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Biomedical subjects

D Scherman

Publications and source records attributed to D Scherman.

At least 109 records · Page 6Linked to original sources
PubMed1989

Striatal dopamine deficiency in Parkinson's disease: role of aging.

The striatal dopaminergic innervation was investigated postmortem in 49 control and 57 parkinsonian brains by assessing the binding of tritiated alpha-dihydrotetrabenazine ([3H]TBZOH), a specific ligand of the vesicular monoamine transporter. The density of [3H]TBZOH binding sites in the caudate nucleus of control subjects decreased significantly with age, suggesting an age-dependent reduction in striatal dopamine innervation. In contrast, an increase with the age at time of death was observed in patients with Parkinson's disease, although the density of [3H]TBZOH binding sites was subnormal. Mean values represented 26.5% and 12.7% of control values in the caudate nucleus and in the putamen, respectively. The binding of [3H]TBZOH in the caudate nucleus decreased exponentially with the duration of Parkinson's disease. The rate of [3H]TBZOH binding decrease, an index of the rate of striatal dopaminergic denervation, was about twice as high in parkinsonian patients as in controls and was not related to the age at onset of the disease. The data suggest that (1) parkinsonian symptoms appear above a threshold degeneration state corresponding to 50% of the normal innervation at the age of 60, and (2) aging does not play a major role in the process of nigrostriatal neuron degeneration in Parkinson's disease.

Aged↗
PubMed1989

Quantitative autoradiography of the rat brain vesicular monoamine transporter using the binding of [3H]dihydrotetrabenazine and 7-amino-8-[125I]iodoketanserin.

The binding of [3H]dihydrotetrabenazine, a specific ligand of the monoamine transporter present on serotonin and catecholamine synaptic vesicles, was studied on rat brain sections. The characteristics of binding (Kd = 5.0 nM, k1 = 0.13 x 10(6) M-1 s-1; k-1 = 0.66 x 10(-3) s-1) were similar to those previously observed on tissue homogenates. The rostrocaudal topographical distribution of dihydrotetrabenazine binding sites was analysed by quantitative autoradiography. High labelling was observed in regions richly innervated by monoaminergic systems: dopamine in the striatum and olfactory tubercles, noradrenaline in the striatal fissure and in the paraventricular and dorsomedial hypothalamus and serotonin in the lateral septum, islands of Calleja and suprachiasmatic nucleus. Cell bodies were also labelled in the substantia nigra and ventral tegmental area (dopamine), in locus coeruleus (noradrenaline) and in raphe nucleus (serotonin). The pituitary gland (particularly the neural lobe) and the pineal gland were also labelled. Low labelling was observed in various areas of the cerebral cortex and in the cerebellum. Unilateral 6-hydroxydopamine lesion of the substantia nigra dramatically reduced [3H]dihydrotetrabenazine labelling in the ipsilateral striatum. Moreover, ketanserin has recently been shown to possess a nanomolar affinity for the vesicular monoamine transporter, and autoradiographic localization of brain monoaminergic synaptic vesicles was also obtained by means of the derivative 7-amino-8-[125I]iodoketanserin in the presence of 5-hydroxytryptamine2 and alpha 1 antagonists, although the non-specific labelling was higher than with [3H]dihydrotetrabenazine. It is concluded that [3H]dihydrotetrabenazine may represent a valuable monoaminergic marker in in vitro autoradiographic studies.

Animals↗
PubMed1989

Predominant cytosolic distribution of serotonin in rat pineal gland in contrast to biogenic monoamine localization in midbrain and adrenal gland.

