Cortical Benzodiazepine Receptors Research Articles

123I-Iomazenil Single-Photon Emission Computed Tomography Imaging in a Patient with Mild Traumatic Subdural Hematoma Accompanied by Delayed Transient Aphasia

Early and late images of 123I-iomazenil(IMZ)single-photon emission computed tomography(SPECT)reflect distributions of cerebral blood flow and those of cortical benzodiazepine receptor binding potential, respectively. Crossed cerebellar diaschisis reflects left-to-right asymmetry of metabolism in the cerebral hemispheres. We present a case of a 67-year-old woman who developed transient aphasia 3 days after the onset of a mild acute subdural hematoma. Computed tomography scan and magnetic resonance imaging during aphasia did not show enlargement of the hematoma or any new lesions. Electroencephalography did not show any abnormalities. Early images of 123I-IMZ SPECT 3 days after the onset of aphasia revealed a decrease in radioactivity in the right cerebellar hemisphere relative to that in the left cerebellar hemisphere. Late images of the same 123I-IMZ SPECT displayed a decrease in radioactivity in the left cerebral hemisphere relative to that in the right cerebral hemisphere. Twenty-four days later, the aphasia disappeared and the left-to-right asymmetries of radioactivity in the cerebellar and cerebral hemispheres on the early and late 123I-IMZ SPECT images also resolved.

Findings of 123I-Iomazenil SPECT During and After Stroke-Like Episodes in a Patient With MELAS

Reduced cortical benzodiazepine receptor binding potential in late images of I-iomazenil SPECT indicates neuronal damage in the cortex. We present the case of a 31-year-old woman with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) who had focal seizures in the right hand. FLAIR imaging in the ictal state revealed a high-intensity lesion in the left post-central gyrus, while I-iomazenil SPECT showed decreased tracer uptake in this lesion. The lesion completely disappeared on FLAIR imaging performed 1 month after the focal seizures; in contrast, I-iomazenil SPECT still revealed a significant decrease in tracer uptake in this lesion.

Regional differences in cortical benzodiazepine receptors of Alzheimer, vascular, and mixed dementia patients

ObjectiveWe examined regional benzodiazepine receptors (rBZR) using single photon emission CT (SPECT) in patients with Alzheimer disease (AD), vascular dementia (VaD), and mixed AD/VaD dementia (MD) and compared the changes in the availability of rBZR with those of regional cerebral blood flow (rCBF). MethodsA total of 7 patients with AD, 6 with MD, and 9 with VaD underwent SPECT studies with N-isopropyl-p-[123I] iodoamphetamine and 123I-iomazenil to measure rCBF and rBZR. The ratios of rCBF and rBZR uptake in brain subregions to the average global activity were compared among these diseases. In addition, we acquired z-score maps using 3-dimensional stereotactic surface projections of SPECT data. ResultsCompared with AD, VaD and MD showed rCBF and rBZR reduction predominantly in the frontal lobe, but rBZR images revealed more extensive and severe defects than rCBF images. In contrast, AD showed rCBF and rBZR reduction predominantly in the parietotemporal lobe compared with VaD and MD, but rCBF images revealed more extensive defects than rBZR images. ConclusionrCBF imaging can detect parietotemporal abnormalities in AD, while rBZR imaging may enable the demonstration of underlying pathophysiological differences in the frontal lobe between VaD, MD and AD, reflecting neuronal integrity in the cerebral cortex.

