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PubMed1995

The essential oil from Tagetes minuta L. modulates the binding of [3H]flunitrazepam to crude membranes from chick brain.

The hypothesis that the essential oil from Tagetes minuta L. can interact with biological membranes was investigated by assessing its ability of perturbing the binding of a benzodiazepine [flunitrazepam (FNTZ)] to crude members from chick brains. The essential oil from T. minuta L. inhibited [3H]FNTZ specific binding to chick brain members. These values were obtained from the analysis of the saturation curve for the kinetic parameters: dissociation equilibrium constant (Kd) = 2.47 +/- 0.32 nM, maximal binding (Bmax) = 556 +/- 5 fmoles/mg protein, and Hill coefficient (n) = 1.00 +/- 0.07 in the absence, and Kd = 6.73 +/- 1.4 nM, Bmax = 583 +/- 69 fmoles/mg protein, and n = 1.02 +/- 0.08 in the presence of 29 microgram/mL of essential oil. The essential oil could self-aggregate with a critical micellar concentration (CMC) of 60 microgram/mL. The marked increase in [3H]FNTZ nonspecific binding starting at 60 micrograms of essence per mL was due to that phenomenon and revealed the ability of self-aggregated structures to interact with members. [3H]FNTZ specific binding decrement as a function of essence concentration cannot be ascribed merely to oil's micelles ability of trapping the lipophilic radioligand molecules, because the discontinuous behavior that characterizes a monomer-aggregate phase transition was not shown. Oil's components might behave as competitive inhibitors or allosteric modulators of FNTZ specific binding. However, their ability to increase FNTZ nonspecific binding at concentrations below oil's CMC suggests that this effect may be due to oil's partitioning into the lipid bilayer. This latter phenomenon would induce an increment in membrane fluidity and a change on FNTZ binding site toward a lower affinity conformation. Therefore, the essential oil components can interact with brain membranes either as monomers, by partitioning into the lipid bilayer, or as self-aggregated structures, through an adsorption to the membrane surface.

Animals↗
PubMed2007

[3H]-flunitrazepam-labeled benzodiazepine binding sites in the hippocampal formation in autism: a multiple concentration autoradiographic study.

Increasing evidence indicates that the GABAergic system in cerebellar and limbic structures is affected in autism. We extended our previous study that found reduced [(3)H]flunitrazepam-labeled benzodiazepine sites in the autistic hippocampus to determine whether this reduction was due to a decrease in binding site number (B (max)) or altered affinity (K (d)) to bind to the ligand. Quantitation of hippocampal lamina demonstrated a 20% reduction in B (max) indicating a trend toward a decreased number of benzodiazepine binding sites in the autistic group but normal K (d) values. A reduction in the number of hippocampal benzodiazepine binding sites suggests alterations in the modulation of GABA(A) receptors in the presence of GABA in the autistic brain, possibly resulting in altered inhibitory functioning of hippocampal circuitry.

Adolescent↗
PubMed1995

An autoradiographical saturation kinetic study of the different benzodiazepine binding sites in rat brain by using [3H] flunitrazepam as a radioligand.

The present study reports on the equilibrium association constant (KD) and receptor density (Bmax) values of a number of brain areas from the mesencephalon, cerebral cortex, hippocampus, and cerebellum for the overall benzodiazepine (BZ) binding sites as well as for benzodiazepine binding site subtype 1 (BZ1) and subtype 2 (BZ2), determined by autoradiographical procedures using [3H] flunitrazepam. The differences between BZ1 and BZ2 binding sites were analyzed using the specific BZ1 agonist zolpidem as inhibitor of the radioligand. Statistically significant differences in the affinities of BZ2 with respect to BZ and BZ1 binding site were mainly found in cortical layers when pKD (negative logarithms of KD values) values were compared (ANOVA-SNK test). The distribution of Bmax, as well as the percentages of BZ1 and BZ2 and Hill coefficients which, surprisingly, are always close to 1 (> 0.9) for all the saturation kinetics analyzed, are also described. The possibility of heterogeneity related to anatomical distribution in the different subtypes is discussed.

Analysis of Variance↗
PubMed1983

[3H]R05-4864 and [3H]flunitrazepam binding in kainate-lesioned rat striatum and in temporal cortex of brains from patients with senile dementia of the Alzheimer type.

