Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “GABA Modulators”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,171 records · Page 65Linked to original sources
PubMed2003

The influence of midazolam and flumazenil on rat brain slices oxygen consumption.

This study investigated the impact of benzodiazepine receptor agonist, midazolam and antagonist, flumazenil, on the rat frontal cortex slices oxygen consumption (QO(2)), in presence and absence of gamma-aminobutyric acid (GABA). QO(2) was polarographically determined, using the biological oxygen monitor. As it was previously shown, GABA on its own decreases QO(2) moderately. Midazolam decreased QO(2) at 1.0mg/kg, whereas flumazenil had no effect. In combination with per se ineffective GABA (10(-6)mol/l), flumazenil showed respiratory depressant action, presumably revealing partial agonistic activity at some of GABA(A) receptor subtypes. However, it completely antagonized effects of midazolam on QO(2), on its own and in presence of GABA. Our results show that in vivo well-established effects of midazolam on cerebral metabolic activity could be reproduced in in vitro settings. Moreover, flumazenil antagonized this action, indicating the role of GABA(A)-benzodiazepine receptor complex activation in QO(2) regulation.

Animals↗
PubMed2000

3-Aryl-[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-ones: tricyclic heteroaromatic derivatives as a new class of benzodiazepine receptor ligands.

A series of 3-substituted [1,2,4]triazino[4,3-c]benzimidazoles V were prepared and tested at the central benzodiazepine receptor (BzR). These compounds were designed as rigid analogues of the previously described N-benzylindolylglyoxylylamide derivatives IV. The title compounds V showed an affinity which depended directly on the presence of the N(10)-H group and an aromatic ring at position 3. Some of them elicited a 2- or 3-fold higher affinity with respect to that of the indolylglyoxylylamide derivatives IV (R = H). The GABA ratio and [(35)S]-tert-butylcyclophosphorothionate binding data revealed an efficacy profile of partial inverse agonists/antagonists for compounds 1c,e,f,j,k, and of a partial agonist for 2c. This last compound proved to be effective in antagonizing pentylenetetrazole-induced seizures in mice. Attempts were made to interpret the structure-affinity relationships of compounds V in the light of possible tautomeric equilibria involving the ligands.

Animals↗
PubMed2000

Mechanism-based modeling of functional adaptation upon chronic treatment with midazolam.

PURPOSE: A mechanism-based model is applied to analyse adaptive changes in the pharmacodynamics of benzodiazepines upon chronic treatment in rats. METHODS: The pharmacodynamics of midazolam was studied in rats which received a constant rate infusion of the drug for 14 days, resulting in a steady-state concentration of 102 +/- 8 ng x ml(-1). Vehicle treated rats were used as controls. Concentration-EEG effect data were analysed on basis of the operational model of agonism. The results were compared to data obtained in vitro in a brain synaptoneurosomal preparation. RESULTS: The relationship between midazolam concentration and EEG effect was non-linear. In midazolam pre-treated rats the maximum EEG effect was reduced by 51 +/- 23 microV from the original value of 109 +/-15 microV in vehicle treated group. Analysis of this change on basis of the operational model of agonism showed that it can be explained by a change in the parameter tissue maximum (Em) rather than efficacy (tau). In the in vitro studies no changes in density, affinity or functionality of the benzodiazepine receptor were observed. CONCLUSIONS: It is concluded that the observed changes in the concentration-EEG effect relationship of midazolam upon chronic treatment are unrelated to changes in benzodiazepine receptor function.

Adaptation, Physiological↗
PubMed1998

Plasma and CSF benzodiazepine receptor ligand concentrations in cirrhotic patients with hepatic encephalopathy: relationship to severity of encephalopathy and to pharmaceutical benzodiazepine intake.

