 1,4-BDL; however, 1,4-BDL exhibited a longer duration of action than GHB. The GHB precursor gamma-butyrolactone, the benzodiazepine diazepam, the neuroactive steroid pregnanolone, the opioid agonist morphine, and the N-methyl-d-aspartate antagonist ketamine elicited substantial GHB-appropriate responding, although none occasioned greater than 66% drug-lever responding. The barbiturate pentobarbital and the GABA(A) receptor agonist muscimol did not occasion greater than 17% drug-lever responding at any dose tested. The benzodiazepine antagonist flumazenil attenuated GHB-lever responding occasioned by diazepam, but not GHB. The GABA(B) receptor antagonist CGP 35348 antagonized GHB-lever responding occasioned by baclofen or GHB. Small doses of the purported GHB receptor antagonist (2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene ethanoic acid (NCS-382) attenuated partially the effects of GHB, whereas larger doses of NCS-382 alone occasioned partial GHB-lever responding. These results implicate GABA(B) mechanisms in the discriminative stimulus effects of GHB and further suggest that the effects of 1,4-BDL under these conditions result from its conversion to GHB. That NCS-382 shares effects with GHB could explain the lack of antagonism reported for NCS-382 in some studies.

4-Butyrolactone↗
PubMed2005

Characterization in rats of the anxiolytic potential of ELB139 [1-(4-chlorophenyl)-4-piperidin-1-yl-1,5-dihydro-imidazol-2-on], a new agonist at the benzodiazepine binding site of the GABAA receptor.

Benzodiazepines are among the most effective drugs for the treatment of anxiety disorders. However, their use is limited by undesired side effects, including sedation, development of tolerance, and drug abuse. The aim of this study was to evaluate the pharmacological profile of ELB139 [1-(4-chlorophenyl)-4-piperidin-1-yl-1,5-dihydro-imidazol-2-on] in different models of anxiety and to correlate these effects with its activity in vitro. ELB139 binds with an IC(50) of 1390 nM to the flunitrazepam binding site in rat forebrain cortical membranes. In rat hippocampal neurons, ELB139 potentiated GABA-induced currents without reaching the maximum effect of diazepam, indicating a partial benzodiazepine agonism. The potentiation was antagonized by the benzodiazepine antagonist flumazenil. ELB139 (10 and 30 mg/kg p.o.) was active in three different animal models of anxiety, i.e., in the elevated plus-maze, the light and dark box, and the Vogel conflict test. The anxiolytic activity in the elevated plus-maze was almost completely reversed by flumazenil (5 mg/kg i.p.), indicating that interaction with the benzodiazepine binding site is central to the pharmacological activity. No hint of sedation was observed at the doses tested in the three anxiety models and the open field. Also, no development of tolerance was observed within 6 weeks b.i.d. treatment with ELB139 in the elevated plus-maze test. In summary, ELB139 elicits strong effects on anxiety-related behavior in rats mediated by its benzodiazepine-like activity without showing sedation or the development of tolerance, a major side effect of benzodiazepines. These characteristics make the compound a prime candidate for clinical development.

Animals↗
PubMed2005

TPA023 [7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine], an agonist selective for alpha2- and alpha3-containing GABAA receptors, is a nonsedating anxiolytic in rodents and primates.

7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (TPA023) is a triazolopyridazine that binds with equivalent high (subnanomolar) affinity to the benzodiazepine binding site of recombinant human GABA(A) receptors containing an alpha1, alpha2, alpha3, or alpha5 subunit but has partial agonist efficacy at the alpha2 and alpha3 subtypes and essentially antagonist efficacy at the alpha1 and alpha5 subtypes. In rats, TPA023 gave time- and dose-dependent occupancy after oral dosing, with 50% occupancy corresponding to a dose of 0.42 mg/kg. It has anxiolytic-like activity in unconditioned (elevated plus maze) and conditioned (fear-potentiated startle and conditioned suppression of drinking) rat models of anxiety with minimum effective doses (MED; 1-3 mg/kg) corresponding to 70 to 88% occupancy. However, there was no appreciable sedation in a response sensitivity (chain-pulling) assay at a dose of 30 mg/kg, resulting in 99% occupancy. Similarly, TPA023 was robustly anxiolytic in the squirrel monkey conditioned emotional response assay, with a MED of 0.3 mg/kg, but did not produce any sedation in a lever-pressing test of sedation even at 10 mg/kg. TPA023 produced no impairment in performance in the mouse Rotarod assay, and there was only a mild interaction with ethanol. In addition to anxiolytic-like efficacy, TPA023 had anticonvulsant activity in a mouse pentylenetetrazole seizure model. Finally, TPA023 did not cause precipitated withdrawal in mice treated for 7 days with the nonselective agonist triazolam, nor did N-methyl-beta-carboline-3-carboxamide (FG 7142) precipitate withdrawal in mice treated for 7 days with TPA023. In summary, the novel alpha2/alpha3-selective efficacy profile of TPA023 translates into a nonsedating anxiolytic profile that is distinct from nonselective agonists.