Angiotensin II AT1 receptor blocker candesartan prevents the fast up-regulation of cerebrocortical benzodiazepine-1 receptors induced by acute inflammatory and restraint stress

Centrally acting Angiotensin II AT1 receptor blockers (ARBs) protect from stress-induced disorders and decrease anxiety in a model of inflammatory stress, the systemic injection of bacterial endotoxin lipopolysaccharide (LPS). In order to better understand the anxiolytic effect of ARBs, we treated rats with LPS (50μg/kg) with or without 3 days of pretreatment with the ARB candesartan (1mg/kg/day), and studied cortical benzodiazepine (BZ) and corticotrophin-releasing factor (CRF) receptors. We compared the cortical BZ and CRF receptors expression pattern induced by LPS with that produced in restraint stress. Inflammation stress produced a generalized increase in cortical BZ1 receptors and reduced mRNA expression of the GABAA receptor γ2 subunit in cingulate cortex; changes were prevented by candesartan pretreatment. Moreover, restraint stress produced similar increases in cortical BZ1 receptor binding, and candesartan prevented these changes. Treatment with candesartan alone increased cortical BZ1 binding, and decreased γ2 subunit mRNA expression in the cingulate cortex. Conversely, we did not find changes in CRF1 receptor expression in any of the cortical areas studied, either after inflammation or restraint stress. Cortical CRF2 receptor binding was undetectable, but CRF2 mRNA expression was decreased by inflammation stress, a change prevented by candesartan. We conclude that stress promotes rapid and widespread changes in cortical BZ1 receptor expression; and that the stress-induced BZ1 receptor expression is under the control of AT1 receptor activity. The results suggest that the anti-anxiety effect of ARBs may be associated with their capacity to regulate stress-induced alterations in cortical BZ1 receptors.

Silent Cortical Neuronal Damage in Atherosclerotic Disease of the Major Cerebral Arteries

In atherosclerotic internal carotid artery (ICA) or middle cerebral artery (MCA) disease, hemodynamic compromise may cause selective neuronal damage manifested as loss of central benzodiazepine receptors (BZRs) in the normal-appearing cerebral cortex, without overt episode of stroke. To investigate the association of decreases in cortical BZRs with hemodynamic compromise and the effect of angiotensin receptor blockers (ARBs) on these receptors in patients whose atherosclerotic ICA or MCA disease is asymptomatic, we measured BZRs using positron emission tomography and 11C-flumazenil in 79 patients with asymptomatic atherosclerotic ICA or MCA disease and no cortical infarction. Three-dimensional stereotactic surface projections were used to calculate the BZR index, a measure of abnormally decreased BZRs in the cerebral cortex within the MCA distribution. Multiple regression analysis showed this index to be positively correlated with the value of oxygen extraction fraction, with the presence of silent subcortical infarcts, and with the presence of ischemic heart disease, whereas it was negatively correlated with the treatment of hypertension with ARBs. In asymptomatic atherosclerotic ICA or MCA disease, hemodynamic compromise is associated with selective neuronal damage manifested as decreases in cortical BZRs in the noninfarcted cerebral cortex, whereas ARBs are associated with preservation of cortical BZRs.

Spontaneous Recovery of Reduced Cortical Central Benzodiazepine Receptor Binding Potential on I-123 Iomazenil SPECT in a Patient With Status Epilepticus

Abstract: A reduction in cortical benzodiazepine receptor binding potential on late images of I-123 iomazenil SPECT indicates irreversible neural damage or loss. We present the case of a 26-year-old woman with status epilepticus in whom SPECT imaging using I-123 iomazenil and I-123 N-isopropyl-p-iodoamphetamine 7 and 9 days after the last seizure, respectively, demonstrated reduction in central benzodiazepine receptor binding potential with hyperperfusion in the affected cerebral hemisphere and crossed cerebellar hypoperfusion. However, 3 months later, repeat studies showed resolution of the reduction in cortical benzodiazepine receptor binding potential, resolution of hyperperfusion, and resolution of crossed cerebellar hypoperfusion.

I-123 Iomazenil SPECT Imaging in a Patient With Hemispheric Brain Damage Due to Cerebral Ischemia During Carotid Endarterectomy

A reduction in cortical benzodiazepine receptor binding potential on I-123 iomazenil SPECT images indicates cortical neural damage or loss. We present the case of a 63-year-old man who underwent endarterectomy for symptomatic cervical internal carotid artery stenosis. While MR imaging 1 month after surgery revealed ischemic lesions only in the white matter of the affected cerebral hemisphere, I-123 iomazenil SPECT at the same time demonstrated the absence of tracer uptake throughout the entire cerebral cortex, where global ischemic lesions and brain atrophy had developed on MR imaging performed 1 year after surgery.