Increased plasma and CSF concentrations of substances which bind to brain benzodiazepine receptors have previously been reported in cirrhotic patients with hepatic encephalopathy (HE). However, their relationship to previous intake of pharmaceutical benzodiazepines has not been clearly established. In the present study, plasma levels of benzodiazepine receptor ligands (BZRLs) were measured using a sensitive radioreceptor assay in 12 control subjects with no evidence of hepatic, neurological or psychiatric illness, 11 cirrhotic patients without HE, 24 cirrhotic patients with moderate (grade I-II) HE and in 45 cirrhotic patients with severe (grade II-IV) HE. In addition, CSF concentrations of BZRLs were measured in 8 cirrhotic patients with HE and an equal number of age-matched controls. Recent intake (within 10 days) of pharmaceutical benzodiazepines was assessed by detailed review of medical files, and interviews with the patient, at least one family member as well as the pharmacist. Significantly increased plasma concentrations of BZRLs were observed in cirrhotic patients with severe encephalopathy (p < 0.02) compared to controls and to cirrhotic patients without (or with mild) neurological impairment. Increased plasma BZRLs could be accounted for by prior exposure to benzodiazepine medication in all cases. CSF concentrations of BZRLs in cirrhotic patients were not significantly different from control values. These findings do not support a role for "endogenous" benzodiazepines in the pathogenesis of HE in chronic liver disease but suggest that pharmaceutic benzodiazepines administered to cirrhotic patients as sedatives or as part of endoscopic work-up could have contributed to the neurological impairment in some patients.

Animals↗
PubMed1999

A follow-up study of the acute behavioral effects of benzodiazepine-receptor ligands in humans: comparison of quazepam and triazolam.

Quazepam, a trifluoroethylbenzodiazepine hypnotic, and triazolam, a triazolobenzodiazepine hypnotic, differ in terms of their benzodiazepine-receptor binding profile. Previous studies have suggested that quazepam produces less performance impairment than triazolam. Whether these effects are due to differences between quazepam and triazolam in terms of their benzodiazepine-receptor binding profile or to the testing of insufficient doses is unknown. The present study compared the acute behavioral effects of triazolam (0.1875, 0.3750, and 0.5625 mg), quazepam (30, 60, and 90 mg), and placebo in 12 healthy humans using a within-subjects, placebo-controlled, crossover design. Quazepam and triazolam produced comparable dose-dependent performance impairment and increased ratings of drug effect and drowsy. Quazepam, but not triazolam, increased ratings of dizzy/light-headed, performance impaired, and sleepy. Triazolam, but not quazepam, increased ratings of high. Thus, across a sufficient range of doses, the performance-impairing effects of quazepam were similar to those of triazolam. By contrast, quazepam and triazolam produced somewhat different constellations of participant-rated drug effects. These differential drug effects may be attributable to differences between quazepam and triazolam in terms of their benzodiazepine-receptor binding profile.

Adult↗
PubMed1998

The effect of a transmembrane amino acid on etomidate sensitivity of an invertebrate GABA receptor.

