Benzodiazepine Receptors In Rat Brain Research Articles

The combined effects of midazolam and propofol sedation on muscle power

We performed a randomised, crossover study to investigate the effects of intravenous sedation on grip strength and bite force. Twenty male volunteers received a bolus intravenous injection of midazolam (0.02 mg.kg(-1)) together with a 30-min propofol infusion designed to achieve an effect-site concentration of 1.0 μg.ml(-1). Observed variables included bispectral index, observer's assessment of alertness/sedation, correct answer rate of Stroop colour-word test, grip strength and bite force. Grip strength decreased from a median (IQR [range]) of 483 (443-517 [380-586]) N to 358 (280-405 [108-580]) N (p < 0.001) during sedation and recovered following flumazenil administration, while bite force increased from 818 (593-1026 [405-1406]) N to 1377 (1243-1585 [836-2357]) N (p < 0.001) during sedation. Although bite force gradually returned to baseline following flumazenil administration, it remained increased throughout the experimental period. We conclude that bite force increased during intravenous sedation and that this may have clinical implications.

The Heteroyohimbine Mayumbine Binds with High Affinity to Rat Brain Benzodiazepine Receptors in vitro

Mayumbine, a naturally occurring heteroyohimbine, was isolated from Rauwolfia vomitoria extracts and shown to potently (IC50 = 76 ± 3.5 nM) inhibit the in vitro binding of 3H-diazepam to the benzodiazepine sites within the rat GABAA receptor complex.

Postnatal development of peripheral-type benzodiazepine receptors in rat brain and peripheral tissues

We examined the postnatal development of peripheral-type benzodiazepine receptors (PBRs), labelled with [ 3H]PK 11195, in rat brain and peripheral tissues. Specific [ 3H]PK 11195 binding exhibited a heterogeneous patterns of postnatal development in the rat: three patterns of increase, decrease and no change. Hence, the density of the PBRs can be independently regulated in each tissue during postnatal development, and the postnatal alterations in the density might be parallel with the functional activities coupled to the receptors.

Direct interactions of androgenic/anabolic steroids with the peripheral benzodiazepine receptor in rat brain: implications for the psychological and physiological manifestations of androgenic/anabolic steroid abuse.

The peripheral benzodiazepine receptor (PBR) is a mitochondrial protein involved in regulating steroid synthesis and transport. We report here the effects of androgenic/anabolic steroids (AAS) on the binding of the PBR-specific ligand [3H] PK11195 to male rat brain cortical synaptoneurosomes. Two synthetic AAS, stanozolol and 17beta-testosterone cypionate (17beta-cyp), significantly inhibited 1 nM [3H] PK11195 binding at concentrations greater than 5 and 25 microM, respectively. Stanozolol was the most effective inhibitor, reducing [3H] PK11195 binding by up to 75%, compared to only 40% inhibition by 17beta-cyp, at 50 microM AAS concentration. Two other AAS, 17alpha-methyltestosterone and nortestosterone decanoate, were incapable of inhibiting [3H] PK11195 binding at concentrations up to 50 microM. On the basis of Scatchard/Rosenthal analysis, [3H] PK11195 binds to two classes of binding sites, and the inhibition of [3H] PK11195 binding by stanozolol appears to be allosteric, primarily reducing binding to the higher affinity [3H] PK11195 binding site. These results, in combination with earlier studies indicating the direct effects of AAS on the function of additional central nervous system receptor complexes, suggest that the behavioral and psychological effects of AAS result from the interactions of AAS with multiple regulatory systems in the brain.

Autoradiographical study of types 1 and 2 of benzodiazepine receptors in rat brain after chronic ethanol treatment and its withdrawal

The effect of chronic ethanol treatment, and its withdrawal on benzodiazepine binding sites in rat brain is described in this autoradiographical study using the benzodiazepine agonist [ 3H]flunitrazepam. Several areas of the rat cerebral cortex, hippocampus, mesencephalon, cerebellum and lateral geniculate nucleus were studied in animals, chronically treated with ethanol, and 24 or 48 hr after ethanol withdrawal. The [ 3H]flunitrazepam binding and the relative percentages of binding to BZ1 and BZ2 sites, using zolpidem as a BZ1 site inhibitor, are described. The cerebellum and red nucleus, which only express BZ1 binding sites, appear to be areas significantly modified by ethanol and its withdrawal. In no other structure did ethanol modify [ 3H]flunitrazepam binding nor change the relative percentage of BZ1 and BZ2 sites.

