Biomedical subjects

S B Ross

Publications and source records attributed to S B Ross.

At least 73 records · Page 4Linked to original sources

PubMed1988

Characterization of [3H]paroxetine binding in rat brain.

The binding of the 5-hydroxytryptamine (5-HT, serotonin) uptake inhibitor [3H]paroxetine to rat cortical homogenates has been characterized. The effect of tissue concentration was examined and, with 0.75 mg wet weight tissue/ml in a total volume of 1,600 microliter, the binding was optimized with an apparent dissociation constant (KD) of 0.03-0.05 nM. Competition experiments with 5-HT, citalopram, norzimeldine, and desipramine revealed a high (90%) proportion of displaceable binding that fitted a single-site binding model. Fluoxetine and imipramine revealed, in addition to a high-affinity (nanomolar) site, also a low-affinity (micromolar) site representing approximately 10% of the displaceable binding. The specificity of the [3H]paroxetine binding was emphasized by the fact that 5-HT was the only active neurotransmitter bound and that the serotonin S1 and S2 antagonist methysergide was without effect on the binding. Both 5-HT- and fluoxetine-sensitive [3H]paroxetine binding was completely abolished after protease treatment, suggesting that the binding site is of protein nature. Saturation studies with 5-HT (100 microM) sensitive [3H]paroxetine binding were also consistent with a single-site binding model, and the binding was competitively inhibited by 5-HT and imipramine. The number of binding sites (Bmax) for 5-HT-sensitive [3H]paroxetine and [3H]imipramine binding was the same, indicating that the radioligands bind to the same sites. Lesion experiments with p-chloroamphetamine resulted in a binding in frontal and parietal cortices becoming undetectable and a greater than 60% reduction in the striatum and hypothalamus, indicating a selective localization on 5-HT terminals. Together these findings suggest that [3H]paroxetine specifically and selectively labels the substrate recognition site for 5-HT uptake in rat brain.

Animals↗

PubMed1988

Dopamine-mediated behaviours produced in naive mice by bromocriptine plus SKF 38393.

The ability of bromocriptine and SKF38393 (2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine) to produce some dopamine-mediated behaviours has been assessed in mice. Soon after injection, SKF38393 produced moderate increases in grooming and sniffing which were not very intense, while bromocriptine (with or without SKF38393) inhibited all grooming behaviour. Bromocriptine alone also depressed rearing and sniffing in the first hour and SKF38393 alone was without effect on rearing, but the combination produced a marked increase in the incidence of both rearing and sniffing, both of which behaviours appeared to be stereotyped. When bromocriptine-induced locomotor stimulation was peaking about 3 h after injection, as measured in automated activity cages in previous studies, there was an increase in sniffing and rearing, the incidence of which was unaffected by the addition of SKF38393, perhaps due to the shorter duration of action of SKF38393 than of bromocriptine. The data indicate that the D-1 agonist SKF38393 can qualitatively and quantitatively alter the behavioural spectrum produced by the D-2 agonist bromocriptine.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1987

Inhibition of 5-hydroxytryptamine accumulation and deamination by substituted phenylalkylamines in hypothalamic synaptosomes from normal and reserpine-pretreated rats.

1. In the present study the abilities of different compounds to inhibit MAO inside and outside the serotonergic neurons, to inhibit the accumulation of 5-HT and to release 5-HT were separated by using different in vitro techniques. With these methods a number of substituted phenylalkylamines, which are reversible inhibitors of monoamine oxidase (MAO) type A, were characterized. 2. The compounds were examined regarding their ability to inhibit the accumulation of 5-HT and to inhibit MAO in the same synaptosomal preparation of hypothalamus from normal and reserpine-pretreated rats. The difference in the uptake of 14C-5-HT (0.1 mumol/l) in the absence and presence of citalopram (0.25 mumol/l) was taken as a measure of the accumulation into the serotonergic synaptosomes. The deamination of 14C-5-HT (0.1 mumol/l) in the presence of citalopram (0.25 mumol/l) was considered as that brought about outside the serotonergic synaptosomes, whereas the difference between the deamination in the absence and presence of citalopram was taken as the MAO activity inside the serotonergic synaptosomes. 3. Most of the phenylalkylamines were slightly more potent as MAO inhibitors outside serotonergic synaptosomes than as inhibitors of 5-HT accumulation in normal rats. The most potent MAO inhibitors, both in absolute terms and in comparison with uptake inhibitory potency, were the 2,6-dichloro-(FLA 365) and the phenylpropylene-(FLA 417) derivatives. 4. A difference in potency on the accumulation in synaptosomes from normal and reserpine-pretreated rats was found for many of the phenylalkylamines with the exception of FLA 365, FLA 417 and the 2,5-dimethyl derivative RAN 113.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