Decrease in cortical benzodiazepine receptors in symptomatic patients with leukoaraiosis: a positron emission tomography study.

[11C]flumazenil (FMZ), a ligand that selectively binds to the central benzodiazepine receptor in the neuronal membrane, is useful for evaluating neuronal viability in a positron emission tomography (PET) scan. Using this ligand, we investigated whether there was a correlation between neuronal integrity in various brain structures and dementia in patients with leukoaraiosis. Twelve patients with extensive leukoaraiosis on magnetic resonance imaging were divided into groups of patients with or without dementia. Based on a 2-compartment, 2-parameter model that included metabolite-corrected arterial input and PET-measured cerebral radioactivity, the distribution volume of FMZ (FMZ-V(d)) was calculated in various regions of interest by nonlinear curve fitting. Additionally, tracer kinetic analysis was applied for voxel-by-voxel quantification of FMZ-V(d), and data analysis was performed by statistical parametric mapping. The presence of dementia was associated with a reduced FMZ-V(d) in widespread areas of the cerebral cortex, including the bilateral frontopolar and frontal/insular areas, the left temporo-occipital border areas, and the left marginal cortical areas. Differences in neuronal integrity in the cerebral cortex might determine whether patients with leukoaraiosis become symptomatic or not.

2-Oxo-2H-Pyrimido[2,1-b]Benzothiazoles Inhibit Brain Benzodiazepine Receptor Binding in vitro

2-Oxo-2H-pyrimido[2,1-b]benzothiazole derivatives were found to inhibit the in vitro binding of ³H-Ro 15-1788 (³H-flumazenil) to rat cortical benzodiazepine receptors with IC₅₀ values in the range of 0.7–13 μmol/l. The most potent compound, 2-oxo-4-phenyl-2H-pyrimido[2,1-b]- benzothiazole showed a similar potency to inhibit ³H-Ro 15-1788 binding to membrane preparations of rat brain cortex, cerebellum and hippocampus as well as to various subunit combinations of recombinant human γ-aminobutyric acid_A/benzodiazepine receptors. Scatchard plot analysis showed that 2-oxo-4-phenyl-2H-pyrimido[2,1-b]benzothiazole is a competitive inhibitor of ³H-Ro 15-1788 binding to rat brain cortical membrane preparations.

Atrophy of the corpus callosum associated with a decrease in cortical benzodiazepine receptor in large cerebral arterial occlusive diseases

OBJECTIVESIt remains controversial whether selective neuronal ischaemic change develops in patients with occlusion of the large cerebral arteries. Previous studies have shown atrophy of the corpus callosum with reduced cortical...

Alterations of benzodiazepine receptors in type II alcoholic subjects measured with SPECT and [123I]iomazenil.

Alterations in cortical benzodiazepine receptor density have been described in postmortem and in vivo studies of alcoholic subjects. The authors attempted to replicate these findings using single photon emission computed tomography and the benzodiazepine receptor radiotracer [123I]iomazenil. They measured the distribution volume of benzodiazepine receptors in 11 recently detoxified patients with type II alcoholism and 11 healthy comparison subjects. The tracer was given as a bolus followed by a continuous infusion to achieve sustained binding equilibrium at the benzodiazepine receptors. Data were analyzed by using a region of interest method (regions of interest were identified on coregistered magnetic resonance imaging scans) and by a pixel-by-pixel method (distribution volume maps were analyzed with statistical parametric mapping for between-group differences). The region of interest analysis revealed that alcoholic patients had significantly lower benzodiazepine distribution volume than comparison subjects in the frontal, anterior cingulate, and cerebellar cortices. Statistical parametric mapping revealed two large excursions in which the distribution volume in alcoholic patients was significantly lower than in comparison subjects: the anterior cingulate, extending into the right middle frontal gyrus, and the left occipital cortex. Benzodiazepine receptor distribution volume is significantly lower in several cortical regions and the cerebellum in alcoholic subjects than in healthy comparison subjects. These results are consistent with previous reports and might indicate either a toxic effect of alcoholism on benzodiazepine receptors or a vulnerability factor for developing alcoholism.

