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Biomedical subjects

C Braestrup

Publications and source records attributed to C Braestrup.

At least 73 records · Page 4Linked to original sources
PubMed1981

[3H]Propyl beta-carboline-3-carboxylate as a selective radioligand for the BZ1 benzodiazepine receptor subclass.

Ethyl beta-carboline-3-carboxylate (beta-CCE) is a mixed-type inhibitor of [3H]flunitrazepam ([3H]FNM) binding to benzodiazepine receptors in noncerebellar regions of rat brain. These findings may represent the presence of either receptor multiplicity or negative cooperativity among benzodiazepine receptors. [3H]Propyl beta-carboline-3-carboxylate ([3H]PrCC) has previously been shown to bind specifically to benzodiazepine receptors of rat cerebellum. In the present study we found no indication of the presence of true negative cooperativity among benzodiazepine receptors when [3H]PrCC was used as radioligand. However, we observed that [3H]PrCC labelled only 57% of [3H]FNM binding sites in rat hippocampus (Bmax values) and 71% in rat cerebral cortex, whereas the number of receptors labelled by both ligands was equal in the cerebellum. Hofstee analyses of the shallow inhibition curves seen in hippocampus and cerebral cortex when [3H]FNM binding was inhibited by beta-CCE indicate that beta-CCE and some other beta-carboline-3-carboxylate derivatives interact preferentially with a subclass of receptors, and that the percentage of this subclass is equivalent to the number of receptors labelled by [3H]PrCC. We conclude that [3H]PrCC at low concentration (0.3-0.4 X 10(-9) M) labels a subclass of benzodiazepine receptors, BZ1, while another class, BZ2 receptors, are not labelled by [3H]PrCC when filtration assays are used. By parallel determinations of the proportion between [3H]FNM and [3H]PrCC binding we calculated the percentage of BZ1 receptors in several regions of rat, guinea pig and calf brain and in mouse forebrain. The values ranged from approximately 50% in hippocampus to 90% in the guinea pig pons.

Animals↗
PubMed1981

[3H]propyl beta-carboline-3-carboxylate binds specifically to brain benzodiazepine receptors.

Ethyl beta-carboline-3-carboxylate has recently been isolated from human urine and it was proposed that derivatives of this compound might be related to an endogenous ligand for benzodiazepine receptors. In the present study we investigated high-affinity binding of [3H]propyl beta-carboline-3-carboxylate ([3H]PrCC) to rat brain membranes. [3H]PrCC binds specifically and with high affinity (half-maximal binding at ca. 1nM) to rat brain membranes. The regional and subcellular distributions of specific [3H]PrCC binding are similar, but not identical, to the distributions of [3H]flunitrazepam or [3H]-diazepam binding. The total numbers of binding sites labelled by [3H]PrCC and [3H]flunitrazepam in rat cerebellum are closely similar, and both ligands bind to cerebellar membranes in a mutually exclusive way. The pharmacological selectivity of [3H]PrCC and [3H]diazepam binding is almost identical. Binding of [3H]PrCC like binding of [3H]diazepam, can be increased in vitro by muscimol, GABA and SQ 20.009. Although subtle differences in binding characteristics were observed, these results indicate that [3H]PrCC and benzodiazepines bind to a common recognition site on benzodiazepine receptors.

Animals↗
PubMed1980

Decreased spiroperidol and LSD binding in rat brain after continuous amphetamine.

Rats were implanted with a silicone tubing pellet continuously releasing amphetamine base for several days. After five days of this treatment specific binding of spiroperidol (dopamine receptors) and LSD (serotonin receptors) was decreased in the corpus striatum and frontal cortex. In the striatum the number of dopamine receptors was decreased while the affinity was unchanged. These results indicate that dopamine and serotonin receptors can be regulated by the release of their own neurotransmitter.

Amphetamine↗
PubMed1980

Ethyl beta-carboline-3-carboxylate shows differential benzodiazepine receptor interaction.

High-affinity binding of 3H-diazepam and 3H-flunitrazepam has provided evidence for the presence of benzodiazepine receptors on brain neurones. Pharmacological evidence showing a clear correlation between receptor affinity and in vivo pharmacological potency for several benzodiazepines and a link between benzodiazepine receptors and GABA (gamma-amino-butyric acid) receptors at the molecular level, indicates that these receptors are relevant to the pharmacological and clinical effects of benzodiazepines. In searching for possible endogeneous ligands for benzodiazepine receptors we have recently isolated ethyl beta-carboline-3-carboxylate (beta-CCE) found human urine and brain, and shown that beta-CCE has a higher affinity than diazepam for brain benzodiazepine receptors. beta-CCE itself is probably not present in the brain, but may be closely related to an endogenous benzodiazepine receptor ligand. We report here that beta-CCE, in contrast to benzodiazepines, can distinguish clearly between benzodiazepine receptors in cerebellum and hippocampus. This result strongly indicates that benzodiazepine receptors are not a single class of non-interacting entities. It has not been possible to determine whether two distinct receptors are present and/or whether true negative cooperativity exists among hippocampal, but not cerebellar, benzodiazepine receptors.