Distribution of the two forms of monoamine oxidase within monoaminergic neurons of the guinea pig brain.

The relative distribution of type A and type B monoamine oxidase (MAO) inside and outside the monoaminergic synaptosomes in preparations from hypothalamus and striatum of the guinea pig was determined by incubation of synaptosomal preparations of these regions with low concentrations of [14C]5-hydroxytryptamine (5-HT), noradrenaline, and dopamine. The deamination within the monoaminergic synaptosomes was hindered by selective amine uptake inhibitors. In the absence of these inhibitors, both intra- and extraneuronal deamination was measured. The two forms of the enzyme were differentiated with the irreversible and selective MAO-A and MAO-B inhibitors clorgyline and selegiline (l-deprenyl), respectively. [14C]5-HT was deaminated greater than 90% by MAO-A both inside and outside the 5-hydroxytryptaminergic synaptosomes prepared from the guinea pig hypothalamus. The deamination of [14C]noradrenaline within the noradrenergic synaptosomes of the hypothalamic preparation was in the ratio 75:25% for MAO-A:MAO-B; the corresponding ratio outside these synaptosomes was 45:55%. The deamination of [14C]dopamine within dopaminergic synaptosomes in the striatal preparation was 65% type A:35% type B, whereas outside these synaptosomes the ratio was 35:65%. Because the relative amounts and the distribution of the two forms of MAO in the guinea pig brain seem to be similar to those previously detected for the human brain, the MAO in the guinea pig brain may be a good model for the MAO in the human brain.

Animals↗

PubMed1987

Proadifen-sensitive high affinity binding of 3H-alaproclate to liver membranes.

3H-Alaproclate, a selective 5-hydroxytryptamine uptake inhibitor, was found to bind to microsomal membranes from the rat liver with high affinity (KD = 3 nM) and large capacity (Bmax about 2 nmol/g liver). This binding was stereoselective since S-(-)-alaproclate was 30 times more potent than the R-(+)-enantiomer to displace the 3H-labelled racemate. Proadifen (SKF 525A), an inhibitor of cytochrome P-450, displaced the 3H-alaproclate binding with the same, high affinity (Ki = 3 nM) as alaproclate itself. Repeated treatment with phenobarbital sodium (5 x 75 mg/kg intraperitoneally) increased the number of alaproclate binding sites 7-8 times without changing the affinity. However, most of the phenobarbital induced 3H-alaproclate binding was not displaceable by proadifen, showing the presence of at least two different high affinity binding sites. The possible involvement of cytochrome P-450 in the alaproclate binding is discussed.

Alanine↗

PubMed1987

Stereoselective high-affinity binding of 3H-alaproclate to membranes from rat cerebral cortex.

The binding of 3H-alaproclate, a selective 5-hydroxytryptamine uptake inhibitor, to membranes prepared from the rat cerebral cortex was investigated by a filtration technique. It was found that 3H-alaproclate bound with high affinity to three or four different sites and to one low affinity site. The binding to two of these sites was displaceable by 1 microM proadifen (SKF 525A), an inhibitor of drug metabolism. From iterative nonlinear regression analysis the KD-values of these sites were calculated to about 1 and 28 nM and the Bmax values 1.5 and 19 pmol/g wet tissue, respectively. The high affinity binding that was not displaceable by proadifen but by 10 microM alaproclate had KD-values of 1 nM and 6 nM and Bmax-values of 0.4 and 2 pmol/g wet tissue. The low affinity binding that was not displaceable by proadifen had a KD-value of about 200 nM and a Bmax-value of about 90 pmol/g tissue. The possible relationship between the proadifen sensitive high affinity binding of 3H-alaproclate and the brain cytochrome P-450 is discussed.

