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PubMed1996

Modulation of ligand binding to components of the GABAA receptor complex by ammonia: implications for the pathogenesis of hyperammonemic syndromes.

The effects of 5-2500 microM concentrations of neutral ammonium salts on the binding of ligands to components of the GABAA receptor complex were investigated. [3H]Flunitrazepam binding to the benzodiazepine receptor was enhanced by ammonium (10-500 microM), but not sodium tartrate with EC50 = 98 microM and Emax = 31%. Further increasing ammonium tartrate concentrations (500-2500 microM) decreased [3H]flunitrazepam binding to control levels. The ammonium tartrate-induced increase in [3H]flunitrazepam binding was manifested as a 50% decrease in Kd. Furthermore, GABA increased the potency of ammonium tartrate in enhancing [3H]flunitrazepam binding by 63%. [3H]Ro 15-1788 and [3H]Ro 15-4513 binding to the benzodiazepine receptor was not significantly enhanced by ammonium tartrate (Emax approximately 13%). Ammonium tartrate also increased, then decreased the binding of 500 nM [3H]muscimol to the GABAA receptor (EC50 = 52 microM, Emax = 30%) in a concentration-dependent manner, but had no effect on [3H]SR 95-531 binding (Emax < 16%). The ammonium tartrate-induced alterations in [3H]muscimol binding were demonstrated in saturation assays as the loss of the high affinity binding site and a 27% increase in the Bmax of the low affinity binding site. These results indicate that ammonia biphasically enhances, then returns ligand binding to both the GABA and benzodiazepine receptor components of the GABAA receptor complex to control levels in a barbiturate-like fashion. This suggests that ammonia may enhance GABAergic neurotransmission at concentrations commonly encountered in hepatic failure, an event preceding the suppression of inhibitory neuronal function observed at higher (> 1 mM) ammonia concentrations. This increase in GABAergic neurotransmission is consistent with the clinical picture of lethargy, ataxia and cognitive deficits associated with liver failure and congenital hyperammonemia.

Ammonia↗
PubMed1982

Enhancement of benzodiazepine and GABA binding by the novel anxiolytic, tracazolate.

Tracazolate (ICI 136,753) 4-butylamine-1-ethyl-6-methyl-1H-pyrazolo[3,4]pyridine-5-carboxylic acid ethyl ester is a non-benzodiazepine with anxiolytic-like activity in animal models. In contrast to the benzodiazepines, it enhances [3H]flunitrazepam binding in rat synaptic membrane fragments. The enhancement is potential by chloride ion and is due to an increase in affinity of the receptor. The enhancement of benzodiazepine binding by gamma-aminobutyric acid (GABA) is additive with that of tracazolate; however, the GABA antagonist bicuculline blocks the enhancement by both compounds. Tracazolate enhances [3H]GABA binding to frozen and thawed Triton X-100-treated membrane fragments. The enhancement is due to an increase in the number of sites and potentiated by chloride. Benzodiazepines also enhanced GABA binding but the effect was due to an apparent change in affinity and not potentiated by chloride. The rank order to chlorodiazepoxide, diazepam and flunitrazepam for enhancement of GABA binding and displacement of [3H]flunitrazepam binding were the same. The enhancement of [3H]GABA binding by flunitrazepam and tracazolate were additive. Possible interactions between these various receptors are discussed.

Animals↗
PubMed1989

Regional GABA/benzodiazepine receptor/chloride channel coupling after acute and chronic benzodiazepine treatment.