In agreement with other workers we report increased [3H]R05-4864 binding in kainate-lesioned rat striatum. [3H]R05-4864 binding, a possible glial marker, was also increased in temporal cortex obtained post-mortem from patients with Alzheimer's disease. [3H]Flunitrazepam binding was decreased in these brain samples, possibly indicative of neuronal cell loss. It is suggested that the poor binding characteristics of [3H]R05-4864 in human brain samples may limit its usefulness in assessing gliosis.

Aged↗
PubMed1986

Brain regional [3H]flunitrazepam binding in rats chronically treated with bupropion or B.W.306U.

After 21 days of twice daily i.p. injections of bupropion (10 mg/kg), B.W.306U (10 mg/kg) or saline, 5 rat brain regions were removed for [3H]flunitrazepam binding assay. Scatchard analysis of the binding data revealed no change in the Bmax in any brain regions in drug-treated rats compared to controls. There was, however, a significant change in the Kd value in the limbic forebrain of B.W.306U-treated rats.

Animals↗
PubMed1989

Effects of chlordiazepoxide, chlorpromazine, diazepam, diphenylhydantoin, flunitrazepam and haloperidol on the voltage-dependent sodium current of isolated mammalian brain neurons.

The effects of chlordiazepoxide, chlorpromazine, diazepam, diphenylhydantoin, flunitrazepam and haloperidol on the voltage-dependent sodium current (INa) were studied on the hippocampal pyramidal neurons, isolated acutely from rats, using a concentration clamp technique. The drugs used here reduced dose-dependently the peak amplitude of INa without affecting its current-voltage relationship. Chlorpromazine was most potent drug inhibiting the INa among them. Chlorpromazine and diphenylhydantoin at the concentration of half inhibition (IC50; 4 x 10(-6) M and 2 x 10(-4) M, respectively) shifted the steady state inactivation curve by more than 20 mV to a hyperpolarizing direction. Both drugs also caused a use-dependent inhibition of the INa. These results suggest that the drugs may block preferentially the inactivated sodium channels. While the concentrations of the drugs for inhibiting the INa are thought to be higher than those for affecting respective receptors for neurotransmitters, the results presented here may provide useful information to elucidate additional modes of action of these drugs in mammalian central nervous system.

Animals↗
PubMed1990

The role of striatopallidal neurones utilizing gamma-aminobutyric acid in the pathophysiology of MPTP-induced parkinsonism in the primate: evidence from [3H]flunitrazepam autoradiography.

The GABA/benzodiazepine receptor complex in the basal ganglia of primates treated with the neurotoxin n-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been studied by semi-quantitative autoradiography with [3H]flunitrazepam ([3H]FNZ). Systemic treatment with MPTP produced a stable and lasting parkinsonian condition, with pronounced bradykinesia, akinesia and tremor. In the lateral segment of the globus pallidus (GPL) there was a significant reduction of [3H]FNZ binding compared with non-treated animals. There were no significant changes in the [3H]FNZ binding in the caudate nucleus, putamen and medial globus pallidus (GPM). This suggests that MPTP-treatment increases GABA release within the GPL exclusively. In view of the available evidence suggesting increased striatal output, and reduced unit activity within the GPL of the MPTP-treated primate, it seems likely that the striatal GABAergic output to the GPL is overactive in this model of Parkinson's disease. Furthermore, as there is no evidence for a change in GABA function within the GPM using this measure, the striatal neurones which innervate the GPM may be differentially affected by loss of dopamine innervation. In line with structural evidence and extrastriatal dopamine receptor distribution this suggests that the two striatopallidal systems are functionally heterogeneous. A hemi-parkinsonian primate model has also been used in this study. This model was produced by injection of MPTP directly into one carotid artery. The substantia nigra pars compacta (SNc) was destroyed on the injected side alone, and consequently the appearance of parkinsonian symptoms was confined to the contralateral side. [3H]FNZ binding in the GPL appears to be bilaterally reduced in this model, suggesting an interaction between the treated and non-treated side of the brain. In addition there is increased binding in the putamen and GPM with respect to the non-treated side of the brain. The increased [3H]FNZ binding in the GPM of the unilateral model may be due to the greater disruption of the nigropallidal and/or nigrostiatal dopamine neurones relative to the systemic model. The former would have the effect of uncoupling D1 dopamine receptors located on the terminals of striatal efferents from nigropallidal dopamine input, and as D1 dopamine receptors are implicated in the presynaptic control of GABA release from the terminals of striatal efferents, this would consequently reduce the level of GABA release in the GPM. The latter possibility would suggest that striatopallidal neurones projecting to GPM are more resistant to the effects of dopaminergic denervation than those projecting to GPL.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1992

Increased hypothalamic [3H]flunitrazepam binding in hypothalamic-pituitary-adrenal axis hyporesponsive Lewis rats.