Alanine↗

PubMed1987

Catecholaminergic activity in idiopathic torsion dystonia.

Day and nighttime melatonin and dopamine-beta-hydroxylase activity were measured in blood from 10 Jewish and 9 non-Jewish dystonics and from 22 nondystonic family members. Groups did not significantly differ on either of these measures. These results do not support a generalized abnormality of noradrenergic release in dystonia.

Adolescent↗

PubMed1986

Inhibition of monoamine oxidase in monoaminergic neurones in the rat brain by irreversible inhibitors.

The irreversible inhibition of monoamine oxidase (MAO) inside and outside monoaminergic neurones in the rat brain by the suicide inhibitors clorgyline, selegiline (l-deprenyl), pheniprazine, phenelzine, iproniazid, pargyline and the d- and l-enantiomers of tranylcypromine was determined. This was achieved by incubating crude synaptosomal preparations of hypothalamus and striatum from rats treated with the inhibitors 24 hr earlier, with low concentrations of [14C]serotonin (0.1 microM), [14C]-noradrenaline (0.25 microM) and [14C]dopamine (0.25 microM) in the absence and presence of selective uptake inhibitors (citalopram, maprotiline and amfonelic acid, respectively). It was found that all inhibitors inhibited the deamination of serotonin and noradrenaline outside the amine neurons at slightly lower doses than that within these neurones. This could at least in part be due to protection of MAO by the endogenous amines in these neurones. The deamination of dopamine was rather more strongly inhibited inside the neutrons than outside, particularly at higher doses. There was no indication that tranylcypromine or phenelzine was accumulated in the neurones by the membranous amine uptake mechanisms. The rate of the recovery of the deaminating activities inside and outside the serotonergic and noradrenergic neurones in hypothalamus after phenelzine and clorgyline inhibition was the same (50% recovery after 12-15 days), which indicates similar rate of synthesis of MAO in different cell types.

Animals↗

PubMed1986

Central noradrenaline depletion antagonizes aspects of d-amphetamine-induced hyperactivity in the rat.

The effects of noradrenaline (NA) depletion upon amphetamine-induced hyperactivity were examined in five experiments. Central NA depletion via either systemic DSP4 or neonatal 6-OHDA antagonised the amphetamine-induced (2 mg/kg SC) increase in rearing behaviour, whereas lesions of the dorsal noradrenergic bundle using 6-hydroxydopamine antagonised the increase in locomotor activity. Peripheral NA depletion following systemic 6-hydroxydopamine to adult rats did not cause any changes in motor activity after acute amphetamine administration. Desipramine, the selective NA uptake inhibitor, blocked the effects of DSP4 upon amphetamine-induced rearing. NA depletion antagonised hyperactivity produced by the 2 mg/kg dose of amphetamine, but not the hyperactivity (rearing or locomotion) effects of amphetamine at 1, 4 or 8 mg/kg.

Animals↗

PubMed1986

The inhibition of the cage-leaving response--a model for studies of the serotonergic neurotransmission in the rat.