Acoustic Stimulation↗
PubMed2002

Discriminative stimulus effects of benzodiazepine (BZ)(1) receptor-selective ligands in rhesus monkeys.

Drug discrimination was used to examine the effects of benzodiazepine (BZ)(1) receptor-selective ligands in rhesus monkeys. In diazepam-treated (5.6 mg/kg, p.o.) monkeys discriminating the nonselective BZ antagonist flumazenil (0.32 mg/kg, s.c.), the BZ(1)-selective antagonist beta-carboline-3-carboxylate-t-butyl ester (beta-CCt) substituted for flumazenil. The onset of action of beta-CCt was delayed with a dose of 5.6 mg/kg beta-CCt substituting for flumazenil 2 h after injection. In monkeys discriminating the nonselective BZ agonist midazolam (0.56 mg/kg, s.c.), the BZ(1)-selective agonists zaleplon (ED(50) = 0.78 mg/kg) and zolpidem (ED(50) = 1.73 mg/kg) substituted for midazolam. The discriminative stimulus effects of midazolam, zaleplon, and zolpidem were antagonized by beta-CCt (1.0-5.6 mg/kg, s.c.), and the effects of zaleplon and zolpidem were also antagonized by flumazenil (0.01-0.32 mg/kg, s.c.). Schild analyses supported the notion of a simple, competitive interaction between beta-CCt and midazolam (slope = -1.08; apparent pA(2) = 5.41) or zaleplon (slope = -1.57; apparent pA(2) = 5.49) and not between beta-CCt and zolpidem. Schild analyses also were consistent with a simple, competitive interaction between flumazenil and zaleplon (slope = -1.03; apparent pA(2) = 7.45) or zolpidem (slope = -1.11; apparent pA(2) = 7.63). These results suggest that the same BZ receptor subtype(s) mediate(s) the effects of midazolam, zolpidem, and zaleplon under these conditions and that selective binding of BZ ligands does not necessarily confer selective effects in vivo.

Acetamides↗
PubMed1988

Pentylenetetrazole inhibits glutamate dehydrogenase and aspartate aminotransferase, and stimulates GABA aminotransferase in homogenates from rat cerebral cortex.

The mechanism by which pentylenetetrazole provokes convulsions in animals has been investigated by measuring its influence in vitro on the activities of several enzymes of glutamate metabolism in rat brain homogenates. Pentylenetetrazole does not affect the specific activities of glutamine synthetase, glutaminase, or glutamate decarboxylase; it inhibits those of glutamate dehydrogenase and aspartate aminotransferase, and stimulates that of gamma-aminobutyric acid (GABA) aminotransferase. The overall consequence of the action of pentylenetetrazole on the activities of these enzymes should be an increase in the concentration of glutamate and a decrease in that of GABA. This modulation of glutamate and GABA metabolism by pentylenetetrazole could contribute to the triggering of convulsions.

4-Aminobutyrate Transaminase↗
PubMed2001

GABA(B) and NMDA receptors contribute to spindle-like oscillations in rat thalamus in vitro.

Thalamic slice preparations, in which intrathalamic connectivity between the reticular nucleus and relay nuclei is maintained, are capable of sustaining rhythmic burst firing activity in rodents and ferret. These in vitro oscillations occur spontaneously in the ferret and have frequencies (6-10 Hz) within the range of sleep spindles observed in vivo. In the rat, mainly lower frequency (2-4 Hz) oscillations, evoked under conditions of low bath [Mg(2+)] and/or GABA(A) receptor blockade, have been described. Here we show that faster rhythms in the range of 4-9 Hz can be evoked in rat thalamic slices by electrical stimulation of the internal capsule and also occur spontaneously. When bath [Mg(2+)] was 2 mM, these spindle-like oscillations were most common in a brief developmental time window, peaking at postnatal day 12 (P12). The oscillations were almost completely blocked by the GABA(A) receptor antagonist picrotoxin, and, in some cases, the frequency of oscillations was increased by the GABA(B) receptor antagonist CGP-35348. The selective blockade of N-methyl-D-aspartate (NMDA) or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors by the antagonists 2-amino-5-phosphonovaleric acid or 1,2,3,4-Tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX), respectively, significantly shortened oscillations but did not completely block them. A combination of the two drugs was necessary to abolish oscillatory activity. The barbituate pentobarbital, which enhances GABA(A)R responses, initially slowed and synchronized oscillations before completely blocking them. When bath [Mg(2+)] was reduced from 2 to 0.65 mM, evoked oscillations became more robust and were often accompanied by spontaneously arising oscillations. Under these conditions, GABA(A) receptor blockade no longer inhibited oscillations, but instead converted them into the slow, synchronous rhythms that have been observed in other studies. The effects of GABA(B) or NMDA receptor blockade were more pronounced in 0.65 mM than in 2 mM external [Mg(2+)]. Thus spindle-like oscillations occur in rat thalamic slices in vitro, and we find that, in addition to the previously demonstrated contributions of GABA(A) and AMPA receptors to these oscillations, NMDA and GABA(B) receptors are also involved. The strong influence of external [Mg(2+)] on GABAergic pharmacology and a contribution of NMDA receptors during oscillations suggest a link between the excitability of NMDA receptors and the activation of GABA(B)R-mediated inhibitory postsynaptic currents.