GABA/benzodiazepine coupling was evaluated in 8 regions of rat brain by the ability of GABA to stimulate 0.5 nM [3H]flunitrazepam binding. Rats were treated acutely with diazepam (p.o) or chronically with flurazepam, offered in the drinking water for 4 weeks, and compared to a pair-handled vehicle-treated control group. Regional variations in GABA/benzodiazepine coupling were found in control membranes. GABA increased benzodiazepine binding maximally (40%) in cerebellum and medulla, and least (25%) in olfactory bulb. A significant decrease in the effect of GABA was found in cortex of chronically treated rats immediately after, but not 2 days following treatment. The Emax for GABA stimulation of [3H]flunitrazepam binding was significantly increased in medulla after acute treatment but was not altered after acute or chronic treatment in other brain areas evaluated. Treatment had no effect on the ability of bicuculline to inhibit [3H]flunitrazepam binding in cortex. Benzodiazepine/Cl- coupling in cortex or hippocampus of acutely and chronically treated rats, evaluated by the ability of Cl- to stimulate specific [3H]flunitrazepam binding, was not changed. The results support the hypothesis that a functional uncoupling of the benzodiazepine recognition site from the GABA receptor in cortex, but not from the anion recognition site, may play a role in tolerance development.

Analysis of Variance↗
PubMed1992

Comparison of behavioral and central BDZ binding profile in three rat lines.

The performance of three widely used rat lines (Sprague-Dawley, Wistar, and Long Evans hooded) were evaluated in behavioral test systems that are sensitive to benzodiazepines. The in vivo effects of flunitrazepam and the brain [3H]Ro 15-1788 binding were determined and compared in these rat lines. The behavioral end points evaluated in this study were anxiolysis, measured using the automated elevated plus-maze; sedation by modification of locomotor activity; hyperphagia following food deprivation; protection for pentylenetetrazol-induced convulsions; and hypothermia. There were comparable results in the hypnotic, hypothermic, anticonvulsant, and feeding tests in these lines following flunitrazepam administration. However, the behavior of the Long Evans hooded rat was most amenable to the detection of drug-induced changes in the anxiety test. There was no difference in the maximum number of binding sites (Bmax) or the affinity (Ki) of the Ro 15-1788 or flunitrazepam binding in either the cerebellum or whole brain (minus cerebellum) in the three rat lines as determined by the competitive binding against [3H]Ro 15-1788. Thus, while these rat lines exhibited similar behavioral profiles in most tests the modest differences in the baseline responses and the ability to detect anxiolysis at lower doses of flunitrazepam observed with Long Evans hooded rats makes them particularly suited for these types of studies.

Animals↗
PubMed1986

Dark-rearing affects the development of benzodiazepine receptors in the central visual structures of rat brain.

The postnatal development of [3H]flunitrazepam binding to benzodiazepine receptors has been studied in the retina, lateral geniculate nucleus, superior colliculus, frontal cortex and visual cortex of the rat. In the frontal and visual cortices, binding reached the highest level at postnatal day 25 and then decreased slightly until adulthood. In the superior colliculus, the adult value of [3H]flunitrazepam binding is already reached at postnatal day 25, whereas in the retina the highest binding was found at postnatal day 50. The ontogeny of benzodiazepine binding sites in the visual regions does not essentially differ from that in other brain regions, suggesting that the appearance of [3H]flunitrazepam binding sites in the visual system is not correlated with the development of retinal function and the functional maturation of the visual system with regard to processing of light stimuli. Raising rats in complete darkness from birth until the age of 25 days resulted in significantly decreased binding levels in the lateral geniculate nucleus and in the superior colliculus by 29% and 17%, respectively, as compared to controls. [3H]Flunitrazepam binding in the other regions studied was not affected by dark-rearing. Presumably, the complete lack of visual experience interferes with the functional development of GABAergic mechanisms involved in the gating function of the subcortical visual centres for visual information transfer.

Age Factors↗
PubMed1996

Neurosteroid modulation of the benzodiazepine receptor in developing chick optic lobe.