We have previously demonstrated that susceptibility of Lewis (LEW/N) rats to inflammatory disease, compared to relatively resistant Fischer (F344/N) rats, is related to deficient glucocorticoid counter-regulation of the immune response resulting from deficient corticotropin-releasing hormone (CRH) responsiveness to inflammatory and other stress mediators. The GABA/benzodiazepine receptor complex is an important negative modulator of CRH secretion and responsiveness to excitatory stimuli. In this study, we have examined in vitro binding of [3H]flunitrazepam to hypothalamic membrane preparations from LEW/N and F344/N rats. LEW/N rats had significantly more hypothalamic benzodiazepine binding sites (Bmax) than F344/N rats, but there were no differences in benzodiazepine binding affinities (Kd) between these two strains. The differences in benzodiazepine receptor number were consistent with the respective plasma corticosterone levels in the two strains, and with previous work indicating a negative correlation between corticosterone levels and benzodiazepine binding site number. Adrenalectomy of F344/N rats increased benzodiazepine binding to levels comparable to LEW/N animals and treatment of adrenalectomized F344/N rats with DEX resulted in lowering of benzodiazepine Bmax to levels that did not differ significantly from those of intact F344/N rats. There was no significant change in receptor number in either adrenalectomized or DEX-treated LEW/N rats. These findings suggest that basal benzodiazepine receptor differences between these strains may be partially related to strain differences in corticosterone levels, however that additional factors may contribute to maintenance of these differences in LEW/N rats. Since benzodiazepines attenuate hypothalamic CRH secretion through GABAergic inhibition, we suggest that strain differences in receptor number could also augment strain differences in hypothalamic-pituitary-adrenal axis function through differential sensitivity to GABA-mediated feedback.

Adrenalectomy↗
PubMed1992

Regulation of flunitrazepam binding in the dorsal horn of the spinal cord by adrenalectomy and corticosteroids.

Adrenal corticosteroids and adrenalectomy (ADX) have opposing effects on benzodiazepine binding sites in brain regions. These treatments were employed to study [3H]flunitrazepam (FLU) binding in regions punched out from the rat spinal cord. We found that binding was higher in dorsal horn than in ventral horn, and minimal in white matter. Clonazepam and RO 15-1788 largely displaced [3H]FLU binding, whereas RO 5-4864 was weakly active. Four days post-ADX, binding increased exclusively in the dorsal horn, and this effect was reversed by administration of corticosterone (CORT), but not dexamethasone (DEX) or aldosterone (ALDO) given over 4 days. When endogenous CORT was increased by administration of cold stress to adrenal-intact rats, reduced benzodiazepine (BDZ) binding was also observed in the dorsal horn. When added in vitro, only ALDO and not CORT or DEX, inhibited [3H]FLU binding. It is suggested that steroids with affinity for the type I corticosteroid receptor (CORT, ALDO) decrease [3H]FLU binding to a neural-type BDZ receptor in the dorsal horn. Reduction of the inhibitory BDZ system may be physiologically important, and can partly explain the enhancement of excitatory synaptic transmission produced by corticosteroids at the level of the spinal cord.

Adrenal Glands↗
PubMed1993

Male rat sexual behavior induces changes in [3H]flunitrazepam binding.

The effect of male rat sexual behavior on the binding of [3H]-flunitrazepam (FNP) in frontal cortex, hypothalamus and hippocampus was measured. The groups included were: (A) control (no sexual experience) handled males; (B) male rats sacrificed 24 h after their fifth mating experience; (C) males sacrificed 48 h after their fifth mating experience; (D) male rats sacrificed after 5 intromissions during the sixth mating experience; and (E) males sacrificed immediately after the ejaculation during the sixth mating experience. Relative to handled controls, significant decreases in maximal [3H]-FNP binding (Bmax) were observed in frontal cortex and hippocampus of animals sacrificed after 5 intromissions and in frontal cortex of rats sacrificed 24 h after the last mating experience. Relative to males sacrificed after 5 intromissions, males sacrificed immediately after ejaculation exhibited a rapid increase in Bmax in frontal cortex and hippocampus. No between-group differences in Kd for [3H]-FNP were noted, and sexual experience had no effect on the Bmax of [3H]-FNP in the hypothalamus.