2-Amino-5-phosphonovalerate↗
PubMed1996

Benzodiazepine receptor antagonist (flumazenil) does not affect sleep-related breathing disorders.

Benzodiazepine drugs may impair breathing during sleep, leading to the development of sleep-disordered breathing or, in subjects with sleep apnoea, an increase in the severity of pre-existing apnoeas. Flumazenil is a selective benzodiazepine-antagonist. We hypothesized that endogenous ligands of benzodiazepine receptors might contribute to the pathogenesis of obstructive sleep apnoea syndrome (OSAS) and that the intensity of OSAS could, therefore, be reduced by flumazenil. Ten male patients (mean age 55 yrs, mean body mass index 42.4 kg.m-2, mean apnoea index (AI) 53.5 and mean respiratory disturbance index (RDI) 74.2) were investigated. None of the patients had been treated for OSAS prior to the study. The study design was randomized, single-blind, placebo-controlled and cross-over. On the first or second study night, patients were randomly assigned to receive i.v. flumazenil (2 mg) or placebo (0.9% NaCl) between 01:00 and 01:30 h. Comparing the polysomnographic results of the placebo night and the flumazenil night in all 10 patients, no significant differences were found regarding obstructive events or sleep architecture. Accordingly, the data concerning sleep-disordered breathing and sleep stages during the 30 min period prior to and the 30 min period following the administration of flumazenil did not differ. It is concluded that endogenous ligands of the benzodiazepine receptor play no role in the pathogenesis of obstructive sleep apnoea syndrome, since respiratory and sleep data are not altered by flumazenil. Therefore, attempts to treat obstructive sleep apnoea syndrome with flumazenil do not seem to be warranted.

Body Mass Index↗
PubMed2002

GABA agonist: clomethiazole.

Neuroprotective agents inhibit reactions in the brain ischaemic injury cascade which lead to neuronal death. Gamma-aminobutyric acid (GABA) is a naturally occurring inhibitory neurotransmitter that increases chloride influx into the neuron and counteracts the toxic effects of glutamate. Clomethiazole is a GABA(A) agonist, which causes membrane hyperpolarization, counteracting depolarization and the subsequent cascade of biochemical events that result in neuronal death. Promising results in animal models resulted in clinical trials conducted in humans. However, large randomized placebo controlled trials in Europe, Canada and North America did not show the superiority of clomethiazole over placebo that was seen in animal models.

Chlormethiazole↗
PubMed2001

Modification of the effects of benzodiazepines on the exploratory behaviors of mice on a hole-board by diabetes.

The effect of diabetes on the emotional behavior of mice was examined using an automatic hole-board apparatus. Changes in the emotional state of mice were evaluated in terms of changes in exploratory activity; i.e., total locomotor activity, numbers and duration of rearing and head-dipping, and latency to the first head-dipping. The number and duration of head-dipping in diabetic mice were less than those in non-diabetic mice. Diazepam (0.1-0.56 mg/kg, i.p.) dose-dependently increased the number and duration of head-dipping at doses that did not produce sedation in both diabetic and non-diabetic mice. In contrast, methyl-beta-carboline-3-carboxylate (1 and 2 mg/kg, i.p.) decreased the number and duration of head-dipping in non-diabetic mice, but not in diabetic mice. The number and duration of head-dipping in diabetic mice were increased by treatment with flumazenil (0.1 and 0.3 mg/kg, i.v.). These doses of flumazenil did not affect the number or duration of head-dipping in non-diabetic mice. The present data indicate that diabetic mice exhibited anxiety in the hole-board test and that a benzodiazepine receptor antagonist affected the attenuated number and duration of head-dipping in diabetic mice. The heightened anxiety in diabetic mice may be due to the dysfunction of the benzodiazepine receptor and/or of central inhibitory systems.

Animals↗