Rapid down-regulation of [ 3H]zolpidem binding to rat brain benzodiazepine receptors during flurazepam treatment

In a previous study, it was found that down-regulation of benzodiazepine (BZ) binding in rats treated 4 weeks with flurazepam was relatively greater and more widespread when measured with [ 3H]zolpidem, a selective ‘BZ 1 receptor’ ligand, than that measured with the non-selective ligand, [ 3H]flunitrazepam. In the present study, the time course for down-regulation of [ 3H]zolpidem binding was studied in rats treated with flurazepam. [ 3H]Zolpidem binding was also studied in rats given a midazolam treatment shown to cause tolerance. Rats were chronically treated with flurazepam for 1 or 2 weeks, or with midazolam for 3 weeks, then killed immediately after the treatment. Another group of rats was acutely treated with desalkyl-flurazepam and killed 30 min later. After 2 weeks of flurazepam treatment, the B max of [ 3H]zolpidem binding was decreased by 22% in cerebral cortex, 26% in cerebellum and 33% in hippocampus, with no change in the K d in any region. After 1 week of flurazepam treatment, the B max was decreased by 23% in cerebellum and 14% in hippocampus, but not changed in cerebral cortex. The K d was increased in cerebral cortex, but not in cerebellum or hippocampus. Neither the B max nor the K d of [ 3H]zolpidem binding was affected by acute desalkyl-flurazepam treatment, or by 3 weeks of midazolam treatment. These results, in combination with previous findings, which showed no change in [ 3H]flunitrazepam binding after 1 or 2 week flurazepam treatment, and no change in cerebellum even after the 4 week treatment, may indicate a shift in BZ receptor subtypes in flurazepam-tolerant rats. Such a shift could be based on possible changes in the subunit composition or conformation of GABA A/BZ receptors after 1 or 2 week flurazepam treatment.

CHOLECYSTOKININ RECEPTOR BINIDIING AFTER LONG-TERM ETHANOL TREATMENT IN RATS

Brain cholecystokinin (CCK) receptors have been implicated in anxiety disorders and suicidal behaviour. We have examined the radioligand binding ability of CCK and benzodiazepine receptors in rat brain after long-term intermittent voluntary vs voluntary and forced low-dose ethanol exposure. During 58 weeks, one group of rats had a choice between ethanol and water as the drinking fluid for 24 hr each week. Another group of rats had the same weekly choice between ethanol and water, but at the end of each 24 hr choice period, ethanol (2.0 g/kg) was injected. During the second period of ethanol treatment, lasting for 32 weeks, both ethanol-treated groups had continuous free access to ethanol and water. These two treatments have previously been shown to induce partially different neurochemical alterations. In the present investigation, benzodiazepine receptor binding in the frontal cortex, hippocampus and striatum was similar in both ethanol treatment groups compared to controls. CCK receptor binding in the hippocampus and striatum did not differ between the three groups; however, in the frontal cortex, there was an increase in the apparent number of CCK binding sites in the group of rats submitted to voluntary plus forced ethanol exposure as compared to the control group or the voluntary intake group. These results suggest that long-term ethanol treatment may lead to alterations in brain CCK-ergic neurotransmission, but that the changes are specific to the treatment schedule.

Imidazo[1,2-b]Pyridazines. XVI. Synthesis and Central Nervous System Activities of Some 6-(Chloro, Alkylthio, Phenylthio, Benzylthio or Pyridinylmethylthio)-3-(unsubstituted, benzamidomethyl or methoxy)-2-(styryl or benzoyl)imidazo[1,2-b]pyridazines

Some 6-( chloro, alkylthio, phenylthio, benzylthio or pyridinylmethylthio )-3-( unsubstituted , benzamidomethyl or methoxy )-2-styrylimidazo[1,2-b] pyridazines and 6-chloro-3-( unsubstituted and benzamidomethyl )-2-benzoylimidazo[1,2-b] pyridazines have been prepared and tested for their ability to displace [3H]diazepam from rat brain plasma membranes. The structures of 6-chloro-2-benzoyl[and 6-fluoro-2-(4′-tolyl)] imidazo [1,2-b] pyridazine have been confirmed by X-ray analyses. The reactions of 6-methylthio(and 6-phenylthio)pyridazin-3-amines with 3-bromo-1-phenylpropane-1,2-dione also have been investigated. The 6-substituted 3-unsubstituted 2-styryl(and benzoyl ) imidazo [1,2-b] pyridazines did not bind strongly to rat brain benzodiazepine receptors; nor did the 3-benzamidomethyl or 3-methoxy derivatives (cf. the 2-phenyl analogues). However, 3-benzamidomethyl-6-(pyridin-3-ylmethylthio)-2-styrylimidazo[1,2-b] pyridazine was an exception with IC50 68 nM.