1. The gamma-aminobutyric acid (GABA)-modulatory and GABA-mimetic actions of etomidate at mammalian GABA(A) receptors are favoured by beta2- or beta3- versus beta1-subunit containing receptors, a selectivity which resides with a single transmembrane amino acid (beta2 N290, beta3 N289, beta1 S290). Here, we have utilized the Xenopus laevis oocyte expression system in conjunction with the two-point voltage clamp technique to determine the influence of the equivalent amino acid (M314) on the actions of this anaesthetic at an etomidate-insensitive invertebrate GABA receptor (Rdl) of Drosophila melanogaster. 2. Complementary RNA-injected oocytes expressing the wild type Rdl GABA receptor and voltage-clamped at -60 mV responded to bath applied GABA with a concentration-dependent inward current response and a calculated EC50 for GABA of 20+/-0.4 microM. Receptors in which the transmembrane methionine residue (M314) had been exchanged for an asparagine (RdlM314N) or a serine (RdlM314S) also exhibited a concentration-dependent inward current response to GABA, but in both cases with a reduced EC50 of 4.8+/-0.2 microM. 3. Utilizing the appropriate GABA EC10, etomidate (300 microM) had little effect on the agonist-evoked current of the wild type Rdl receptor. By contrast, at RdlM314N receptors, etomidate produced a clear concentration-dependent enhancement of GABA-evoked currents with a calculated EC50 of 64+/-3 microM and an Emax of 68+/-2% (of the maximum response to GABA). 4. The actions of etomidate at RdlM314N receptors exhibited an enantioselectivity common to that found for mammalian receptors, with 100 microM R-(+)-etomidate and S-(-)-etomidate enhancing the current induced by GABA (EC10) to 52+/-6% and 12+/-1% of the GABA maximum respectively. 5. The effects of this mutation were selective for etomidate as the GABA-modulatory actions of 1 mM pentobarbitone at wild type Rdl (49+/-4% of the GABA maximum) and RdlM314N receptors (53+/-2% of the GABA maximum) were similar. Additionally, the modest potentiation of GABA produced by the anaesthetic neurosteroid 5alpha-pregnan-3alpha-ol-20-one (Rdl = 25+/-4% of the GABA maximum) was not altered by this mutation (RdlM314N = 18+/-3% of the GABA maximum). 6. Etomidate acting at beta1 (S290)-containing mammalian GABA(A) receptors is known to produce only a modest GABA-modulatory effect. Similarly, etomidate acting at RdlM314S receptors produced an enhancement of GABA but the magnitude of the effect was reduced compared to RdlM314N receptors. 7. Etomidate acting at human alpha6beta3gamma2L receptors is known to produce a large enhancement of GABA-evoked currents and at higher concentrations this anaesthetic directly activates the GABA(A) receptor complex. Mutation of the human beta3 subunit asparagine to methionine (beta3 N289M found in the equivalent position in Rdl completely inhibited both the GABA-modulatory and GABA-mimetic action of etomidate (10-300 microM) acting at alpha6beta3 N289Mgamma2L receptors. 8. It was concluded that, although invertebrate and mammalian proteins exhibit limited sequence homology, allosteric modification of their function by etomidate can be influenced in a complementary manner by a single amino acid substitution. The results are discussed in relation to whether this amino acid contributes to the anaesthetic binding site, or is essential for transduction. Furthermore, this study provides a clear example of the specificity of anaesthetic action.

Allosteric Regulation↗
PubMed2006

Dopamine and benzodiazepine-dependent mechanisms regulate the EtOH-enhanced locomotor stimulation in the GABAA alpha1 subunit null mutant mice.

The present study investigated the role of the alpha1-containing GABA(A) receptors in the neurobehavioral actions of alcohol. In Experiment 1, mice lacking the alpha1 subunit (alpha1 (-/-)) were tested for their capacity to initiate operant-lever press responding for alcohol or sucrose. Alcohol intake in the home cage was also measured. In Experiment 2, the alpha1 (-/-) mice were injected with a range of alcohol doses (0.875-4.0 g/kg; i.p.) to evaluate the significance of the alpha1 subunit in alcohol's stimulant actions. In Experiment 3, we determined if the alcohol-induced stimulant effects were regulated via dopaminergic (DA) or benzodiazepine (BDZ)-dependent mechanisms. To accomplish this, we investigated the capacity of DA (eticlopride, SCH 23390) and BDZ (flumazenil, betaCCt) receptor antagonists to attenuate the alcohol-induced stimulant actions. Compared with wild-type mice (alpha1 (+/+)), the null mutants showed marked reductions in both EtOH and sucrose-maintained responding, and home-cage alcohol drinking. The null mutants also showed significant increases in locomotor behaviors after injections of low-moderate alcohol doses (1.75-3.0 g/kg). betaCCt, flumazenil, eticlopride, and SCH 23390 were able to attenuate the alcohol-induced stimulation in mutant mice, in the absence of intrinsic effects. These data suggest the alpha1 receptor plays an important role in alcohol-motivated behaviors; however, it also appears crucial in regulating the reinforcing properties associated with normal ingestive behaviors. Deleting the alpha1 subunit of the GABA(A) receptor appears to unmask alcohol's stimulatory effects; these effects appear to be regulated via an interaction of both DA- and GABA(A) BDZ-dependent mechanisms.