The subcellular distribution of serotonin and norepinephrine in the rat pineal gland was studied by tissue fractionation and compared with that of biogenic monoamines in the adrenal gland and midbrain. Homogenized tissues were fractionated by ultracentrifugation or by filtration through cellulose ester membranes. Most of the epinephrine (70-80%) and norepinephrine (62-82%) present in the adrenal glands was detected in the particulate fraction. The same distribution was found for serotonin (68.5%) and norepinephrine (59%) in the midbrain and for norepinephrine (62.5%) in the pineal gland. However, most of the serotonin in the pineal was found in the soluble fraction (89.5-98%). This suggests that the great majority of serotonin in the rat pinealocytes is cytosolic and thus is not stored in subcellular vesicles, in contrast to the biogenic monoamines in the midbrain or adrenal gland.

Adrenal Glands↗
PubMed1988

Characteristics of the transport of the quaternary ammonium 1-methyl-4-phenylpyridinium by chromaffin granules.

1-Methyl-4-phenylpyridinium (MPP+), an active metabolite of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine which induces Parkinson's disease in man, is a substrate of the monoamine uptake system of chromaffin granules. It is accumulated without chemical modification by bovine chromaffin granule membrane vesicles in the presence of ATP. The transport is saturable and is characterized by a Km value of 0.8 microM at pH 8.0, similar to that of serotonin (5-HT). Transport occurs through the monoamine transporter since it is competitively inhibited by 5-HT and since MPP+ competitively inhibits [3H]5-HT uptake. Moreover, [3H]MPP+ uptake is blocked by the monoamine transporter inhibitors tetrabenazine and reserpine. Finally, MPP+ efficiently displaces [3H]reserpine and [3H]dihydrotetrabenazine from their binding sites on the transporter. In the pH range 6-8, the Km for [3H]MPP+ uptake and the EC50 of MPP+ for the displacement of [3H]dihydrotetrabenazine decrease logarithmically with the pH. MPP+ is the first quaternary ammonium salt shown to be a substrate of the monoamine transporter and it has the same pH-dependency as monoamines.

1-Methyl-4-phenylpyridinium↗
PubMed1988

D1 and D2-type dopamine receptors in patients with Parkinson's disease and progressive supranuclear palsy.

The densities of D1- and D2-type dopamine receptors were measured with [3H]SCH23390 and [3H]spiperone, in the caudate nucleus and putamen of a large series of patients with Parkinson's disease or progressive supranuclear palsy, in relation to markers of dopaminergic and cholinergic innervation of the striatum ([3H]dihydrotetrabenazine binding and choline acetyltransferase activity). Correlations were sought between these parameters and clinical characteristics of the patients (abnormal involuntary movements, dementia, confusional syndrome or treatment). In Parkinson's disease, the densities of both types of receptors were unchanged, whereas in PSP, the density of D2, but not D1-type dopamine receptors, was decreased in the caudate nucleus and the putamen. No correlations between the biochemical and clinical data were found.

Adenylyl Cyclases↗
PubMed1988

Molecular pharmacology of niaprazine.

1. The pharmacological profile of niaprazine was investigated using in vitro ligand binding techniques. 2. Niaprazine exhibits a low affinity for the vesicular monoamine transporter and for D2, alpha 2, beta, H1 and muscarinic cholinergic receptors. Niaprazine, particularly the (+)stereoisomer, has a higher affinity for alpha 1 (Ki = 77 nM) and 5-HT2 (Ki = 25 nM) binding sites, but is poorly recognized by 5-HT1A and 5-HT1B binding sites (Ki sigma mciroM). In contrast, p-fluoro-phenylpiperazine, a major metabolite of niaprazine, exhibits a higher affinity for the 5-HT1 subclasses than for the 5HT2 class. 3. These results suggest that the pharmacological properties of niaprazine reflect both its non-reserpinic catecholamine depletor effect and its action on alpha 1 and 5-HT2 receptors. A role of p-fluoro-phenylpiperazine via 5-HT1 sites cannot be excluded.

Adrenal Medulla↗
PubMed1988

Time required for transmitter accumulation inside monoaminergic storage vesicles differs in peripheral and in central systems.

