Benzodiazepine Receptors In Cerebral Cortex Research Articles

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.

Peripheral benzodiazepine receptors in cerebral cortex, but not in internal organs, are increased following inescapable stress and subsequent avoidance/escape shuttle-box testing

Stress-induced alterations in peripheral benzodiazepine receptor (PBR) density have been reported in humans and in rats. However, the PBR response is highly specific, and its function remains largely unexplained. The aim of the present study was to investigate the relationship between behavior in the two-way active avoidance paradigm (2WAA) and post-test PBR densities in adrenal, testis, kidney, and cerebral cortex. Adult male Wistar rats were tested in the 2WAA either in the naive state (AA) or 24 h following shock preexposure (PE), known to interfere with avoidance/escape response acquisition, and decapitated immediately after testing. Control subjects were decapitated without experimental experience. The stressful characteristic of the experiment was validated by significantly increased post-test corticosterone levels in AA and PE subjects compared with controls, with a trend towards higher corticosterone levels in PE relative to AA rats. Similarly, PE compared with AA subjects tended to show retarded acquisition of the escape/avoidance response. PBR densities in adrenal, kidney, and testis and central benzodiazepine receptors (CBR) in the cerebral cortex remained unaffected by avoidance testing. Cerebral cortex PBR density was significantly increased in PE subjects. These findings suggest that avoidance testing, although stressful to the animals, led to changes confined to cerebral cortex PBR, indicating that the hypothalamic–pituitary–adrenal (HPA) response occurs independently of the PBR response in peripheral organs, and also suggest that the opportunity for coping alters the impact of the stressor on the subject and prevents the expression of PBR response in peripheral organs.

Central- and peripheral-type benzodiazepine receptors: Similar regulation by stres and GABA receptor agonists

Central- and peripheral-type benzodiazepine (BD) receptors were labelled either by 3H-flunitrazepam or 3H-Ro 5-4864 in vitro after stress and in vivo administrationof GABA A and GABA B agonists. A significant increase in the density of cerebral cortex and kidney BD binding sites was observed in rats after forced swimming stress. Similar changes in both type of BD receptors were also followed when naive (stressed) and handling-habituated (unstressed) rats were used. Stress in both models was unable to change the affinity of BD receptors in cerebral cortex, but significantly lowered it in kidneys. Acute treatment of rats with muscimol (1.5 mg/kg) or (−)baclofen (5 mg/kg) resulted in marked increase in the affinity of BD binding not only in cerebral cortex but also in kidneys. After (−)baclofen treatment the number of BD binding sites was lowered in the structures studied. In a separate study mice selected according to their behavioral response to (−)baclofen (1 mg/kg) were studied. Two weeks after the selection it appeared that baclofen responders were behaviorally more “anxious” than baclofen nonresponders. The number of BD binding sites was reduced in cerebral cortex, cerebellum, heart and kidneys in baclofen responders as compared to baclofen nonresponders. In several cases the changes in peripheral BD binding sites were even more pronounced than those in central ones. The data presented here evidence that peripheral- and central-type BD receptors are regulated similarly by GABA and some models of stress. The physiological mechanisms involved in similar regulation of central- and peripheral-type BD receptors are yet unknown.

Behavioral differences in an elevated plus-maze: correlation between anxiety and decreased number of GABA and benzodiazepine receptors in mouse cerebral cortex.

In an elevated plus-maze model of anxiety mice treated with the benzodiazepine inverse agonist DMCM (0.5-1.5 mg/kg i.p.) spent significantly less time on the open arms and showed the decreased number of open arm entries. The opposite i.e. increased time spent on the open arms and the higher number of open arm entries was registered after diazepam (1.5 mg/kg). The results are consistent with the results obtained in the other animal tests and support the idea that this procedure is suitable for detecting anxiolytic/anxiogenic effects of benzodiazepine receptor ligands. After testing of 84 mice in an elevated plus-maze substantial differences were detected between the individuals. According to the behavioral response two subgroups of animals with DMCM or diazepam like exploratory activity (as compared to the whole group data) termed as "anxious" or "non-anxious", respectively, were chosen for further binding studies. "Anxious" animals had significantly lower numbers of 3H-flunitrazepam and 3H-muscimol binding sites as compared to "non-anxious" animals in cerebral cortex but not in cerebellum. No differences in the affinity were found between the two groups studied. The results indicate that behavioral anxiety in mice is in correlation with the decreased number of GABA and benzodiazepine receptors in cerebral cortex.

Regulation of central and peripheral benzodiazepine receptors in progesterone-treated rats

The effects of progesterone treatment to male rats on cortical and hippocampal central benzodiazepine (BZ) receptors and peripheral BZ binding sites (PBS) in kidney, testis and heart were evaluated. Chronic progesterone treatment resulted in a 30% elevation of the density of central BZ receptors in cerebral cortex accompanied by a 24% augmentation of PBS in the kidney. No significant change in the density of central BZ receptors in the hippocampus or of PBS in the testis or heart was observed. No change in the affinity of [ 3H]flunitrazepam and [ 3H]PK 11195 binding to central BZ receptors and PBS, respectively, was observed. The increase in PBS in the kidney might be associated with the natriuretic effect of this hormone and the adaptatory increase in aldosterone secretion. The up-regulatory effect of progesterone on cortical central BZ receptors may be involved in the neurobehavioral activities of progesterone.

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.

Increased thermolability of benzodiazepine receptors in cerebral cortex of a baboon with spontaneous seizures: a case report.

The benzodiazepine receptor in the cortex of 1 spontaneously epileptic baboon exhibited an increased rate of thermal inactivation at 65 degrees C when compared with those from 3 other baboons. In other respects (receptor concentration, affinities for flunitrazepam and diazepam, and response to changing pH), the benzodiazepine receptor from this animal was very similar to the receptors in the cortex of 3 other baboons. The 3H-QNB (muscarinic) and 3H-naloxone (opiate) binding sites in the brain of all 4 baboons appeared very similar with respect to all parameters studied (thermal stability, concentration, regional distribution, and affinities for respective ligands). An endogenous factor stabilizing the benzodiazepine receptor could be lacking in the spontaneously epileptic baboon.