Animals↗
PubMed1996

Quantitative autoradiography using selective radioligands for central and peripheral-type benzodiazepine receptors in experimental Wernicke's encephalopathy: implications for positron emission tomography imaging.

Wernicke's encephalopathy (WE) is difficult to diagnose during life, with up to 80% of cases being missed by routine neurological evaluation in both alcoholics and AIDS patients. Therefore, there is a need for noninvasive diagnostic procedures. Using the pyrithiamine-treated rat, an animal model of WE, we have studied, using radioligands for central (neuronal) and "peripheral-type" (glial) benzodiazepine receptors, the regional distribution of changes in the densities of these receptors in relation to the degree of reactive gliosis accompanying neuronal loss. Histological studies revealed neuronal loss in selective regions, including the thalamus, inferior colliculus, inferior olivary nucleus, and mammillary body. Autoradiographic studies demonstrated increases in densities of [3H]PK11195 binding sites that closely paralleled the topographic distribution of neuronal cell loss and reactive gliosis. In contrast, [3H]Ro15-178 showed poor spatial correlation, with the neuronal loss seen in pyrithiamine-induced thiamine deficiency. The positron emission tomography ligand [11C]PK11195 may be useful for the assessment of thiamine deficiency-induced brain damage in human alcoholics.

Animals↗
PubMed1998

Regional increases in [11C]flumazenil binding after epilepsy surgery.

INTRODUCTION: Animal experiments suggest that epileptic seizures alter the expression of mRNA for neuro-receptors. PET measurements with [11C]flumazenil show that patients with partial seizures have a reduced density of benzodiazepine (BZ) receptors in the epileptogenic regions (ER) and some of the target areas for seizure activity, the so called projection areas. Recent data suggest that the degree of BZ receptor reduction in ER is correlated to seizure frequency. We therefore hypothesized that seizure activity can alter the BZ receptor binding, and that some of these changes could normalize when the seizures disappeared. METHODS: In 4 patients whose seizures were generated by mesial temporal lobe structures, BZ receptor density was measured with [11C]flumazenil PET before, and 1 year after the epilepsy surgery and cessation of seizures. By use of a computerized anatomical brain atlas the same regions were analyzed in both PET scans, and the results related to data from 7 healthy controls. RESULTS: Presurgical PET scans showed reductions in BZ receptor density in the epileptogenic region and some of its primary projection areas. Other cortical regions had normal values. Postsurgically, the calculated BZ receptor density normalized (29+/-17% increase) in several of the affected projection areas, whereas the values in other cortical regions remained unaltered. CONCLUSION: Regional reductions in BZ receptor density may be dynamic and related to seizures. The present preliminary observations encourage further studies on seizure-related changes in regional receptor binding in humans.

Adult↗
PubMed2003

Structural requirements for imidazobenzodiazepine binding to GABA(A) receptors.

Several structural subclasses of ligands bind to the benzodiazepine (BZD) binding site of the GABA(A) receptor. Previous studies from this laboratory have suggested that imidazobenzodiazepines (i-BZDs, e.g., Ro 15-1788) require domains in the BZD binding site for high-affinity binding that are distinct from the requirements of classic BZDs (e.g., flunitrazepam). Here, we used systematic mutagenesis and the substituted cysteine accessibility method to map the recognition domain of i-BZDs near two residues implicated in BZD binding, gamma(2)A79 and gamma(2)T81. Both classic BZDs and i-BZDs protect cysteines substituted at gamma(2)A79 and gamma(2)T81 from covalent modification, suggesting that these ligands may occupy common volumetric spaces during binding. However, the binding of i-BZDs is more sensitive to mutations at gamma(2)A79 than classic BZDs or BZDs that lack a 3'-imidazo substituent (e.g., midazolam). The effect that gamma(2)A79 mutagenesis has on the binding affinities of a series of structurally rigid i-BZDs is related to the volume of the 3'-imidazo substituents. Furthermore, larger amino acid side chains introduced at gamma(2)A79 cause correspondingly larger decreases in the binding affinities of i-BZDs with bulky 3' substituents. These data are consistent with a model in which gamma(2)A79 lines a subsite within the BZD binding pocket that accommodates the 3' substituent of i-BZDs. In agreement with our experimental data, computer-assisted docking of Ro 15-4513 into a molecular model of the BZD binding site positions the 3'-imidazo substituent of Ro 15-4513 near gamma(2)A79.