The modulation of [3H]flunitrazepam binding by 3 alpha-hydroxy-5 alpha-dihydroprogesterone (3 alpha-OH-DHP) and 3 alpha, 5 alpha-tetrahydrodeoxicorticosterone (3 alpha-THDOC) was investigated in synaptic membranes isolated from chick optic lobe at three developmental stages, in order to evaluate the role of neurosteroids in central nervous system functional maturation. It was demonstrated that both steroids modulate [3H]flunitrazepam binding in a concentration-dependent manner at embryonic day 14, hatching and adult stage, producing maximal [3H]flunitrazepam binding enhancement at early stages of development and declining thereafter. EC50 values for 3 alpha-OH-DHP were lower than for 3 alpha-THDOC at all stages examined. On the other hand, Emax values were higher with 3 alpha-OH-DHP than with 3 alpha-THDOC. Scatchard analysis performed at embryonic day 14, hatching and adult stage showed that dissociation constants (Kd) were of 22.23 +/- 0.15, 18.38 +/- 1.15 and 19.86 +/- 0.62 nM, and maximal number of binding sites (Bmax) were 1.95 +/- 0.15, 3.13 +/- 0.21 and 2.25 +/- 0.13 pmol/mg protein, respectively. By adding 4 microM of either 3 alpha-OH-DHP or 3 alpha-THDOC, Kd values decreased significantly to 10.65 +/- 0.62, 9.71 +/- 0.85 and 13.25 +/- 0.74 nM or 9.54 +/- 0.65, 11.20 +/- 1.27 and 12.96 +/- 1.38 nM, at the above mentioned stages, respectively. Thus, either drug at the given concentration increased the affinity of benzodiazepine receptor sites for [3H]flunitrazepam, while the density of receptor sites remained unchanged. Our results suggest that these steroids display a positive allosteric modulation of benzodiazepine receptor sites which is inversely related to age.

Animals↗
PubMed1981

Benzodiazepine receptor binding in young, mature and senescent rat brain and kidney.

Clinical reports have described age-altered pharmacological effects of anxiolytic drugs especially an increased susceptibility to their sedative actions. In order to test whether such changes may be due to age-related alterations in central benzodiazepine receptors, 3H-flunitrazepam binding was assayed in the frontal cortex and cerebellum of young, mature and senescent rats. The numbers of 3H-flunitrazepam binding sites and their affinity was determined by Scatchard analysis of saturation isotherms and the relative abundance of type I and type II benzodiazepine receptors was assessed by drug-inhibition studies using diazepam and the triazolopyridazine, CL 218,872. In addition, age related changes in the kidney and hippocampus of the Ro5-4864-sensitive benzodiazepine receptor were studied using 3H-Ro5-4864. No age-related alterations were noted in the binding characteristics of 3H-flunitrazepam. Furthermore, drug-inhibition of 3H-flunitrazepam binding by diazepam and CL 218,872 was nearly identical in young, mature and senescent rats, indicating that also the ratio of type I and type II receptors does not change with age. Binding of 3H-Ro5-4864 to membranes from rat hippocampus was not age-related. However, a significant decrease in 3H-Ro5-4864 binding to kidney membranes was demonstrated. Hence, central benzodiazepine receptors appear unaltered in the senescent rat model of aging. The clinical findings of an increased susceptibility to the sedative effects of benzodiazepines in the elderly may therefore be attributed to pharmacokinetic variables, or to events occurring secondarily to receptor activation.

Age Factors↗
PubMedDate not supplied

Age-related levels of GABA/benzodiazepine binding sites in cerebrum of F-344 rats: effects of exercise.

We examined gamma-aminobutyric acid (GABA), benzodiazepine and convulsant sites of postsynaptic GABA/benzodiazepine receptors (GBZR) in cerebral membranes of inbred Fischer 344 male rats as a function of age. In aged rats (23 to 24 months), the benzodiazepine binding site as determined by [3H]flunitrazepam was 47% and 43% lower than corresponding values in young adult (3 to 4 months) and mature (10 to 12 months) rats, respectively. The decrease was due to the loss of binding density rather than a change in affinity. No statistically significant age-related changes in [3H]muscimol binding were observed when 5 nM or 40 nM labeled muscimol were used. GABA produced a dose-dependent stimulation of flunitrazepam binding in all age groups, but the maximum stimulation in aged animals was significantly higher (24%) than in young and mature animals. The [35S]TBPS binding site, the convulsant site of GABA/benzodiazepine receptors, was unaffected with age. We also studied the effects of exercise on GBZR binding sites of aged rats. The decline of flunitrazepam binding sites and the high sensitivity of flunitrazepam binding to regulation by GABA in aged animals were reversed by 8 to 10 weeks of endurance exercise. Endurance exercise did not have any significant effect on muscimol or TBPS binding sites. Results suggest that there are aged-related alterations of GBZR binding sites and that these modifications can be reversed by exercise.