Is upregulation of benzodiazepine receptors a compensatory reaction to reduced GABAergic tone in the brain of stressed mice?

Effects of various forms of stress on the GABAA receptor-chloride ionophore complex in the brain of NMRI mice were investigated. Male albino mice were subjected to stress by placing them on small platforms (SP; 3.5 cm diameter) surrounded by water for 24 h. This experimental model contains several stress factors like rapid eye movement (REM) sleep deprivation, isolation, immobilization, falling into water and soaking. As additional stress control groups we used animals subjected to isolation, large platform (9.0 cm diameter) and repeated swimming stress. SP stress induced an increase in the number of cortical benzodiazepine (BDZ) receptors and a reduction in the GABA-stimulated 36Cl-uptake by brain microsacs, whereas none of these changes could be observed in animals exposed to isolation, swimming or large platform stresses. Furthermore, the amount of GABA-induced stimulation of [3H]flunitrazepam binding was reduced in cortical brain membranes of SP-stressed animals, an effect due to fact that these animals displayed an increase in the basal [3H]flunitrazepam binding, whereas the absolute level of maximally enhanced BDZ binding in the presence of GABA did not differ from those found in controls. Neither basal [3H]muscimol binding or thiopentone sodium-induced stimulation of [3H]flunitrazepam binding were changed in any group of stressed mice. It is proposed that the observed upregulation in the number (Bmax) of cortical BDZ receptors in SP-stressed mice may represent a compensatory response to a stress-induced attenuation of GABAergic neurotransmission.

Influences of housing conditions and ethanol intake on binding characteristics of D 2, 5-HT 1A, and benzodiazepine receptors of rats

The effects of different housing conditions and ethanol treatment (6 vol % in the drinking water) on the in vitro binding characteristics of striatal dopaminergic D 2 ([ 3H]spiperone), hippocampal serotonergic 5-HT 1A ([ 3H]8-OH-DPAT), and cortical benzodiazepine ([ 3H]flunitrazepam) receptors have been examined. Social deprivation due to contact caging, short- (1 day) and long-term isolation (5 weeks) yielded a significant decrease of striatal D 2 receptor density with the greatest decrease after long-term isolation (− 21% B max) without changes of K d in comparison to group animals. The effect of ethanol on striatal D 2 receptor density depended on the housing conditions. Whereas ethanol treatment reduced receptor density of group animals (down to 88%), chronic exposure to ethanol under long-term isolation elicited no significant alteration of D 2 receptor density compared with group animals. Different housing and ethanol treatment had no effect on S-HT 1A receptor affinity and density. Alterations of benzodiazepine receptor density were not found, but social deprivation as well as ethanol treatment of group animals caused an increased affinity of [ 3H]flunitrazepam (reduced K d value). These results indicate that different housing conditions of adult rats evoked significant alterations in D 2 and benzodiazepine receptor binding assays, which were modified by ethanol treatment in the case of striatal D 2 receptor density.

PS-28-2 Cortical benzodiazepine receptor imaging SPECT in 10 patients with temporal lobe epilepsy

PS-28-2 Cortical benzodiazepine receptor imaging SPECT in 10 patients with temporal lobe epilepsy

CL 284,846, a novel sedative‐hypnotic: Evaluation of its metabolites for pharmacological activity in vitro and in vivo