It was observed that rats that had been given drugs that enhance serotonergic neurotransmission, e.g. the serotonin releasing compounds p-chloroamphetamine (PCA) and fenfluramine, the MAO-A inhibitors and serotonin releasing agents amiflamine and alpha-ethyltryptamine and the serotonin agonists 5-methoxy-N, N-dimethyltryptamine (5-MeODMT), 8-hydroxy-2-(di-n-propylamino) tetraline (8-OH-DPAT), m-chlorophenyl piperazine (m-CPP) and 5-methoxy-3 (1,2,3,6-tetrahydropyridin-4-yl)1H-indole (RU 24969), did not leave their home-cages when the grid-covers were removed in contrast to normal rats who almost immediately left the cages. The association between the serotonin neurotransmission and the inhibitory effect of PCA on the cage-leaving response was indicated by the findings that 1. Serotonin uptake inhibitors (alaproclate and citalopram) antagonized the effect of PCA. 2. High, neurotoxic doses of PCA antagonized the effect of PCA when tested one week after the former administration. The serotonin uptake inhibitor zimeldine counteracted the effect of neurotoxic PCA. 3. Depletion of brain serotonin with p-chlorophenylalanine counteracted the effect of acute PCA. 4. Repeated treatment of rats for 7 days with zimeldine, amiflamine, alpha-ethyltryptamine or clorgyline plus a low dose of PCA counteracted the effect of acute PCA probably due to a functional down-regulation at postsynaptic receptors. Clorgyline or a low dose of PCA by themselves had no effect. 5. Compounds interacting with dopamine or noradrenaline mechanisms, e.g. alpha-methyltyrosine, N-2-chloroethyl-N-ethyl-2-bromobenzylamine (DSP 4), pimozide, remoxipride and prazosin did not antagonize the effect of PCA nor did (+)-amphetamine inhibit the cage-leaving response. None of the serotonin receptor antagonists (cinanserin, ketanserin, metergoline, methysergide, metitepine, mianserin, pirenperone) blocked the inhibition of the cage-leaving response produced by PCA, indicating that the receptors involved may not be of the S1- and S2- types. Observation of the cage-leaving response may be a valuable technique in studies of drugs that enhance the serotonin neurotransmission in the rat brain.

Animals↗

PubMed1986

Concentrations of monoamine metabolites in the cerebrospinal fluid of twins and unrelated individuals--a genetic study.

The concentrations of the major monoamine metabolites, homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylethylene glycol (MOPEG), and 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF), of platelet monoamine oxidase (MAO) and of dopamine beta-hydroxylase (DBH)-activity in serum and CSF were determined in pairs of healthy mono- and dizygotic twins, brothers and unrelated individuals. Intraclass correlations were calculated for each category of pairs. Of the monoamine metabolites, only MOPEG was found to be under any major genetic influence. Genetic heritability for MOPEG was 0.74 with no evidence of cultural heritability or environment common to twins. For HVA and 5-HIAA, a familial influence was found, where the cultural heritability was higher than the genetic. As in previous studies of MAO in blood platelets and of DBH activity in serum, there was strong evidence for a genetic component. The genetic heritability for MAO was 0.78. For DBH in serum the genetic component was 0.98, and for DBH in CSF, 0.83. The demonstration of a familial influence on 5-HIAA and HVA in CSF requires a more detailed analysis of the character of such environmental and genetic influences, using more direct techniques.

Adolescent↗

PubMed1986

Failure to detect any transport of the irreversible monoamine oxidase inhibitor N-cyclopropyl-4-chloroamphetamine by the carrier of 5-hydroxytryptamine in the brain of the rat in vivo.

N-Cyclopropyl-4-chloroamphetamine (LY 93716) was examined for its potential preference for inhibiting the activity of monoamine oxidase (MAO) within serotonergic nerve terminals in the hypothalamus of the rat. Such an effect should support the hypothesis of Fuller and Perry (1977) (Neuropharmacology 16: 495-497) that this compound is transported by the uptake mechanism for 5-hydroxytryptamine (5-HT). By using a small (0.1 microM) substrate concentration of [14C]5-HT and a synaptosomal preparation incubated in the absence and presence of a selective inhibitor of the uptake of 5-HT (citalopram) it is possible to measure the activity of MAO in serotonergic nerve terminals. It was found that LY 93716 caused greater inhibition outside than inside the serotonergic nerve terminals when the activity of MAO was analysed 24 hr after the injection, but an inverted relationship was observed when analysed 72 hr after administration. Inhibition of uptake did not cause any change in the inhibition of MAO within the serotonergic nerve terminals at the former time but antagonized the inhibition observed 72 hr after the injection. It is concluded that the latter effect was due to antagonism of the neurotoxic action of LY 93716 and that no evidence was found that LY 93716 is transported by the uptake carrier for 5-HT.

