Tissue specific regulation of “peripheral-type” benzodiazepine receptor density after chemical sympathectomy
Abstract
The characteristics of [3H]Ro 5-4864 binding to “peripheral” benzodiazepine receptors (PBR) in the central nervous system and peripheral tissues were examined after chemical sympathectomy with 6-hydroxydopamine (6-OHDA). One week after the intracisternal administration of 6-OHDA, the number of [3H]Ro 5-4864 binding sites (Bmax) in the hypothalamus and striatum increased 41 and 50%, respectively, concurrent with significant reductions in catecholamine content. An increase (34%) in the Bmax of [3H]Ro 5-4864 to cardiac ventricle was observed one week after parenteral 6-OHDA administration. In contrast, the Bm a x of [3H]Ro 5-4864 to pineal gland decreased 48% after 6-OHDA induced reduction in norepinephrine content. The Bmax values for [3H]Ro 5-4864 binding to other tissues (including lung, kidney, spleen, cerebral cortex, cerebellum, hippocampus and olfactory bulbs) were unaffected by 6-OHDA administration. The density of pineal, but not cardiac PBR was also reduced after reserpine treatment, an effect reversed by isoproterenol administration. These findings demonstrate that alterations in sympathetic input may regulate the density of PBR in both the central nervous system and periphery in a tissue specific fashion.
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Cited by (23)
Peripheral benzodiazepine receptors and mitochondrial function
2002, Neurochemistry InternationalFor over 20 years, numerous investigations have focused on elucidating the function of the peripheral benzodiazepine receptor (PBR). This relatively small protein (18 kDa) arouses great interest because of its association with numerous biological functions, including the regulation of cellular proliferation, immunomodulation, porphyrin transport and heme biosynthesis, anion transport, regulation of steroidogenesis and apoptosis. Although the receptor was first identified as a binding site for the benzodiazepine, diazepam, in peripheral organ systems, the PBR was subsequently found to be distinct from the central benzodiazepine receptor (CBR) in terms of its pharmacological profile, structure, subcellular localization, tissue distribution and physiological functions. The PBR is widely expressed throughout the body, with high densities found in steroid-producing tissues. In contrast, its expression in the CNS is restricted to ependymal cells and glia. The benzodiazepine Ro5-4864 and the isoquinoline carboxamide PK11195 exhibit nanomolar affinity for the PBR, and are the archtypic pharmacological tools for characterizing the receptor and its function. Primary among these functions are its regulation of steroidogenesis and apoptosis, which reflect its mitochondrial localization and involvement in oxidative processes. This review will evaluate the basic pharmacology and molecular biology of the PBR, and highlight its role in regulating mitochondrial function, the mitochondrial transmembrane potential and its sensitivity to reactive oxygen species (ROS), and neurosteroid synthesis, processes relevant to the pathogenesis of a number of neurological and neuropsychiatric disorders.
Regulation of cardiac and renal peripheral benzodiazepine receptor binding in rapid eye movement sleep-deprived rats
2000, Life SciencesThis study was designed to examine the effects of rapid eye movement (REM) sleep deprivation and stress on the properties of peripheral benzodiazepine receptors (PBRs). Rats were deprived of REM sleep for 96 hours by a small pedestal (water tank) method. Using radioligand assays with the selective antagonist [3H]PK11195, receptor density (Bmax) and affinity were measured in the heart and kidney in three groups: 1) REMSD group (REM sleep deprived-group), 2) TC group (tank control group; large pedestal), and 3) CC group (cage control group). REMSD group showed an increase in the density of PBRs in the heart (18%; p<0.002), but not in the kidney (−5%; p=0.058) compared to TC group, and TC group showed an increase in the density of these receptors in the heart (17%; p<0.014), and the kidney (12%; p<0.002) compared to CC group. While the cardiac Kd value was 37% (p<0.0004) and 36% (p<0.002) higher in the REMSD group than in the CC and TC groups, respectively, the renal Kd value was lower (−5%; p=0.057 and −16%; p<0.0004, respectively). The changes in PBRs observed herein are tissue- and treatment-specific, and may suggest a close functional relationship between REM sleep and PBRs.
Determination of isatin, an endogenous monoamine oxidase inhibitor, in urine and tissues of rats by HPLC
1998, General Pharmacology- 1.
We have previously identified isatin as one of the endogenous monoamine oxidase (MAO) inhibitors in the urine and the brain of stroke-prone spontaneously hypertensive rats (SHRSP), using gas chromatography-mass spectrometry (GC-MS).
- 2.
In this study, we attempted to develop a convenient assay to determine isatin using high performance liquid chromatography with an ultraviolet detector (HPLC-UV). The standard curve for authentic isatin was linear at a range from 2 to 20 nmol per ml. The coefficient of variance was within 3% for both intra-assay and inter-assay. The sensitivity was 20 pmol per 10 μl of urine sample.
- 3.
