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Biomedical subjects

C Braestrup

Publications and source records attributed to C Braestrup.

At least 91 records · Page 5Linked to original sources
PubMed1978

Pharmacological characterization of benzodiazepine receptors in the brain.

Receptors in rat brain membranes which specifically bind 3H-diazepam were characterized pharmacologically using reference substances representing several pharmacological classes of drugs. Of 28 benzodiazepines tested, several "classical" ones (diazepam, clonazepam, lorazepam, oxazepam, nitrazepam, flurazepam, bromazepam and chlorazepate) with known clinical efficacy, as well as three newer "triazolo" benzodiazepines (estazolam, U 35,005, U 31,957), one new "imidazolo" benzodiazepine, U 31,219, and one new 2-carbamoylmethylene-benzodiazepine, displaced 3H-diazepam binding at low concentrations (Ki=1--60 nM). For these benzodiazepines there was a stastically significant correlation between Ki values for displacement and ED50 (or MED) values in several pharmacological tests predictive of anxiolytic activity in man. More than 100 nonbenzodiazepines, representing 22 distinct pharmacological classes as well as 14 presumed neurotransmitters in the CNS, including 4 peptides, were much weaker as 3H-diazepam displacers (K2 greater than 0.1 nM). These results suggest that in vitro 3H-diazepam binding represents the physiologically relevant binding to hitherto unknown receptors in the CNS.

Animals↗
PubMed1978

Benzodiazepine receptor in brain.

The evidence that the brain possesses specific receptors for benzodiazepines is summarized. Further we present a series of brain lesion experiments in rats showing that specific neuronal destructions by 6-hydroxydopamine, kainic acid in the striatum, X-ray irradiation of the hippocampus, intraperitoneal 3-acetyl-pyridine or hemisection at the thalamic level do not reduce the level of benzodiazepine receptors in striatum, hippocampus, cortex or cerebellum. These results show that the benzodiazepines are not positioned on dopamine or noradrenaline terminals, cholergic or GABA-ergic neurons in the striatum, granular cells in the hippocampus or climbing fibers in the cerebellum.

Animals↗
PubMed1978

Brain specific benzodiazepine receptors.

Brain membranes from rat and human contain a single class of brain specific binding sites for pharmacologically and clinically active benzodiazepines. There is good correlation between the pharmacological effects of benzodiazepines and the affinity for the 3H-diazepam binding site. Benzodiazepine binding sites are not present on glial cells. Selective neuronal degeneration experiments in rats indicate a neuronal localization. 3H-Flunitrazepam is a very suitable ligand for affinity binding and it binds to the same class of binding sites as 3H-diazepam. Our results indicate that the in vitro 3H-diazepam and 3H-flunitrazepam binding sites are the receptors which in vivo mediate various pharmacological and clinical effects of benzodiazepines.

Animals↗
PubMed1977

Uptake inhibition of biogenic amines by newer antidepressant drugs: relevance to the dopamine hypothesis of depression.

The dopamine theory of depression was studied by assessing the effect of antidepressant drugs on uptake of dopamine, noradrenaline, and serotonin in synaptosomes from rat brain. Five newer drugs--butriptyline, maprotiline, trimipramine, iprindole, and mianserine--exhibited rather potent inhibition of 3H-dopamine uptake in corpus striatum, as their IC50 values, which were in the order of 10(-6)-10(-5) M, were only about 50 times higher than for nomifensine (IC50 = 10(-7) M). The five drugs were weak, compared to chlorimipramine, on 14C-serotonin uptake in the whole forebrain, as their IC50 were about 10(-5) M. Butriptyline, trimipramine, and iprindole were very weak uptake inhibitors of 3H-noradrenaline in the occipital cortex. Their IC50 values were about 10(-6) M, which is almost 1000 times higher than for desmethylimipramine. These results are discussed in relation to comprehensive recent literature as further indicating a link between dopamine and depression.

Animals↗
PubMed1977

Changes in drug-induced stereotyped behavior after 6-OHDA lesions in noradrenaline neurons.

Drug-induced stereotyped behaviors are often assessed by rating scales where the eventual appearance of sniffing, licking, and biting are rated as increasing intensity of dopaminergic stimulation. A 6-OHDA induced bilateral lesion (4 X 3-8 mug/4 mul 6-OHDA) in the ascending noradrenaline neurons, lateral to the medial raphe nucleus, of 180 g Wistar rats, affecting selectively noradrenaline and not dopamine or 5-hydroxytryptamine neurons, caused a change in the d-amphetamine sulphate (5-3 mg/kg s.c.) and phenethylamine hydrochloride (40 mg/kg) induced stereotyped sniffing behavior to the performance of discontinuous or continuous licking behavior; biting/gnawing was rarely induced. The site of the lesion and the partial antagonism of 6-OHDA by the uptake inhibitor protriptyline indicate a noradrenergic influence on the behavioral expression of the dopaminergically mediated stereotyped behavior.

Animals↗
PubMed1977

Specific benzodiazepine receptors in rat brain characterized by high-affinity (3H)diazepam binding.