Chronic ethanol consumption and withdrawal affects mitochondrial benzodiazepine receptors in rat brain and peripheral organs

Ethanol administration to rats for 30 days resulted in a significant decrease (−28%; P< 0.05) in the density of mitochondrial benzodiazepine receptors (MBR) in the olfactory bulb. The reduction in [ 3H]PK 11195 binding persisted 24 hr after cessation of alcohol and had returned to normal values when measured 4 days later. Alterations were confined to this brain region and were not detected in the cerebral cortex, cerebellum or hippocampus. [ 3H]PK 11195 binding was elevated in the liver (100%; P<0.01), heart (43%; P< 0.01) and testis (27%; P<0.05) 30 days following ethanol consumption and this persisted for 1 and 4 days after abrupt withdrawal. A transitory decrease (−20%; P<0.05) in MBR density was observed in the adrenal gland following 30 days of alcohol ingestion, but disappeared during withdrawal. The alterations in these receptors may be relevant to the cellular damage or dysfunction induced by chronic exposure to ethanol.

Central and peripheral benzodiazepine receptors in rat brain and platelets: effects of treatment with diazepam and clobazam

Tolerance to the effects of benzodiazepines (BZ) may be mediated by changes in benzodiazepine receptors (BZRs). Peripheral BZRs (in brain and platelets) and central BZRs (in brain) were measured in rats following intraperitoneal administration of diazepam and clobazam each for 4 and 12 days. BZRs were measured by binding assays using [ 3H] PK 11195 (peripheral) and [ 3H] flunitrazepam (central) as radioligands. Diazepam, but not clobazam, increased peripheral BZR numbers in platelets (both P < 0.005), but not in brain, after 4 and 12 days' treatment compared with appropriate controls. Neither drug altered central BZR affinities or numbers in rat brain. BZ effects on peripheral BZRs in platelets cannot be extrapolated to predict changes in brain receptors, either peripheral or central.

Effects of GABA Agonist, Sodium Valproate, on GABA and Benzodiazepine Receptors in Rat Brain

Psychiatry and Clinical NeurosciencesVolume 44, Issue 1 p. 156-157 Effects of GABA Agonist, Sodium Valproate, on GABA and Benzodiazepine Receptors in Rat Brain Nobutaka Motohashi, Nobutaka Motohashi Department of Neuropsychiatry, Yamanashi Medical College, YamanashiSearch for more papers by this authorKunihiko Shioe, Kunihiko Shioe Department of Neuropsychiatry, Yamanashi Medical College, YamanashiSearch for more papers by this authorTetsuhiko Kariya, Tetsuhiko Kariya Department of Neuropsychiatry, Yamanashi Medical College, YamanashiSearch for more papers by this author Nobutaka Motohashi, Nobutaka Motohashi Department of Neuropsychiatry, Yamanashi Medical College, YamanashiSearch for more papers by this authorKunihiko Shioe, Kunihiko Shioe Department of Neuropsychiatry, Yamanashi Medical College, YamanashiSearch for more papers by this authorTetsuhiko Kariya, Tetsuhiko Kariya Department of Neuropsychiatry, Yamanashi Medical College, YamanashiSearch for more papers by this author First published: March 1990 https://doi.org/10.1111/j.1440-1819.1990.tb00465.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume44, Issue1March 1990Pages 156-157 RelatedInformation

CGS 8216 treatment decreases central-type benzodiazepine receptors in rat brain

Central- and peripheral-type benzodiazepine receptors were analyzed in several brain areas of rats (n = 8–9) that had been treated for five days with CGS 8216 (20 mg/kg per day). Twenty-four hours after cessation of drug treatment a significant decrease of central-type benzodiazepine receptors as labeled by [ 3H]β-carboline-3-carboxylate ethyl ester ([ 3H]βCCE) and [ 3H]flunitrazepam ([ 3H]FNZ), but not of peripheral-type benzodiazepine receptors as labeled by [ 3H]RO 5-4864 could be observed in the animals treated with CGS 8216.