Aging↗
PubMed1983

Benzodiazepine receptors in the rat hippocampal formation: action of catecholaminergic, serotoninergic and commissural denervation.

The problem of benzodiazepine receptor localization in the rat hippocampal formation has been approached using several methods of selective deafferentation, followed by [3H]flunitrazepam binding studies. The intraventricular injection of 6-hydroxydopamine reduced, after 14 days, the norepinephrine content of the hippocampal formation by 68.4%, and decreased the number of binding sites by 32%, without change in affinity. The intraventricular injection of 5,6 dihydroxytryptamine reduced the serotonin content by 61.5% but did not alter the [3H]flunitrazepam binding. The intraventricular bilateral injection of 0.5 micrograms kainic acid selectively destroyed the pyramidal neurons in area CA3 of both hippocampi and produced an increase of 28% in [3H]flunitrazepam binding, without change in affinity. These results are discussed in relation to our previous observations about benzodiazepine receptor changes after fimbria-fornix transection. The reduction in [3H]flunitrazepam binding after administration of 6-hydroxydopamine suggests the possible localization of the benzodiazepine receptors on adrenergic presynaptic terminals. The increase in binding sites after destruction of CA3 pyramidal cells, which are the site of origin of commissural fibers, is tentatively interpreted as resulting from the sprouting of mossy fibers that replace the associational-commissural projections.

5,6-Dihydroxytryptamine↗
PubMed1988

Benzodiazepine receptor sites in the human brain: autoradiographic mapping.

Receptor autoradiography was used to localize and quantify the distribution of benzodiazepine receptor sites in human post mortem materials using [3H]flunitrazepam. The distribution and density of these sites was analysed in the brains of 21 patients dying without reported neurological disease. The distribution of benzodiazepine receptors in the human brain was found to be comparable from case to case although differences in the density occurred among the brains examined. No influence of the post mortem delay, age, gender or pre mortem drug treatment on the distribution and densities was observed in our series. The highest densities of benzodiazepine receptors in human brain were localized in cortical and hippocampal areas, nucleus accumbens, amygdala and mammillary bodies. Intermediate densities were found in the basal ganglia and thalamic and hypothalamic nuclei. [3H]Flunitrazepam binding was low in the brainstem nuclei and very low in white matter. The triazolopyridazine Cl 218872, reported to differentiate between type I and type II benzodiazepine receptor sites, exhibited regional differences in affinity when used to block [3H]flunitrazepam binding. Benzodiazepine receptors in the cerebellar cortex were more sensitive to this compound than those in the dentate gyrus of the hippocampus and the tuberal nuclei of the hypothalamus. An enrichment in the concentration of type I benzodiazepine receptor Cl 218872-sensitive sites was observed in motor areas as compared to structures of the limbic system. The addition of GABA to the incubation medium resulted in an increase of [3H]flunitrazepam binding, suggesting the coupling of these sites to a GABAA receptor. The increase in binding was directly proportional to the density of benzodiazepine receptors but unrelated to the density of high-affinity GABAA sites. The distribution of benzodiazepine receptor sites in the human brain compares well with that previously described in the rat brain. The high densities of receptors localized in the limbic system and in the cortical areas suggest that the effects of benzodiazepines are mediated through an interaction with the sites we have visualized in these anatomical structures. Our results provide a detailed map of the distribution of benzodiazepine receptors and a basis for the understanding of pharmacological effects of these drugs in humans and for future studies of modifications of these receptors in neurological and neuropsychiatric conditions in humans.