[3H]Diazepam appears to bind specifically to a single, saturable, binding site located on rat brain membranes, with an affinity constant near 3 nM at pH 7.4. Specific binding constitutes more than 90% of total binding at 0 degrees and less than 10% of total binding at 37 degrees. Arrhenius plots suggest a sharp conformational change in the diazepam receptor near 18 degrees. Mitochondrial fractions from rat kidney, liver, and lung exhibit some [3H]diazepam binding that can be displaced by nonradioactive diazepam and several other benzodiazepines. However, Ro-4864, which is almost inactive in displacing [3H]diazepam from brain membranes, is extremely potent in displacing it from kidney mitochondria. Conversely, clonazepam, the most potent inhibitor of brain binding, is an extremely weak inhibitor of kidney binding. Furthermore, diazepam binding to kidney mitochondria has an affinity constantof 40 nM, about 15 times higher than that in brain. No specific diazepam binding was detected in intestine or skeletal muscle. Thus, specific [3H]diazepam binding to membranes appears to be restricted to brain, where it is unevenly distributed: the density of diazepam receptors is about five times higher in cortex (the highest density) than in pons-meddula (lowest density). Trypsin and chymotrypsin completely abolished specific [3H]diazepambinding in brain and kidney.

Animals↗
PubMed1977

Biochemical differentiation of amphetamine vs methylphenidate and nomifensine in rats.

Amphetamine-like stimulants were divided into two groups, one in which the stereotyped behaviour was not antagonized by reserpine [(+)-amphetamine, (-)-amphetamine, methamphetamine, phenmetrazine and phenethylamine] and another group in which the behavioural effects were blocked by reserpine (methylphenidate, nomifensine, pipradrol and amfonelic acid (NCA; Win 25978)). Both groups increased homovanillic acid (HVA) in whole brain 2 h after administration. The 'methylphenidate group' also increased brain 3,4-dihydroxyphenylacetic acid (DOPAC) in naive rats; whereas the '(+)-amphetamine group' decreased DOPAC in naive rats, as well as in reserpinized rats, alpha-methyl-p-tyrosine-treated rats and after acute hemisection. The reserpine antagonism of the 'methylphenidate group'-induced stereotyped behaviour was partially reversed by type A monoamine oxidase inhibition. The '(+)-amphetamine group'-induced stereotyped behaviour was not blocked by short time pretreatment with alpha-methyltyrosine, only by longer pretreatment intervals. The mechanisms by which the two groups are differentiated biochemically is discussed with special attention to possible intra-neuronal inhibition of dopamine oxidation by the '(+)-amphetamine group'.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1977

Mass fragmentographic demonstration of low amounts of beta-phenylethylamine in human urine.

beta-Phenylethylamine (PEA) is determined with a simple, rapid and highly specific assay, 5 ml human urine, using GLC combined with mass fragmentography. The 24 h urinary excretion of PEA in ten healthy male subjects ranged from 28 to 131 nmol/24 h with a mean (+/- SD) of 66 (+/- 9) nmol/24 h. It is concluded that reinvestigation of PEA-excretion in psychiatric patients is needed, since earlier less specific methods have measured much higher levels of PEA in human urine.

Chromatography, Gas↗
PubMed1976

Methylphenidate-like effects of the new antidepressant drug nomifensine (HOE 984).

Nomifensine (HOE 984) belongs to a chemically new class of drugs with reported antidepressant properties. Nomifensine, like methylphemidate, d-amphetamine and apomorphine, induces strong, intense stereotypes behaviour in the rat. The nomifensine-induced stereotyped behaviour was completely antagonized by pretreatment with reserpine (7.5 mg/kg, 18 h) but not by short-time pretreatment with alpha-methyltyrosine (250 mg/kg, 2 h.) Nomifensine thus differs from d-amphetamine and apomorphine but resembles methylphenidate on stereotyped behaviour. Nominfensine, M1 (8-amino-2-methyl-4-(4-hydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline fumarate) (Hoechst), methylphenidate and d-amphetamine induced a strong increase in the brain level of homovanillec acid (HVA), whereas the dopamine uptake inhibitor benztropine induced no changes in HVA and cocaine induced only a small increase. Nomifensine and the M1 metabolite, like methylphenidate, also increased 3,4-dihydroxyphenylacetic acid (DOPAC) whereas amphetamine, apomorphine, benztropine and cocaine decreased this dopamine metabolite. This suggests that the stereotyped licking and/or biting activities in the rat are related to dopamine releasing properties of nomifensine, methylphenidate and amphetamine. This is further supported by an inverse relationship between the in vitro dopamine uptake inhibitory concentrations and the sterotypy-inducing dose levels of nomifensine and d-amphetamine. Amphetamine caused a strong, and nomifensine and apormorphine a week increase in brain 3-methoxy-4-hydroxyphenylglycol (MOPEG).

Animals↗
PubMed1976

A method for the assay of conjugated 3,4-dihydroxyphenylglycol, a major noradrenaline metabolite in the rat brain.

We present the first published procedure for the measurement of endogenous conjugated 3,4-dihydroxyphenylglycol (DOPEG) in the rat brain. Conjugated DOPEG is estimated from brain extracts after enzymic hydrolysis, isolation of hydrolysed DOPEG on alumina, methylation of DOPEG to 3-methoxy-4-hydroxyphenylglycol (MOPEG) and gas chromatographic quantification of MOPEG. The level of conjugated DOPEG in the CNS of rats (65.7 +/- 0.7 ng/g whole brain tissue corrected for recovery) almost equals the level of conjugated MOPEG. The sensitivity of the method is about 6 ng/g brain tissue. After inhibition of monoamine oxidase with clorgyline (30 mg/kg) conjugated DOPEG and MOPEG both disappeared from the brain with a half-life of about 1 h. Turnover calculations indicate that conjugated DOPEG and MOPEG are the two major noradrenaline end-metabolites in the rat brain. The method of estimating conjugated DOPEG also allows the measurement of noradrenaline, dopamine and total MOPEG in an extract from one half of a rat brain.

Aluminum Oxide↗