Benzodiazepine receptors in rat brain are altered by adrenalectomy

The effects of adrenalectomy on benzodiazepine receptors in discrete regions of rat brain were examined using [ 3H]flunitrazepam as a binding ligand. The concentration of benzodiazepine receptors was significantly increased by 25, 50 and 71% in hippocampus, striatum and hypothalamus, respectively, after adrenalectomy. In contrast, adrenalectomy did not affect the concentration of benzodiazepine receptors in cerebral cortex, olfactory bulb and cerebellum. No significant differences in the apparent binding affinity ( K d ) values were seen following adrenalectomy in any brain region examined. The adrenalectomy-induced increases [ 3H]flunitrazepam binding sites were completely reversed by glucocorticoid replacement with dexamethasone. These results demonstrate that adrenalectomy is capable of selectively modulating benzodiazepine receptors in brain regions presumably involved with glucocorticoid negative feedback. The data further suggest additional mechanisms by which endogenous hypothalamic-pituitary-adrenocortical hormones may affect ‘anxiety’ levels.

Modulation of specific [3H]phenytoin binding by benzodiazepines.

We have shown that diazepam (ED50 2.4 microM), flunitrazepam (ED50 10.2 microM) and Ro5-4864 (ED50 5 microM) are able to enhance both total and specific [3H]phenytoin binding. Picrotoxin (IC50 1.43 microM) and chloride, either NaCl or KCl (IC50 42.4 microM) inhibit both the increase in total and specific binding of [3H]phenytoin, Ro15-1788 does not. The optimum time for this enhancement was 3-4 hours. While the ED50's for the benzodiazepines are high their order of potency suggests that an involvement of both the "peripheral type" benzodiazepine receptor and the GABA-chloride ionophore complex is likely. Clonazepam (IC50 23 microM), oxazepam (IC50 12 microM) chlordiazepoxide (IC50 35 microM) and Ro8682-10, a convulsant benzodiazepine (IC50 16 microM) all inhibit both total and specific [3H]phenytoin binding. These effects were not blocked by chloride ions, picrotoxin or Ro 15-1788, and reached equilibrium within 45 minutes. This order of potency also parallels that for the "peripheral' benzodiazepine receptor in rat brain. These data suggest the presence of a micromolar benzodiazepine receptor site which may play a role in the control of CNS excitability. Nitrazepam, medazepam, bromazepam and the tetralobenzodiazepines U38335, U42794, U43434, and U37834 had no effect on total or specific [3H]phenytoin binding nor on the actions of the other benzodiazepines described in concentrations up to 50 microM.

Allosteric modulation of flunitrazepam binding to rat brain benzodiazepine receptors by methyl beta-carboline-3-carboxylate.

The inhibition of flunitrazepam (FNP) binding to rat brain benzodiazepine (BZ) receptors by methyl beta-carboline-3-carboxylate (MCC) was studied. Biphasic dissociation was observed for [3H]FNP and [3H]MCC in cerebral cortex, cerebellum, and hippocampus, although the dissociation of [3H]MCC was much faster. The dissociation rate of [3H]FNP was increased by MCC in the cerebellum, but was not altered in cerebral cortex or hippocampus. [3H]FNP binding stimulated by gamma-aminobutyric acid was enhanced in the presence of MCC in all three regions examined. These results indicate that MCC exerts these effects by interacting with allosteric sites that are different from the FNP recognition sites on the BZ receptors.

Antidepressant-anxiolytic interaction: Decreased density of benzodiazepine receptors in rat brain following chronic administration of antidepressants

Antidepressant-anxiolytic interaction: Decreased density of benzodiazepine receptors in rat brain following chronic administration of antidepressants

The benzodiazepine receptor in rat brain and its interaction with ethyl beta-carboline-3-carboxylate.

[3H]Ethyl beta-carboline-3-carboxylate ( [3H] beta-CCE) binds to a homogeneous population of recognition sites in rat whole brain membranes with high affinity. The [3H]beta-CCE binding is completely displaceable by low concentrations of a number of benzodiazepines with similar potencies found when using a 3H-benzodiazepine as the ligand. This suggests that the recognition sites for beta-CCE and the benzodiazepines are identical or that they are involved in a close interaction. The binding of [3H]beta-CCE does not obey simple mass-action kinetics. [3H]Flunitrazepam dissociation from its receptor population is biphasic, and different methods of initiation of this dissociation indicate that cooperative interactions take place within the receptor population. We conclude that the benzodiazepine receptor is a single entity that can exist in two conformations, the equilibrium between which may be controlled by some as yet unidentified factor.