Aged↗
PubMed1993

Benzodiazepine binding to GABAA receptors: differential effects of sulfhydryl modification.

The effects of sulfhydryl modification on benzodiazepine binding to gamma-aminobutyric acid type A (GABAA) receptors have been studied in membrane preparations from bovine cerebral cortex. After reduction of membranes with increasing concentrations of dithiothreitol, the binding of the partial inverse agonist [3H]Ro15-4513 (2.5 nM) was inhibited with an IC50 of 4.6 mM, while the binding of the classical agonist [3H]flunitrazepam was affected only at much higher concentrations (> 30 mM). Prior desensitization of the GABAA receptor by incubation with 10 microM muscimol had no effect on dithiothreitol inhibition of [3H]Ro15-4513 binding. In equilibrium assays, 10 mM dithiothreitol increased the KD for [3H]Ro15-4513 binding by more than three-fold and reduced the density of binding sites by more than one-third. The binding sites for [3H]Ro15-4513 were protected from the effects of dithiothreitol by carrying out the reduction step in the presence of 10 microM Ro15-4513 or 10 microM flunitrazepam. Alkylation of brain membranes by N-ethylmaleimide inhibited the binding of both [3H]Ro15-4513 and [3H]flunitrazepam with a similar concentration dependence. Equilibrium binding assays in the presence of 10 mM N-ethylmaleimide showed that both the affinity and number of binding sites for [3H]Ro15-4513 were reduced, whereas only the KD for [3H]flunitrazepam binding was affected. These results demonstrate that sulfhydryl modification of GABAA receptors has different effects on the binding of a classical benzodiazepine agonist and a partial inverse agonist, suggesting differences in the modes of binding of the two ligands.

Animals↗
PubMed1995

Triethyllead decreases central benzodiazepine receptor binding in rat cerebellum ex vivo.

Effect of triethyllead on the specific [3H]flunitrazepam binding was studied in rat cortical and cerebellar P2 fractions in vitro and in tissue homogenates of several rat brain regions ex vivo after 5 daily subcutaneous doses of 1.9 mg/kg triethyllead acetate to rats. Up to concentration of 100 microM, triethyllead did not affect significantly the specific [3H]flunitrazepam binding but attenuated marginally (14-18%) the GABAA receptor agonist, muscimol-induced elevation of [3H]flunitrazepam binding in cerebellar tissue. After the subacute treatment of rats with triethyllead, the specific [3H]flunitrazepam binding was 27% lower in cerebellum compared to control animals. In other brain regions the receptor binding was not changed. The data suggest that triethyllead modified the cerebellar GABAA receptor complex causing decreased binding in the benzodiazepine site. Such an inhibitory effect in the GABAA receptor complex may decrease cerebellar inhibitory output and augment the triethyllead induced convulsions and tremor.

Animals↗
PubMed2004

Chronic exposure of cells expressing recombinant GABAA receptors to benzodiazepine antagonist flumazenil enhances the maximum number of benzodiazepine binding sites.

The aim of this study was to better understand the mechanisms that underlie adaptive changes in GABAA receptors following their prolonged exposure to drugs. Exposure (48 h) of human embryonic kidney (HEK) 293 cells stably expressing recombinant alpha1beta2gamma2S GABAA receptors to flumazenil (1 or 5 microM) in the presence of GABA (1 microM) enhanced the maximum number (Bmax) of [3H]flunitrazepam binding sites without affecting their affinity (Kd). The flumazenil-induced enhancement in Bmax was not counteracted by diazepam (1 microM). GABA (1 nM-1 mM) enhanced [3H]flunitrazepam binding to membranes obtained from control and flumazenil-pretreated cells in a concentration-dependent manner. No significant differences were observed in either the potency (EC50) or efficacy (Emax) of GABA to potentiate [3H]flunitrazepam binding. However, in flumazenil pretreated cells the basal [3H]flunitrazepam and [3H]TBOB binding were markedly enhanced. GABA produced almost complete inhibition of [3H]TBOB binding to membranes obtained from control and flumazenil treated cells. The potencies of GABA to inhibit this binding, as shown by a lack of significant changes in the IC50 values, were not different between vehicle and drug treated cells. The results suggest that chronic exposure of HEK 293 cells stably expressing recombinant alpha1beta2gamma2S GABAA receptors to flumazenil (in the presence of GABA) up-regulates benzodiazepine and convulsant binding sites, but it does not affect the allosteric interactions between these sites and the GABA binding site. Further studies are needed to elucidate these phenomena.