Amphetamines↗

PubMed1986

Selective inhibition of monoamine oxidase by p-aminosubstituted phenylalkylamines in catecholaminergic neurones.

The in vivo inhibition of monoamine oxidase (MAO) inside and outside noradrenergic and dopaminergic nerve terminals in the hypothalamus and striatum, respectively, was examined in the rat after oral administration of a series of substituted p-aminophenethylamines and some related compounds. This was achieved by measuring their ability to protect MAO from irreversible inhibition by phenelzine, determined by the deaminating activity of synaptosomal preparations in the absence and presence of maprotiline, a selective inhibitor of the uptake of noradrenaline, or of amfonelic acid, a potent inhibitor of the uptake of dopamine, with small (0.25 microM) concentrations of [14C]noradrenaline or [14C]dopamine as substrate. It was found that several of these compounds were much more potent in protecting MAO within the noradrenergic neurones than MAO in other cells. Since the inhibitors of the uptake of noradrenaline, desipramine and CPP 199 antagonized this preference for noradrenergic MAO it is concluded that these MAO inhibitors are accumulated in the noradrenergic neurones by the membranal uptake carrier. Hence the selectivity for MAO within noradrenergic neurones seems to reflect the ability of the compounds to be transported by this carrier. The structure-activity relationship obtained showed the greatest selectivity for the unsubstituted p-dimethylamino-(FLA 289), p-methylamino-(FLA 727) and p-amino-(FLA 334)-amphetamines, whereas the 2-fluoro compound (FLA 558) had the greatest potency. N,N-didesmethylamiflamine [FLA 668(+)] had an almost specific effect in the noradrenergic nerve terminals. The primary p-amino derivatives, FLA 334 and FLA 668, produced a marked selective protection of MAO in dopaminergic nerve terminals, whereas the tertiary and secondary derivatives had much less preference for dopaminergic MAO.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Selective monoamine oxidase inhibitors. 3. Cyclic compounds related to 4-aminophenethylamine. Preparation and neuron-selective action of some 5-(2-aminoethyl)-2,3-dihydroindoles.

Nine 5-(2-aminoethyl)-2,3-dihydroindole derivatives were synthesized and tested as monoamine oxidase (MAO) inhibitors in vitro and in vivo. All compounds were found to be selective MAO-A inhibitors in vitro, the most active ones, 5-[1-(2-aminopropyl)]-2,3-dihydro-4-methylindole acetate (3), 5-[1-(2-aminopropyl)]-4-chloro-2,3-dihydroindole acetate (5), 5-[1-(2-aminopropyl)]-2,3-dihydro-1-ethyl-4-methylindole tartrate (6), 5-[1-(2-aminopropyl)]-2,3-dihydro-1-ethyl-6-methylindole tartrate (7), and 5-[1-(2-aminobutyl)]-4-chloro-2,3-dihydroindole acetate (9) being equipotent with amiflamine, (S)-(+)-4-(dimethylamino)-2, alpha-dimethylphenethylamine. Some of the compounds, 3, 6, 5-[1-(2-aminopropyl)]-2,3-dihydroindole acetate (1), and 5-[1-(2-amino-2-methylpropyl)]-2,3-dihydroindole acetate (8), were found to be very potent inhibitors of MAO in serotonergic and/or noradrenergic nerve terminals in the rat brain in vivo, inhibiting MAO within these neurons at doses 1/10 of those required to inhibit MAO in other neurons or cells. Compound 1 was also a potent and selective inhibitor of MAO within dopaminergic nerve terminals in vivo. This neuron selectivity is due to the uptake of these compounds by the neuronal uptake mechanisms.

Animals↗

PubMed1986

Selective monoamine oxidase inhibitors. 4. 4-Aminophenethylamine derivatives with neuron-selective action.

Nine 4-aminophenethylamine derivatives were synthesized and tested for monoamine oxidase (MAO) inhibitory effects with particular attention to their selectivity for MAO within monoaminergic neurons in the rat brain. All compounds selectively inhibited the A form of MAO in vitro. Some of the compounds inhibited the MAO within the monoaminergic neurons at much lower doses than those required for inhibition of MAO within other cells in vivo. The most potent compounds in this respect were 4-amino-2-fluoro-alpha-methylphenethylamine (5) and 4-amino-2-chloro-alpha-methylphenethylamine (4).