Animals↗
PubMed1994

Chick imprinting performance and susceptibility to acute stress associated to flunitrazepam receptor increase.

One-day-old chicks were selected on their performance in imprinting behaviour and termed high-imprinted (H-I), partially imprinted (P-I) and low-imprinted (L-I) chicks. Then, H-I and L-I chicks were submitted to acute handling stress and [3H]flunitrazepam receptor-binding was performed on synaptosomal membranes from forebrain at various times after handling. The receptor number significantly increased in L-I but not in H-I chicks at 30 min after handling while the affinity remained unchanged at all times. In addition, when the three selected groups were maintained to reach 15 days of age and then they were submitted to acute swimming stress, the degree of receptor increase was also inversely related to the degree of imprinting performance. The receptor increase associated to swimming stress was higher in the left hemisphere, suggesting an interhemispheric asymmetry of stress effects. The results suggest that more-imprinted chicks are less susceptible than less-imprinted chicks to acute stress associated to central benzodiazepine receptor increase, probably due to differences in the degree of endogenous emotionality.

Animals↗
PubMed1982

Anion-dependent modulation of [3H]muscimol binding and of GABA-stimulated [3H]flunitrazepam binding by picrotoxin and related CNS convulsants.

Picrotoxin, isopropylbicyclophosphate (IPTBO) and related CNS-convulsants have allosteric effects on the binding of ligands to the GABA/benzodiazepine receptor complex. When binding experiments were performed at 23 degrees C and at 35 degrees C, these drugs inhibited [3H]muscimol binding and muscimol- or GABA-stimulated [3H]flunitrazepam binding, respectively. Both effects required the presence of C1-, Br-, I- but not of F- or SO4(2-). Picrotoxin and IPTBO could only partially inhibit [3H]muscimol binding. In contrast other GABA antagonists and convulsants like bicuculline, 3 alpha-hydroxy-16-imino-5 beta-17-aza-androstan-11-one (R 5135), strychnine and d-tubocurarine interferred completely with [3H]muscimol binding, also in the absence of those ions mentioned above which were essential for the effects of picrotoxin. Our results support the notion that drugs like picrotoxin and IPTBO which interfere with the GABA receptor effector system, may lead to an allosteric perturbation of GABA-recognition sites.

Animals↗
PubMed1983

Parallel changes in brain flunitrazepam binding and density of noradrenergic innervation.

The neonatal injection of neurotoxic compounds such as 6-hydroxydopa (6-OH-DOPA) and DSP 4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride) produces marked changes in the development of central noradrenergic neurons, i.e. permanent denervation of the cerebral cortex and hyperinnervation of the brain stem and the cerebellum. Adult animals treated at birth with both neurotoxins were used to study the binding of [3H]flunitrazepam (FNZ) to membranes isolated from these regions. The administration of both toxins produced a marked and similar increase in the number of FNZ binding sites in the cerebellum. In the brain stem, 6-OH-DOPA increased the density of these receptors much more than DSP 4 (33% vs. 13%), a difference similar to that observed between the effects of both compounds on brain stem NA. In the cerebral cortex, both compounds reduced the maximal number of FNZ binding sites. No changes were observed in the affinity of FNZ binding sites in the different structures. When adult rats treated at birth with 6-OH-DOPA received an injection of DSP 4 7 days later, the number of FNZ binding sites was reduced by 43% in the cerebellum, 53% in the brain stem and 11% in the cerebral cortex. In these structures, DSP 4 reduced the absolute number of FNZ binding sites to the same level both in rats treated at birth with 6-OH-DOPA and in non-treated animals receiving DSP 4 7 days before killing. These results are further support for the existence of close parallelism between the density of benzodiazepine receptors, as demonstrated by FNZ binding, and the density of brain noradrenergic innervation.

Animals↗
PubMed1987

Postnatal handling reduces novelty-induced fear and increases [3H]flunitrazepam binding in rat brain.

Postnatal handling of rat pups alters their response to novelty. We have now shown that, as adults, rats handled for the first three weeks of life showed a suppression of feeding in a novel environment that was less, and a [3H]flunitrazepam binding in whole brain that was greater than in non-handled animals. These data suggest that variations in benzodiazepam binding capacity could be related to individual differences in the fear response to novelty.