Allosteric Regulation↗
PubMed1980

Urinary and brain beta-carboline-3-carboxylates as potent inhibitors of brain benzodiazepine receptors.

Benzodiazepines probably exert their anxiolytic, hypnotic, and anticonvulsant effects by interacting with brain-specific high-affinity benzodiazepine receptors. In searching for possible endogenous ligands for these receptors we have purified a compound 10(7)-fold from human urine by extractions, treatment with hot ethanol, and column chromatography. The compound was identified as beta-carboline-3-carboxylic acid ethyl ester (IIc) by mass spectrometry, NMR spectrometry, and synthesis; IIc was also isolated from brain tissues (20 ng/g) by similar procedures. Very small concentrations of IIc displaced [3H]diazepam completely from specific cerebral receptors, but not from liver and kidney binding sites; the concentration causing 50% inhibition of specific [3H]diazepam binding (IC50) was 4-7 nM compared to ca. 5 nM for the potent benzodiazepine lorazepam. Specific binding sites for quinuclidinyl benzilate, naloxone, spiroperidol, serotonin, muscimol, and WB 4101 were not affected by IIc. In contrast to benzodiazepines, IIc exhibits "mixed type" competitive inhibition of forebrain benzodiazepine receptors (negative cooperativity). We surmise that an endogenous ligand for benzodiazepine receptors may be a derivative of beta-carboline-3-carboxylic acid.

Binding, Competitive↗
PubMed1980

Benzodiazepine receptors.

It appeared recently that the important group of psychoactive drugs, the benzodiazepines, binds with high affinity to a single class of saturable sites on brain membranes of all higher vertebrates including man. There was a good correlation between the pharmacological effects of different benzodiazepines and their affinity for 3H-diazepam and 3H-flunitrazepam binding sites, indicating that the binding site is the physiological relevant receptor upon which benzodiazepines act. The most active benzodiazepines, like lorazepam and triazolam, act in concentrations of about 1 nmol/l. The highest concentration of benzodiazepine receptors in human brain was found in cerebral cortical regions, intermediate levels were found in midbrain and some limbic structures, while white matter areas exhibit low levels. This indicates that benzodiazepines act preferentially in cortical areas. The presence of benzodiazepine receptors suggests that there may an endogenous ligand for these receptors. Hypoxanthine, inosine and nicotinamide have been isolated from brain tissue and proposed as endogenous ligands. These three compounds are very weak on benzodiazepine receptors. The most promising compound has been isolated from human urine and brain and is a lipophilic, small-molecular weight aromatic compound, which exhibits very high affinity (Ki congruent to 0.003 mumol/l) for benzodiazepine receptors.

Animals↗
PubMed1979

Benzodiazepine receptors in the brain as affected by different experimental stresses: the changes are small and not undirectional.

Rats and mice were exposed to several different stress situations to investigate whether brain benzodiazepine receptors were sensitive to altered external or internal environmental circumstances. All stresses were applied for several days. Electrical foot shock and post-natal isolation of newborn pups resulted in small (7--25%; P less than 0.05--0.001) decreases in benzodiazepine receptor binding in some cerebral cortex or hippocampal areas while immobilization stress resulted in a small (9%; P less than 0.05) increase in frontal cortex. Other brain areas (i.e., striatum, cerebellum, pons-medulla, and occipital cortex) and other stress forms (isolation of male mice, forced swimming in cold water, or chronic amphetamine intoxication) did not change receptor binding. The effect of prolonged stress on benzodiazepine receptors is complex and not very pronounced.

Aggression↗
PubMed1979

Some properties of brain specific benzodiazepine receptors: new evidence for multiple receptors.

Several new lines of evidence suggest the existence of two or more distinct types of benzodiazepine receptors, in contrast to earlier results suggesting the presence of only one class of receptors. Appropriate thermoinactivation experiments indicate two receptors with different thermostabilities. Several triazolopyridazines, with some of the pharmacological properties of anxiolytics have recently been shown to displace 3H-diazepam and 3H-flunitrazepam with Ki values in the 6 to 100 nanomolar range. These new substances are active in conflict tests in rats and monkeys and prevent metrazol induced seizures in vivo, but strikingly lack the ataxia and sedative properties of the benzodiazepines. Hill analyses of dose-response curves for some of these substances yields Hill coefficients in the range of 0.4--0.6, suggesting that these compounds may be able to discriminate between several types of benzodiazepine receptors.

Amino Acids↗
PubMed1979

Neuronal localisation of benzodiazepine receptors in cerebellum.

The cellular localisation of benzodiazepine receptors was studied. Kainic acid induced neuronal lesions (2 x 0.25-2 x 2 micrograms; 2-26 days in rat cerebellum decreased specific binding of [3H]flunitrazepam down to 35% of controls. Specific binding of [3H]flunitrazepam was also decreased (to 80% of controls) in the cerebllum of mutant nervous mouse (nr/nr) where Purkinje cells are degenerated but in the mutant weaver mouse where granule cells are degenerated. These results show that benzodiazepine receptors are located mainly on neurons; both on Purkinje cells and other neurons, but not to a great extent on granule cells.

Animals↗
PubMed1979

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.

Animals↗