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C Braestrup

Publications and source records attributed to C Braestrup.

At least 55 records · Page 3Linked to original sources
PubMed1983

Reduction of 3H-spiroperidol binding in rat striatum and frontal cortex by chronic amphetamine: dose response, time course and role of sustained dopamine release.

After 5 days of continuous treatment with d-amphetamine base in doses greater than 0.5 mg/kg/h maintained by subcutaneously implanted osmotic minipumps, specific binding of 3H-spiroperidol was reduced in rat striatum and frontal cortex as previously reported. These effects were dose-dependent at lower doses of amphetamine, whereas with higher doses an apparent ceiling for the reduction in binding was reached at approximately 70% of control values. Similarly, increasing the exposure time to amphetamine for up to 14 days only slightly augmented the reduction in 3H-spiroperidol binding already present after 5 days of treatment. In rats treated for 5 days with amphetamine, concomitant treatment with the dopamine (DA) synthesis inhibitor alpha-methyl-p-tyrosine prevented the decrease in 3H-binding in corpus striatum, and attenuated the decrease in frontal cortex. Furthermore, in rats with unilateral 6-hydroxydopamine lesions of the nigro-striatal DA tract, 5 days of chronic amphetamine had no significant effect on 3H-spiroperidol binding in the denervated striatal tissue. Since a major effect of amphetamine is to release DA from nerve terminals, these results indicate that the reduction of DA receptors by chronic amphetamine in the striatum is mediated by sustained release of DA.

Amphetamine↗
PubMed1983

Binding of 3H-DMCM to benzodiazepine receptors; chloride dependent allosteric regulation mechanisms.

DMCM is a convulsant agent with negative efficacy at benzodiazepine (BZ) receptors. 3H-DMCM binds to benzodiazepine receptors in vitro. The sensitivity of 3H-DMCM binding to agents presumed to act on chloride channels associated with the BZ/GABA-receptor-complex was investigated at 37 degrees C. Chloride ions (200 mM) enhanced the specific binding of 3H-DMCM four-fold. Similarly the specific binding of 3H-DMCM was enhanced by picrotoxinine in the absence but not in the presence of chloride ions. (+)-Etomidate and pentobarbital reduced the specific 3H-DMCM binding in a partially chloride ion dependent and picrotoxinine sensitive manner. The results obtained are consonant with the idea that 3H-DMCM binds to the BZ/GABA-receptor-chloride ionophor complex; furthermore, binding of 3H-DMCM seems to involve a chloride dependent allosteric regulation mechanism.

Animals↗
PubMed1983

Benzodiazepine receptor ligands with positive and negative efficacy.

Recent studies have shown that benzodiazepine receptors can be affected not only by benzodiazepine agonists and antagonists but also by a new class of ligands which produce effects opposite to those of benzodiazepines, that is they produce convulsions and anxiety. These ligands can be described as having a negative efficacy at the receptor; tentatively they are named "inverse agonists". Pharmacological experiments indicate that agonists, antagonists and inverse agonists comprise a whole continuum of agents with a graduated variety of efficacy at the receptor. Biochemical studies, supported by published electrophysiological data, indicate that the benzodiazepine receptor allosterically up- or down-regulates the gain in the GABAergic system depending on the nature of the ligand.

Acoustic Stimulation↗
PubMed1983

Binding of [3H]DMCM, a convulsive benzodiazepine ligand, to rat brain membranes: preliminary studies.

DMCM (methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate) produces convulsions in mice and rats, probably by interacting with benzodiazepine (BZ) receptors. Investigation of specific binding of [3H]DMCM to rat hippocampus and cortex revealed polyphasic saturation curves, indicating a high-affinity site (KD = 0.5-0.8 nM) and a site with lower affinity (KD = 3-6 nM). BZ receptor ligands of various chemical classes, but not other agents, displace [3H]DMCM from specific binding sites--indicating that [3H]DMCM binds to BZ receptors in rat brain. The regional distribution of [3H]DMCM binding is complementary to that of the BZ1-selective radioligand [3H]PrCC. Specific binding of [3H]DMCM (0.1 nM) was reduced by gamma-aminobutyric acid (GABA) receptor agonist to approximately 20% of the control value at 37 degrees C in chloride-containing buffers; the reduction was bicuculline methiodide- and RU 5135-sensitive. The effective concentrations of 10 GABA analogues in reducing [3H]DMCM binding correlated closely to published values for their GABA receptor affinity. Specific binding of [3H]DMCM is regulated by unknown factors; e.g. enhanced binding was found by Ag+ treatment of membranes, in the presence of picrotoxinin, or by exposure to ultraviolet light in the presence of flunitrazepam. In conclusion, [3H]DMCM appears to bind to high-affinity brain BZ receptors, although the binding properties are different from those of [3H]flunitrazepam and [3H]PrCC. These differences might relate in part to subclass selectivity and in part to differences in efficacy of DMCM at BZ receptors.