AbstractCL 284,846, N‐[3‐3‐cyanopyrazolo[1,5‐a]pyrimidin‐7‐yl(phenyl)]‐N‐ethylacetamide, is a novel non‐benzodiazepine sedative‐hypnotic with benzodiazepine‐like sedative effects, but with less apparent liability for accompanying undesired side effects. Three metabolites of the parent sedative‐hypnotic have been isolated and identified, a desethyl metabolite, CL 284,859, a desethyl‐5‐keto metabolite, CL 345,644, and a 5‐keto metabolite, CL 345,905. In experiments to determine the ability of these compounds to displace [3H]‐flunitrazepam from rat cortical benzodiazepine receptors, the IC50 values were 205 nM for CL 284,846 compared to 4.5 nM for diazepam as a positive control, and 11 μM for CL 284,859. The other two metabolite, CL 345,644 and CL 345,905, failed to displace [3H]‐flunitrazepam. In a second experiment designed to evaluate in vivo receptor‐mediated activity, CL 284,846 (3.0 mg/kg; 9.836 μmol/kg) was established as a discriminative stimulus (DS) in rats. While CL 284,846 (0.03ndash;3.0 mg/kg; 0.098–9.836 μmol/kg) showed a doserelated increase in drug‐appropriate responding and one dose of triazolam (0.3 mg/kg; 0.875 μmol/kg) substituted as a positive control, all three metabolites (3.0–100.0 mg/kg; 10.3–341.3 μmol/kg for CL 284,859; 6.0–201.2 μmol/kg for CL 345,644; 9.3–311.5 μmol/kg for CL 345,905) failed to substitute for the DS effects of CL 284,846. These results suggest that CL 284,859, CL 345,644, and CL 345,905, the metabolites of the sedative‐hypnotic CL 284,846, have no significant neuropharmacological effects at central benzodiazepine receptors and, thus, do not contribute to the activity of the parent compound. © 1994 Wiley‐Liss, Inc.

Acute swim stress increases benzodiazepine receptors, but not GABAA or GABAB receptors, in the rat cerebral cortex.

We have examined the effects of swim stress on gamma-aminobutyric acidA (GABAA), GABAB and benzodiazepine (BZD) receptors in synaptic membranes from rat brain. Acute, but not repeated, stress increased the number of BZD receptors in the cerebral cortex. The stress manipulation did not change BZD receptors either in the hippocampus or cerebellum. Furthermore, both GABAA and GABAB receptors did not change in the cerebral cortex, hippocampus or cerebellum after acute and repeated stress. GABA-stimulated BZD binding was not changed following acute or repeated stress. These results suggest that cortical BZD receptors are closely related to responses to acute stress.

Solubilization of benzodiazepine receptors from long- and short-sleep mice

Previous studies have shown that long-sleep (LS) and short-sleep (SS) mice, which were selectively bred for differential responses to the sedative-hypnotic actions of ethanol, also differ in response to several other agents that act at the GABAergic receptor. Binding at cortical benzodiazepine receptors is enhanced differentially by GABA and ethanol in membranes prepared from the two lines of mice with SS receptors enhanced to a greater extent. Heat denaturation studies and other biochemical characterizations of these receptors suggest that the GABAergic receptor complex from the two lines of mice differs. The present study examined whether perturbation of receptor-membrane interactions by treatment with detergent altered either GABA enhancement of [ 3H]flunitrazepam binding or ethanol enhancement of this binding. Octylglucopyranoside (OCTG), 3-[(3-cholamidopropyldimethylammonio]-1-propanesulfonate (CHAPS), or deoxycholate solubilization of cortical membranes resulted in a loss of the LS/SS difference in GABA enhancement. Ethanol's effects on binding were altered differently from those of GABA by treatment with OCTG as an increase, not a decrease, in enhancement was observed in both lines of mice. These results suggest that protein-membrane interactions play an important role in mediating LS/SS differences in the allosteric interactions within the GABAergic receptor complex.