Photoaffinity labeling of benzodiazepine receptors in rat brain with flunitrazepam alters the affinity of benzodiazepine receptor agonist but not antagonist binding.

Recently, it was proposed that beta-carbolines interact with a subset of benzodiazepine (BZD) binding sites in mouse brain. This postulate was based upon evidence showing changes in binding properties of the BZD receptor following photoaffinity labeling of membranes with flunitrazepam (FLU). Under conditions in which 80% of specific [3H]diazepam binding was lost in photolabeled membranes, specific [3H]propyl beta-carboline-3-carboxylate [( 3H]PCC) binding was spared. In this study, the binding of the BZD antagonists [3H]PCC, [3H]Ro15 1788 and [3H]CGS 8216 was examined in rat brain membranes following photoaffinity labeling with FLU. No significant changes in the apparent KD and small reductions in the Bmax of 3H antagonist binding were observed. However, in the same membranes, up to 89% of specific [3H]FLU binding was lost. When [3H]PCC (0.05 nM) was used to label the receptors in control and photolabeled membranes, the ability of BZD receptor agonists to inhibit [3H]PCC binding was greatly diminished in the photolabeled membranes. In contrast, the potency of BZD antagonists remained the same in both control and treated membranes. Based upon PCC/[3H]Ro15 1788 competition experiments, the ability of PCC to discriminate between BZD receptor subtypes was unaffected by photoaffinity labeling of cortical membranes.(ABSTRACT TRUNCATED AT 250 WORDS)

Heterogeneity of benzodiazepine receptors: experimental differences between [3H]flunitrazepam and [3H]ethyl-beta-carboline-3-carboxylate binding sites in rat brain membranes.

Abstract: This study was designed to analyze possible differences in the binding of [3H]flunitrazepam ([3H]FNZP) and [3H]ethyl ‐ β ‐ carboline ‐ 3 ‐ carboxylate ([3H]β‐CCE), to rat brain membranes, in various experimental conditions. In cerebral cortex, hippocampus, cerebellum, and orain stem the number of binding sites for [3H]β‐CCE was higher than for [3H]FNZP; both were displaced by clonazepam. Until the 7th day of postnatal brain development the numbers of [3H]FNZP and [3H]β‐CCE sites were equivalent; but later on, the β‐carboline sites increased to a higher level. Noradrenergic denervation by 6‐hydroxydopamine was followed in the hippocampal formation. Already after 2 days, there was a decrease in [3H]FNZP sites, which reached 70% of control after 14 days. Similar results were obtained with DSP‐4 denervation. This change was only in Bmax and not in KD, In contrast, the [3H]β‐CCE sites did not change with denervation. Neonatal injection of l ‐ 2,4,5 ‐ trihydroxyphenylalamine or DSP‐4 produced in the adult a decrease in [3H]FNZP sites in the cerebral cortex, in parallel with the noradrenergic denervation. On the other hand, there was an increase in the cerebellum and brain stem, in correspondence with the hyperinnervation by sprouting. In these rats, the number of sites for [3H]β‐CCE did not change in the different brain regions. With 0.1% Triton X‐100, applied to synaptosomal membranes, [3H]FNZP binding was reduced by 35%, while that of [3H]β‐CCE was not significantly changed. These results suggest that there is heterogeneity of binding sites for benzodiazepine receptors in rat brain. A tentative interpretation of the experiments involving noradrenergic denervation and hyperinnervation, as well as those with Triton X‐100, is that [3H]FNZP binds to pre‐ and postsynaptic receptors, while [3H]β‐CCE binds mainly to postsynaptic benzodiazepine receptors.

Solubilization of Brain Benzodiazepine Receptors with a Zwitterionic Detergent: Optimal Preservation of Their Functional Interaction with the GABA Receptors

Rat brain benzodiazepine receptors have been solubilized by means of the zwitterionic detergent CHAPS under conditions in which the GABA stimulation of [3H]flunitrazepam binding to the benzodiazepine receptors is maintained intact. This stimulation is partially or totally abolished when using other conventional detergents.