Animals↗
PubMed2005

Abnormal cortical excitability in sporadic but not homozygous D90A SOD1 ALS.

BACKGROUND: Excitotoxicity is one pathogenic mechanism proposed in amyotrophic lateral sclerosis (ALS), and loss of cortical inhibitory influence may be contributory. Patients with ALS who are homozygous for the D90A superoxide dismutase-1 (SOD1) gene mutation (homD90A) have a unique phenotype, associated with prolonged survival compared with patients with sporadic ALS (sALS). In this study, transcranial magnetic stimulation (TMS) was used to explore cortical excitation and inhibition. Flumazenil binds to the benzodiazepine subunit of the GABA(A) receptor, and (11)C-flumazenil positron emission tomography (PET) was used as a marker of cortical neuronal loss and/or dysfunction, which might in turn reflect changes in cortical inhibitory GABAergic mechanisms. METHODS: Cortical responses to single and paired stimulus TMS were compared in 28 patients with sALS and 11 homD90A patients versus 24 controls. TMS measures included resting motor threshold, central motor conduction time, silent period, intracortical inhibition (ICI), and facilitation. (11)C-flumazenil PET of the brain was performed on 20 patients with sALS and nine with homD90A. Statistical parametric mapping was used to directly compare PET images from the two patient groups to identify those areas of relatively reduced cortical (11)C-flumazenil binding that might explain differences in cortical excitability seen using TMS. RESULTS: Increased cortical excitability, demonstrated by reduction in ICI, was seen in the patients with sALS but not the homD90A patients. A relative reduction in cortical (11)C-flumazenil binding was found in the motor and motor association regions of the superior parietal cortices of the patients with sALS. CONCLUSIONS: A cortical inhibitory deficit in sALS was not demonstrable in a homogeneous genetic ALS population of similar disability, suggesting a distinct cortical vulnerability. (11)C-flumazenil PET demonstrated that neuronal loss/dysfunction in motor and motor association areas may underlie this difference. The corollary, that there may be relative preservation of neuronal function in these areas in the homD90A group, has implications for understanding the slower progression of disease in these patients.

Adult↗
PubMed2000

Response to flumazenil in women with premenstrual dysphoric disorder.

OBJECTIVE: The authors sought to determine whether the administration of flumazenil would induce marked panic symptoms in women suffering from premenstrual dysphoric disorder. METHOD: Ten women with premenstrual dysphoric disorder and 11 comparison subjects were injected with flumazenil or placebo in a double-blind, randomized, balanced crossover design in a single session in the luteal phase of their menstrual cycles. RESULTS: Flumazenil induced a much greater panic response in the women with premenstrual dysphoric disorder than in the comparison subjects. CONCLUSIONS: These preliminary results are consistent with a dysregulation of the g-aminobutyric acid A/benzodiazepine receptor complex during the premenstruum of women suffering from premenstrual dysphoric disorder.

Cross-Over Studies↗
PubMed2000

PET measures of benzodiazepine receptors in progressive supranuclear palsy.