Binding Sites↗
PubMed1997

Allosteric interactions between gamma-aminobutyric acid, benzodiazepine and picrotoxinin binding sites in primary cultures of cerebellar granule cells. Differential effects induced by gamma- and delta-hexachlorocyclohexane.

Allosterism between gamma-aminobutyric acid (GABA), benzodiazepine and picrotoxinin recognition sites on the GABAA receptor was studied in primary cultures of cerebellar granule cells. The increase in [3H]flunitrazepam binding induced by GABA was inhibited by bicuculline and picrotoxinin and the decrease in [35S]t-butylbicyclophosphorothionate ([35S]TBPS) binding mediated by GABA was reverted by bicuculline. The effects of hexachlorocyclohexanes (the convulsant gamma- and the depressant delta-isomers, both acting at the picrotoxinin recognition site) on GABA and benzodiazepine sites were studied. delta-Hexachlorocyclohexane, but not the gamma-isomer (lindane), increased [3H]flunitrazepam binding in a concentration-dependent manner (EC50: 8.3 microM). This increase in [3H]flunitrazepam binding was reduced by bicuculline and picrotoxinin. The gamma-isomer reduced the increase in [3H]flunitrazepam binding induced by GABA or delta-hexachlorocyclohexane. Neither delta- nor gamma-hexachlorocyclohexane inhibited [3H]GABA binding. Moreover, the inhibition of [35S]TBPS binding induced by delta-hexachlorocyclohexane was not reverted by bicuculline. The results obtained in this study in vitro agree with the pharmacological properties and the effects of gamma- and delta-hexachlorocyclohexane in vivo. It is concluded that delta-hexachlorocyclohexane acts as a positive allosteric modulator and gamma-hexachlorocyclohexane acts as a non-competitive antagonist of the GABAA receptor.

Animals↗
PubMed1997

Zolpidem binding sites on the GABA(A) receptor in brain from human cirrhotic and non-cirrhotic alcoholics.

The displacement of [3H]flunitrazepam by unlabelled flunitrazepam or zolpidem was used to assess the affinity and density of sub-types of GABA(A) receptors in the superior frontal and primary motor cortices of ten alcoholic, seven alcoholic-cirrhotic and ten matched control cases. The binding was best fitted by a model with a single site for flunitrazepam, but two sites for zolpidem. Neither the patients' age nor the post-mortem interval were significantly correlated with the affinity or density of any of the binding sites. The affinity of all ligands did not differ either between cortical regions or across case groups. Hence, the density of each binding site was analyzed at constant affinity. The densities of flunitrazepam and high-affinity zolpidem binding sites were invariant across cortical regions and case groups. Low-affinity zolpidem binding sites were significantly more dense in the frontal than in the motor cortex of alcoholic cases irrespective of cirrhosis, whereas this regional difference was not significant in control cases.

Adult↗
PubMed2001

Mercury interaction with the GABA(A) receptor modulates the benzodiazepine binding site in primary cultures of mouse cerebellar granule cells.