Animals↗

PubMed1986

A and B forms of monoamine oxidase within the monoaminergic neurons of the rat brain.

The inhibition of the A and B forms of monoamine oxidase (MAO) inside and outside serotonergic, noradrenergic, and dopaminergic synaptosomes in homogenates of rat hypothalamus or striatum by clorgyline, a selective and irreversible MAO-A inhibitor, and selegiline, a selective and irreversible MAO-B inhibitor, was examined. Intrasynaptosomal deamination at low concentrations of the substrates [14C]5-hydroxytryptamine ([14C]5-HT; 0.1 microM), [14C]noradrenaline (0.25 microM), [14C]3,4-dihydroxyphenylethylamine ([14C]dopamine; 0.25 microM), and [14C]tyramine (0.25 microM) was hindered by selective uptake inhibitors (citalopram, maprotiline, and amfonelic acid) in the incubation media. Thus, the difference between the deamination of 14C-amine in the absence and presence of the appropriate selective uptake inhibitor provided a measure of deamination in the specific aminergic synaptosomes. This was verified by determining the loss of MAO activity within noradrenergic and serotonergic systems after degeneration of the nerve terminals by the neurotoxins N-chloroethyl-N-ethyl-2-bromobenzylamine and p-chloroamphetamine. Results with the two inhibitors revealed that the A and B forms were responsible for 80 and 20%, respectively, of the deamination of [14C]5-HT within serotonergic synaptosomes from the hypothalamus. The deamination of [14C]noradrenaline within the noradrenergic synaptosomes from the hypothalamus and that of [14C]dopamine and [14C]tyramine within the striatal dopaminergic synaptosomes were due to MAO-A. About 10% of the deamination of [14C]noradrenaline, [14C]dopamine, and [14C]tyramine outside the noradrenergic or dopaminergic synaptosomes was brought about by the B form, with the remainder being deaminated by MAO-A.

Amines↗

PubMed1986

Serum dopamine-beta-hydroxylase activity in patients with major depressive disorders.

The dopamine-beta-hydroxylase (DBH) activity in serum was assayed in 32 acutely ill inpatients with major disorder and in 33 healthy control subjects. Twenty-six of these patients were also studied in a state of remission. The DBH activity was compared to the serum levels (studied during a 24 h period) of T4, T3, TSH, prolactin and melatonin as well as to the outcome of the dexamethasone suppression and TRH test and to various clinical symptoms, as estimated by different rating procedures. No significant differences in DBH activity were found between the acutely ill patients, patients in remission, or normal subjects. Thus, the determination of the activity does not seem to be of practical importance as a laboratory diagnostic tool for major depressive disorder. A significant positive correlation was found between the DBH activity and the TSH levels, estimated by several parameters during the 24 h period, in the acutely ill patients, whereas no significant correlation was found in patients in remission or in the normal subjects. No significant correlation was found between the DBH activity in any group and the other laboratory or clinical parameters. The mechanism behind the significant correlation between the DBH activity and TSH levels remains to be clarified.

Adult↗

PubMed1986

Comparison between a serotonin and a noradrenaline reuptake blocker in the treatment of depressed outpatients. Biochemical aspects.

Seventy-five outpatients with major depressive disorder (RDC) were randomly referred to treatment with a dominant 5-HT reuptake blocker (zimeldine, 100 mg b.i.d.) or a dominant NA reuptake blocker (maprotiline 75 mg b.i.d.). Pretreatment biochemical, pharmacodynamic and pharmacokinetic variables were studied and related to the treatment outcome with the two drugs. Female responders to the dominant 5-HT reuptake blocker were characterized by low pretreatment accumulation of 14C-5-HT in rat synaptosomes, when incubated in patient plasma. Among zimeldine responders there was a relationship between antidepressive effect and steady-state concentrations of zimeldine and norzimeldine. These findings support the hypothesis of a subgroup of depression characterized by serotonin disturbance.

Animals↗