OBJECTIVE: To evaluate the integrity of neurons containing benzodiazepine receptors in metabolically affected regions of the brain in patients with clinically diagnosed progressive supranuclear palsy (PSP). METHODS: The cerebral distribution of [11C]flumazenil (FMZ), a ligand that binds to the gamma-aminobutyric acid A (GABAA) receptor, and [18F]fluorodeoxyglucose (FDG), a measure of local cerebral glucose metabolism, was determined with PET in 12 patients with PSP and 10 normal control subjects. Tracer kinetic analysis was applied to quantify data and analysis was performed using three-dimensional stereotactic surface projections and stereotactically determined volumes of interest. RESULTS: There was a global reduction in FMZ binding of 13%, with a reduction in the anterior cingulate gyrus of 20% (p = 0.004), where glucose metabolic rates also showed the greatest reduction. CONCLUSIONS: PSP causes loss of benzodiazepine receptors in the cerebral cortex. Consistent with postmortem studies, the authors did not find significant changes in FMZ binding in subcortical nuclei that exhibit the most pathologic change. This study suggests that both loss of intrinsic neurons containing benzodiazepine receptors and deafferentation of the cerebral cortex from distant brain regions contribute to cerebral cortical hypometabolism in PSP.

Aged↗
PubMed1997

Roles of gamma-aminobutyric acidB (GABA B) and gamma-hydroxybutyric acid receptors in hippocampal long-term potentiation and pathogenesis of absence seizures.

Experiments were performed to examine the roles of gamma-aminobutyric acid(B) (GABA(B)) and gamma-hydroxybutyric acid (GHB) receptors in long-term potentiation (LTP) of the hippocampal CA1 region in vivo and in the genesis of the spike and wave discharges (SWDs) associated with absence seizures. When tetanic stimulation was delivered to the CA3 region, stable LTP was observed in the CA1 region in saline-treated mice. In mice treated with 5 mg/kg baclofen, the population spike amplitude was significantly potentiated by tetanic stimulation and the degree of potentiation was the same as that induced in saline controls. However, this potentiation decayed to the baseline level about 90 min after stimulation. The decay was reversed by pretreatment with 200 mg/kg P-[3-aminopropyl]-P-diethoxymethylphosphinic acid (CGP 35348), a selective GABA(B) receptor antagonist. In mice treated with 50 mg/kg gamma-butyrolactone (GBL), a prodrug of GHB, stable LTP was observed 90 min after tetanic stimulation and was greater than that in saline controls. GBL-induced potentiation of LTP was antagonized by 50 mg/kg NCS 382, a putative GHB receptor antagonist. Administration of baclofen (20 mg/kg) or GBL (70 mg/kg) induced absence-like seizures associated with 3-6 Hz SWDs, and CGP 35348 suppressed both baclofen- and GBL-induced SWDs. NCS 382 also attenuated SWDs induced by GBL and baclofen. These results suggest that baclofen and GHB have different effects on LTP in the CA1 region of the hippocampus in vivo, although they have a common mode of action on the thalamocortical functions related to the pathogenesis of absence seizures.

4-Butyrolactone↗
PubMed1999

The role of gamma-aminobutyric acid (GABA)-benzodiazepine neurotransmission in an animal model of methamphetamine-induced psychosis.

Repeated administration of amphetamine or methamphetamine (MA) results in an augmentation of its locomotor-activating effects, which is a phenomenon known as behavioral sensitization. In humans, chronic use of the drug elicits a progressive augmentation in paranoid symptoms that closely resemble schizophrenia. Behavioral sensitization has some common properties with other forms of neural plasticity such as kindling, learning and long-term potentiation (LTP). The author examined in the present study whether behavioral sensitization could be blocked by GABA-benzodiazepine agonists, known to inhibit kindling, learning as well as LTP. Rats (Male Wistar-King rats) treated with MA (1 mg/kg, s.c.) for 10 days displayed significantly enhanced motor activity when tested with MA (1 mg/kg) after a 7-8 day withdrawal period indicating the acquisition of behavioral sensitization. Treatment with clonazepam (CZP) (0.5 and 2.0 mg/kg), a GABA-benzodiazepine agonist, prior to MA administration prevented the acquisition of sensitization. In contrast, treatment with flumazenil (Flu) (10 mg/kg), a GABA-benzodiazepine antagonist, prior to MA administration did not affect the acquisition of sensitization. And treatment with Flu prior to CZP administration suppressed the inhibitory effect of CZP. CZP had no effect on the expression of sensitization in the sensitized rats, when given prior to the MA readministration. These results suggest that stimulation of GABA-benzodiazepine receptors plays a role in the acquisition but not in the expression of behavioral sensitization.