Mercury compounds are neurotoxic compounds with a great specificity for cerebellar granule cells. The interaction of mercury compounds with proteins in the central nervous system may underlie some of their effects on neurotransmission. In this work we study the interaction of mercuric chloride (HgCl2) and methylmercury (MeHg) with the GABA(A) receptor in primary cultures of cerebellar granule cells. Both compounds increased, dose dependently, the binding of [3H]flunitrazepam to the benzodiazepine recognition site. EC50 values for this effect were 3.56 and 15.24 microM for HgCl2 and MeHg, respectively, after 30 min exposure of intact cultured cerebellar granule cells. The increase of [3H]flunitrazepam binding by mercury compounds was completely inhibited by the GABA(A) receptor antagonists bicuculline and picrotoxinin, and by the organochlorine pesticide alpha-endosulfan. It was also partially inhibited by the anion transporter blocker DIDS, however this effect could be due to a possible chelation of mercury by DIDS. Intracellular events, like intracellular calcium, kinase activation/inactivation or antioxidant conditions did not affect [3H]flunitrazepam binding or its increase induced by mercury compounds. The sulfhydryl alkylating agent N-ethylmaleimide mimicked the effect of mercury compounds on [3H]flunitrazepam binding suggesting a common mechanism. We conclude that mercury compounds interact with the GABA(A) receptor by the way of alkylation of SH groups of cysteinyl residues found in GABA(A) receptor subunit sequences.

Alkylation↗
PubMed2004

Chronic prenatal ethanol exposure alters hippocampal GABA(A) receptors and impairs spatial learning in the guinea pig.

Chronic prenatal ethanol exposure (CPEE) can injure the developing brain, and may lead to the fetal alcohol syndrome (FAS). Previous studies have demonstrated that CPEE upregulates gamma-aminobutyric acid type A (GABA(A)) receptor expression in the cerebral cortex, and decreases functional synaptic plasticity in the hippocampus, in the adult guinea pig. This study tested the hypothesis that CPEE increases GABA(A) receptor expression in the hippocampus of guinea pig offspring that exhibit cognitive deficits in a hippocampal-dependent spatial learning task. Timed, pregnant guinea pigs were treated with ethanol (4 g/kg maternal body weight per day), isocaloric-sucrose/pair-feeding, or water throughout gestation. GABA(A) receptor subunit protein expression in the hippocampus was measured at two development ages: near-term fetus and young adult. In young adult guinea pig offspring, CPEE increased spontaneous locomotor activity in the open-field and impaired task acquisition in the Morris water maze. CPEE did not change GABA(A) receptor subunit protein expression in the near-term fetal hippocampus, but increased expression of the beta2/3-subunit of the GABA(A) receptor in the hippocampus of young adult offspring. CPEE did not change either [(3)H]flunitrazepam binding or GABA potentiation of [(3)H]flunitrazepam binding, but decreased the efficacy of allopregnanolone potentiation of [(3)H]flunitrazepam binding, to hippocampal GABA(A) receptors in adult offspring. Correlational analysis revealed a relationship between increased spontaneous locomotor activity and growth restriction in the hippocampus induced by CPEE. Similarly, an inverse relationship was found between performance in the water maze and the efficacy of allopregnanolone potentiation of [(3)H]flunitrazepam binding in the hippocampus. These data suggest that alterations in hippocampal GABA(A) receptor expression and pharmacological properties contribute to hippocampal-related behavioral and cognitive deficits associated with CPEE.

Animals↗
PubMed1997

Potentiation by ethanol of GABA-induced current and facilitation of its desensitization in cultured rat cortical neurons.

1. Patch-clamp whole cell recording was performed to elucidate whether or not ethanol, at low concentration, has an effect on the GABAA receptor in cultured rat cortical neurons as compared with flunitrazepam. 2. Bath application of ethanol (0.01%) or flunitrazepam (1 mM) potentiated the peak amplitude of GABA-induced (10 microM) current without affecting the equilibrium potential. 3. The decay time constant and time to peak of GABA-induced current were shortened in the presence of ethanol or flunitrazepam. 4. These findings indicate that a low concentration of ethanol and flunitrazepam potentiates the GABA-induced current concomitantly with acceleration of desensitization to the drug.

Animals↗