Animals↗
PubMed1983

Decreased number of benzodiazepine receptors in frontal cortex of rat brain following long-term lithium treatment.

Chronic administration of lithium led to a decreased number of benzodiazepine receptors (ca. 20%) in frontal cortex of rat brain, whereas no change was observed in the binding characteristics in the remaining part of the cortex and in the hippocampus and the cerebellum. Long-term lithium treatment did not change the binding of [3H]lysergic acid diethylamide and [3H]quinuclidinyl benzilate to membranes of various brain regions in the rat. We concluded that the effect of lithium on the benzodiazepine receptor is brain region specific and cannot be explained as a consequence of a reduced gamma-aminobutyric acid-ergic stimulation of benzodiazepine receptor, as the change in receptor binding was due to a change in the number of receptors rather than in the affinity constant.

Animals↗
PubMed1982

Modulation of GABA binding to rat brain membranes by alkyl beta-carboline-3-carboxylate esters.

The effects of the methyl, ethyl and propyl esters of beta-carboline-3-carboxylic acid were assessed on low affinity binding of GABA to rat brain membranes, and the enhancement of such binding by diazepam. The propyl ester acted as a benzodiazepine agonist in enhancing low affinity GABA binding, while the methyl and ethyl esters acted as benzodiazepine antagonists in reversing the stimulation of GABA binding by diazepam. These effects on low affinity GABA binding in vitro are consistent with pharmacological and behavioural actions of these esters in vivo and support the hypothesis that such actions are mediated via a GABA-benzodiazepine receptor complex.

Animals↗
PubMed1982

Anxiety.

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Animals↗
PubMed1982

Does the reversal of the anticonflict effect of phenobarbital by beta-CCE and FG 7142 indicate benzodiazepine receptor-mediated anxiogenic properties?

In mice and rats, the high affinity ligand for brain benzodiazepine (BZ) receptors beta-CCE, and the more stable congener FG 7142, failed to exert anticonflict activity in conflict situations but instead reversed the anticonflict effect of lorazepam. In contrast to Ro 15-1788, beta-CCE and FG 7142 also antagonized the anticonflict effect of phenobarbital in rats. This effect suggests that beta-CCE and FG 7142 may produce anxiety by either inducing a conformational change in the BZ receptors which is directly opposite to that induced by the benzodiazepines, or binding to a particular subclass of BZ receptors.

Animals↗
PubMed1982

Interaction of convulsive ligands with benzodiazepine receptors.

The gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex, which is composed of distinct proteins embedded in the neuronal plasma membrane, is important for several effects of benzodiazepines, including protection afforded against convulsions. During structural modification of ethyl beta-carboline-3-carboxylate an agent was discovered which has high affinity for brain benzodiazepine receptors but which is a potent convulsant. Also in contrast to benzodiazepines, this type of benzodiazepine receptor ligand favors benzodiazepine receptors in the non-GABA-stimulated conformation, which may explain the convulsive properties.

Allosteric Regulation↗
PubMed1982

The benzodiazepine/GABA receptor complex during severe ethanol intoxication and withdrawal in the rat.

The benzodiazepine/GABA (gammaaminobutyric acid) receptor complex was investigated during severe ethanol intoxication and withdrawal in the rat. The intragastric intubation technique was used to establish physical ethanol dependence in the animals. Cerebral cortex from male Wistar rats was studied 1) after 3 1/2 days of severe ethanol intoxication, 2) during the ethanol withdrawal reaction and 3) in a control group. The effect of GABA-ergic activation by muscimol and THIP (4,5,6,7-tetrahydroisoxazole(5,4-c)pyridin-3-01) on 3H-diazepam binding was unchanged during ethanol intoxication and withdrawal, as was the affinity constant (KD) and the maximal number of binding sites (Bmax) for 3H-flunitrazepam. In conclusion, the benzodiazepine/GABA receptor complex is unlikely to play any causal part in physical ethanol dependence.

Alcoholic Intoxication↗
PubMed1982

Peripheral metabolism of beta-carboline-carboxylic acid esters.

Esters of beta-carboline-3-carboxylic acid have recently been identified as potent inhibitors of brain benzodiazepine receptors in vitro. Ethyl beta-carboline-3-carboxylate (beta-CCE), however, is a rather weak inhibitor in vivo of benzodiazepine receptors in mice. The ED50-value was 91 mg/kg intraperitoneally 35 min after administration (ED50 is that dose which inhibits by 50% the specific binding of 3H-flunitrazepam intravenously). ED50 for beta-CCE was 2-20 fold lower in mice pretreated with organophosphorus esterase inhibitors, concomitantly with the observation of strong inhibition of liver and kidney hydrolyzing activity, using 3H-propyl beta-carboline-3-carboxylate as substrate. The rat brain contains only approximately 0.1% of the hydrolyzing activity as compared to the liver. It is concluded that some esters of beta-carboline-3-carboxylate exhibit only weak effects on benzodiazepine receptors in living animals due to hydrolysis outside the brain.

Animals↗