Cerebellar and frontal cortical benzodiazepine receptors in human alcoholics and chronically alcohol-drinking rats

Postmortem cerebellar and frontal cortical membrane homogenates from human alcoholics, control subjects without neurological or psychiatric illnesses, and rats that chronically drank alcohol were studied to determine the binding characteristics of an imidazobenzodiazepine, [ 3H]Ro 15-4513. This ligand binds to classical γ-aminobutyric acid A (GABA A)/benzodiazepine receptors, as well as to a “diazempam-insensitive” site associated with the GABA A receptor complex in the cerebellar granule cell layer. There were no differences in the density of the binding sites between alcoholics and their controls, between alcohol-drinking AA rats that had a choice between 10% alcohol or water for about 10 weeks and their controls, or between Wistar rats that had been given 20% alcohol as their only fluid for 4 months and their controls, which were pair-fed isocalorically with sucrose. The affinity for the cerebellar binding of [ 3H]Ro 15-4513 was higher in the alcoholics than the controls. No differences were observed in the frontocortical binding. No affinity differences were observed in the rat models. There were no differences between the groups in the characteristics of [ 3H]Ro 15-4513 binding to human cerebellum in the presence of micromolar diazepam, thus revealing the diazepam-insentitive binding. When this component was subtracted from the total cerebellar binding, to reveal the diazepam sensitive binding, both the K D and B max were lower in the alcoholic than the control group. The binding of [ 3H]muscimol, a GABA A,agonist, tended to be higher in the frontal cortices of alcoholics; a similar trend for greater effects was observed in the alcoholics for the GABA inhibition of [ 3H]Ro 15-4513 binding. These results suggest that no drastic changes occur through chronic alcohol abuse in the numbers of cerebellar and frontocortical benzodiazepine receptors in humans and rodent models; however, the data indicate that the alcoholics have either acquired or innate differences in classical benzodiazepine recognition sites of the cerebellum and in the coupling of these sites to GABA A sites in the frontal cortex, without any differences in cerebellar granule cell-specific diazepam-insensitive [ 3H]Ro 15-4513 binding sites.

Cortical Benzodiazepine Receptor Binding in Patients with Generalized and Partial Epilepsy

Impaired cortical inhibition may be involved in epileptogenic mechanisms. In a positron-emission tomography (PET) study, we demonstrated a reduction of the cortical benzodiazepine (BZD) receptor density in the epileptic foci of patients with partial epileptic seizures. In the present study, we used the same method in 10 patients with primary generalized epilepsy to determine whether an altered BZD receptor binding could also be demonstrated in this patient group. The [11C]-labeled BZD receptor antagonist Ro 15-1788 was used as ligand. Receptor affinities and densities were calculated in various cortical regions and then compared with the values from corresponding "nonepileptic" regions in the previously examined partial epilepsy patients. Focal alterations of the BZD receptor density or affinity were not demonstrated in patients with generalized epilepsy. This patient group had a slight tendency toward lower mean cortical BZD receptor density, however, as compared with corresponding values from 10 patients with partial epilepsy. Our results strongly suggest that a focal alteration of cortical inhibition is not a prominent feature of human generalized epilepsy. The observed tendency toward lower mean cortical BZD receptor density may be a consequence of diffusely impaired cortical inhibition. Further investigations of this issue are therefore indicated.

Evidence for the presence of a benzodiazepine receptor binding substance in cerebrospinal fluid of a rabbit model of hepatic encephalopathy

Based on the reversal of hepatic encephalopathy in animal models with administration of specific benzodiazepine receptor antagonists, it has been postulated that this syndrome may be mediated by an endogenous benzodiazepine-like compound. In this study using a radio-receptor assay, evidence for the existence of this substance has been demonstrated in cerebrospinal fluid but not sera of rabbits with hepatic encephalopathy due to galactosamine-induced hepature failure. Cerebrospinal fluid from rabbits with hepatic encephalopathy caused 36.1 +/- 5.03% displacement of 3H-Ro 15-1788 specific binding to cortical benzodiazepine receptors, compared to 11.7 +/- 0.76% in control animals (P less than 0.01). The benzodiazepine receptor binding activity has been shown to behave as a competitive inhibitor of radiolabeled benzodiazepine receptor binding. The finding of endogenous benzodiazepine binding activity affords a potential explanation for the amelioration of hepatic encephalopathy in this model with the administration of benzodiazepine receptor antagonists.