Animals↗
PubMed1991

Correlation between enhancement of [3H]flunitrazepam binding and suppression of pentylenetetrazol-induced seizures by L-lysine.

L-Lysine enhanced the specific [3H]flunitrazepam (FTZ) binding of bovine brain membranes in vitro. Inhibition of specific [3H]FTZ binding to brain membranes in vitro by pentylenetetrazol (PTZ) at concentrations 0.46 mM and below was reversed by increasing L-lysine concentrations in the incubation mixture; further increase of L-lysine concentration enhanced this binding. However, inhibition of [3H]FTZ binding by PTZ higher than 2.3 mM was reversed only partially by L-lysine. L-Lysine enhanced specific [35S]t-butylbicyclophosphorothionate (TBPS) binding on mouse brain membranes in a dose-dependent manner (EC approximately 5 microM). This enhancement was inhibited by PTZ dose dependently. Inhibition of [35S]TBPS binding by PTZ was attenuated slightly by L-lysine. L-Lysine enhanced [3H]FTZ binding in intact mice in a dose- or concentration-dependent manner with an ED50 of 6 mmol/kg body weight or EC50 of 3 mumol/g brain tissue, respectively. Similar effect was observed for L-lysine in ex vivo [3H]FTZ binding study when [3H]FTZ was incubated in vitro with an ED50 of 1 mmol/kg mouse or EC50 of 0.7 mumol/g brain. PTZ not only induced seizures, but also inhibited specific [3H]FTZ binding to brain membranes in a dose-dependent manner. L-Lysine, in a dose-dependent manner, suppressed seizures caused by PTZ at 50 or 60 mg/kg, or prolonged the time of seizure onset (seizure latency) caused by higher doses of PTZ (90 or 100 mg/kg). Pretreatment with L-lysine at 1, 5, 10 or 20 mmol/kg not only reversed the inhibition of the specific [3H]FTZ binding caused by PTZ at 50, 90 or 100 mg/kg, but also enhanced this binding above control level.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Potency of several type I-benzodiazepine receptor ligands for inhibition of [3H]flunitrazepam binding in different rat brain tissues.

The potency of several different non-selective and type I-benzodiazepine receptor-selective ligands as inhibitors of [3H]flunitrazepam binding was measured in different rat brain tissues. In contrast to the non-selective ligands, which had a similar potency in all brain tissues investigated, the potency of the type I-receptor-selective ligands was highest in cerebellar membranes and varied in other brain tissues.

Aging↗
PubMed1995

S-adenosyl-L-homocysteine and 5'-methylthioadenosine inhibit binding of [3H]flunitrazepam to rat brain membranes.

The effect of inhibitors of transmethylation reactions, S-adenosylhomocysteine and 5'-methylthioadenosine, on [3H]flunitrazepam-specific binding to the rat brain membranes has been investigated. Both S-adenosylhomocysteine and 5'-methylthioadenosine are able to inhibit binding with Ki values of 7.9 microM and 15.8 microM respectively. These compounds therefore may be candidate endogenous benzodiazepine-receptor ligands. In light of these and other data possible correlations between phospholipid methylation and gamma-aminobutyric acid (GABA) receptor function are discussed.

Animals↗
PubMed1986

Characterization of benzodiazepine binding sites after short-wave photo-affinity labeling with flunitrazepam.

Membranes prepared from rat cerebral cortex were irradiated with short-wave UV light in the presence of flunitrazepam (FZ). This photo-affinity labeling (PAL) drastically reduces the potency of FZ binding to these membranes, but the binding of 3H-beta-carboline-3-carboxylate ethyl ester (3H-BCCE) was found to be essentially unchanged. 3H-BCCE binding was therefore determined in the presence of an antagonist (BCCE itself), an agonist (FZ) and a compound reported to discriminate between multiple benzodiazepine sites (CL 218,872). The results with BCCE are consistent with a single population of sites, but FZ binds to some of the sites with a reduced affinity (KI = 30 nM) and to the remaining sites with a very low affinity (KI approximately equal to 1 microM). CL 218,872 shows a reduced affinity but appears to interact with all of the sites. Taken together, these results indicate that the binding domains for BCCE and FZ are not identical, and that CL 218,872 interacts more strongly with the antagonist domain.

Affinity Labels↗