Isatin concentration correlated significantly and positively with endogenous MAO activity (tribulin-like activity) in both urine (r=0.924, P<0.001) and kidney extracts (r=0.862, P<0.01). There was a significant difference in urinary isatin between Wistar Kyoto rats (WKY) and SHRSP. Oral administration of isatin increased urinary isatin concentration and systolic blood pressure in WKY.
- 4.
Determination of isatin using HPLC-UV may be useful for elucidating role of isatin in various conditions of stress and disease.
- 1.
Peripheral-type benzodiazepine receptor ligands and serum steroid hormones
1997, Brain ResearchThe peripheral-type benzodiazepine receptors (PBR) are involved in various cellular functions, including steroidogenesis. The impact of these receptor ligands has been demonstrated mainly in steroidogenic cells. The aim of the present study was to assess in intact female rats the effect of chronic (21 days) administration of the PBR ligands PK 11195 (15 mg/kg) and Ro 5-4864 (5 mg/kg), the mixed ligand diazepam (5 mg/kg), and the central benzodiazepine receptor ligand clonazepam (1 mg/kg) on PBR binding characteristics in steroidogenic (ovary and adrenal) and non-steroidogenic (uterus and kidney) organs, as well as on serum hormonal steroids (estradiol, progesterone, and corticosterone). Selective and mixed PBR ligands up-regulated PBR density in the two steroidogenic organs, while Ro 5-4864 also induced elevation of the receptor density in the non-steroidogenic organs. In contrast to Ro 5-4864, PK 11195 treatment down-regulated renal PBR. Clonazepam elevated adrenal PBR. On the serum hormonal level, Ro 5-4864 suppressed estradiol secretion. The other ligands did not affect hormonal steroid levels. It appears that in female rats, at least at these doses and dosing schedules, there is no correlation between the impact of chronic in vivo exposure to these agents on PBR density and ovarian and adrenal hormone levels.
Environmentally induced changes in peripheral benzodiazepine receptors are stressor and tissue specific
1995, Pharmacology, Biochemistry and BehaviorThe stress-induced changes in peripheral benzodiazepine receptors (PBR) can be observed in a number of different tissues, depending upon the nature and chronicity of the aversive experience. In addition, virtually all stress procedures that cause rapid changes in PBR simultaneously increase the physical activity or metabolic rate of the subjects. The present study analyzed the contributions of rapid alterations in activity or metabolic rate with and without aversive stimulation and their subsequent impact on PBR. Mechanically induced increases in activity by forced running stress results in a significant reduction in [3H]Ro 5-4864 binding to PBR in olfactory bulb, opposite to the PBR changes in this tissue following forced cold-water swim stress. Pharmacological induction of increased locomotor activity as well as metabolic rate by d-amphetamine causes a significant increase in cardiac PBR binding, again, opposite to the response typically observed following inescapable shock stress. Finally, administration of the anxiogenic beta-carboline, FG-7142, causes increases in both hippocampus and adrenal gland PBR binding reminiscent of acute noise stress exposure. These experiments demonstrate that increased locomotor activity or metabolic rate alone is not a necessary and sufficient condition for previous stress-induced changes in PBR. Conversely, increased metabolic rate coupled with an aversive stimulus appears to be an important factor for inducing stress-like changes in PBR. This data, coupled with previous reports, suggests that rapid alterations in these sites are Stressor and tissue dependent. Finally, we propose that the PBR may be involved in many aspects of the stress response including: a) a biowarning system in adrenal gland, b) participation in stress-induced hypertension via renal PBR, and c) a modulator of stress-induced immunosuppression and subsequent recovery of function or recuperation by actions on immune cells.
Antidepressants reverse the olfactory bulbectomy-induced decreases in splenic peripheral-type benzodiazepine receptors in rats
1995, European Journal of PharmacologyThe present study investigated the effects of 21-day administration of clorgyline (1 mg/kg/day), desipramine (10 mg/kg/day) or paroxetine (10 mg/kg/day) on peripheral-type benzodiazepine receptors in rat peripheral tissues following bilateral olfactory bulbectomy. Thymus and spleen weights decreased as a result of bulbectomy. Subsequent antidepressant drug administration had no further effects on the weights of thymus glands but increased those of spleens. In thymus glands, higher densities of peripheral-type benzodiazepine receptors were observed in medulla than in cortex; no significant variations were observed following bulbectomy or antidepressant drug administration. In spleen, higher densities were observed in white pulp than in red pulp. The bulbectomy-induced decreases in binding densities observed in both regions were reversed following administration of antidepressants. Adrenal peripheral-type benzodiazepine receptors were not altered by bulbectomy or subsequent treatment with clorgyline or desipramine while paroxetine upregulated these receptors. No changes in kidney peripheral-type benzodiazepine receptors were observed. The present study confirms that cell lines of the rat immune system possess high densities of peripheral-type benzodiazepine receptor binding sites and further support the contention that, following olfactory bulbectomy, rats may present an antidepressant-reversible immunitary dysfunction.