Animals↗
PubMed1999

Altered GABA(A)-benzodiazepine receptor number and pharmacology in the adult guinea pig cerebral cortex after chronic prenatal ethanol exposure.

BACKGROUND: The effects of chronic prenatal ethanol exposure on GABA(A)-benzodiazepine receptor number and binding pharmacology were examined in the cerebral cortex of the postnatal guinea pig. METHODS: [3H]Flunitrazepam binding to GABA(A)-benzodiazepine receptors was measured in a cerebral cortical cell membrane preparation obtained at postnatal days 11 (preweaning), 21 (postweaning), and 61 (adulthood). Zolpidem, a GABA(A)-benzodiazepine type 1 receptor-selective ligand, was used in a [3H]flunitrazepam competition study. 3a-Hydroxy-5alpha-pregnan-20-one (allopregnanolone) potentiation of [3H]muscimol and [3H]flunitrazepam binding, and GABA potentiation of [3H]flunitrazepam binding were measured in these same animals. RESULTS: At postnatal day 61, but not at the younger ages studied, the following was observed: (1) [3H]Flunitrazepam binding exhibited an increased receptor number (Bmax) and decreased affinity (increased K(D)) in the ethanol-treated offspring compared with isocaloric-sucrose (with pair-feeding) and water-treated controls; and (2) the relative proportion of GABA(A)-benzodiazepine receptors that had high-affinity binding sites for zolpidem was decreased in the ethanol-treated offspring by 31% and 38% compared with the isocaloric-sucrose/pair-fed and water-treated controls, respectively. Chronic prenatal ethanol exposure did not alter the efficiency of coupling between GABA, benzodiazepine, and neurosteroid binding sites at any postnatal ages studied. CONCLUSIONS: These results suggest that, in the cerebral cortex of the adult guinea pig, chronic prenatal exposure to ethanol results in increased GABA(A)-benzodiazepine receptor number, decreased affinity for flunitrazepam, and decreased relative proportion of the GABA(A)-benzodiazepine type 1 receptor.

Animals↗
PubMed2000

Fluorescent-labeled ligands for the benzodiazepine receptor. Part 1: Synthesis and characterization of fluorescent-labeled benzodiazepines.

Because radioactive labeled ligands in receptor assays have several disadvantages, we synthesized a number of fluorescent-labeled benzodiazepines. Several fluorophores were attached at different positions of 1,4-benzodiazepine molecules in order to assess the impact of the fluorophores and their coupling position on the affinity for the benzodiazepine receptor. Besides the 1,4-benzodiazepines, the 1,2-annelated 1,4-benzodiazepines were also used for labeling. A metabolite of flumazenil (18), desethylflumazenil (Ro15-3890, 19), was labeled with the fluorophore 4-bromomethyl-7-methoxycoumarin, with and without the incorporation of a spacer chain, yielding the methyl-methoxycoumarin (Mmc) derivatives Mmc-Ro15-3890 (20a) and Mmc-O-CO-(CH2)3-Ro15-3890 (20b), respectively. After the synthesis, the fluorescent-labeled benzodiazepines were purified by HPLC, using an analytical RP-C18 column. For the purification of 20b, the chromatographic system was optimized, using multi-criteria decision making (MCDM) techniques. The binding affinities for the benzodiazepine receptor and the fluorescence characteristics were determined for the resulting products.

Animals↗
PubMed2002

Two flavones from Scutellaria baicalensis Georgi and their binding affinities to the benzodiazepine site of the GABAA receptor complex.

A new flavone 6,2'-dihydroxy-5,7,8,6'-tetramethoxyflavone (1) together with one known flavone 5,7,2'-trihydroxy-6,8-dimethoxyflavone (2) were isolated from the roots of Scutellaria baicalensis Georgi. Their structures were elucidated on the basis of spectral evidence and their affinities for the benzodiazepine (BDZ) site of the GABAA receptor complex were evaluated with a radioligand receptor binding assay.

Animals↗