Monoamine storage vesicles accumulate transmitters via an active transport process which presents similar pharmacological and bioenergetic properties in all monoaminergic systems. Using [3H]reserpine, a specific ligand of the vesicular monoamine transporter on isolated storage vesicles, we have determined the molecular turnover number of the monoamine transporter and found in various monoaminergic systems an identical value of 135 molecules of substrate transported per min. Using high performance liquid chromatography-electrochemical monoamine determination and the binding of [3H]dihydrotetrabenazine, a specific ligand of the vesicular monoamine transporter in tissue homogenates, we have measured the ratio of transmitter molecules per transporter in various rat tissues containing high amounts of monoamines. This ratio is about 500 in brain regions (striatum, hypothalamus, midbrain) and in the maxillary gland, it varies from 2000 to 7000 in sympathetic nerve terminals in the heart, brown adipose tissue and vas deferens, and it is 6000 in platelets and 280,000 in the adrenal medulla. The minimal time required in vivo for biogenic amine accumulation inside storage vesicles could be derived from these data. Values of 2-4 min were found for brain or maxillary gland synaptic vesicles, 15-50 min for heart, brown adipose tissue or vas deferens sympathetic vesicles and for platelet granules, and 35 h for adrenal medulla chromaffin granules. Thus the maturation time of monoaminergic vesicles, in terms of monoamine accumulation, is highly variable, being short in the brain and maxillary glands, 5-20-fold longer in the sympathetic nervous system and in platelets, and much increased in adrenals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

[3H]dihydrotetrabenazine, a new in vitro monoaminergic probe for human brain.

The monoamine transporter of dopamine (DA), noradrenaline, and 5-hydroxytryptamine synaptic vesicles was assayed in rat and human brain homogenates by in vitro binding of [3H]dihydrotetrabenazine. [3H]Reserpine, a second ligand of the vesicular monoamine transporter, could not be used. [3H]Dihydrotetrabenazine binding in rat brain was stable after 72 h at 22 degrees C postmortem. In major human brain regions, [3H]dihydrotetrabenazine binding was specific and saturable (KD, 2.7 nM). Displacement constants by substrates or inhibitors of vesicular monoamine uptake, and regional distribution in human brain were similar to those found in rodents. The highest densities of binding sites were observed in caudate nucleus, putamen, and accumbens nucleus. In caudate nucleus and in putamen from normal human subjects, [3H]dihydrotetrabenazine binding and homovanillic acid concentration were significantly or nearly significantly correlated. A weaker correlation was found between [3H]dihydrotetrabenazine binding and DA, in association with a higher variability of DA. [3H]Dihydrotetrabenazine binding in caudate nucleus and in putamen decreased significantly with age, unlike DA and homovanillic acid concentrations. The results establish [3H]dihydrotetrabenazine as a presynaptic monoaminergic ligand of interest for studies on postmortem human brain.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1988

Hydrophobicity of the tetrabenazine-binding site of the chromaffin granule monoamine transporter.

The catecholamine uptake inhibitor tetrabenazine (TBZ) binds to a high affinity site on the chromaffin granule membrane, presumably on the monoamine transporter. The hydrophobicity of the TBZ-binding site was investigated by comparing the potency of drugs to displace [3H]dihydrotetrabenazine (TBZOH), a ligand of the TBZ-binding site, with the lipophilicity of these drugs reflected by their octanol/buffer apparent partition coefficient (P o/b). Drugs tested were five substrates of the transporter, seven TBZ derivatives, and the inhibitors reserpine, haloperidol, and chlorpromazine. The validity of apparent P o/b as an index of lipophilicity was shown by measuring drug partitioning between buffer and chromaffin granule membranes. For most of the inhibitors tested, octanol/buffer and membrane/buffer apparent partition coefficients were correlated. For substrates of uptake and TBZ derivatives, the potency of a compound to displace [3H]TBZOH from its binding site was correlated to its apparent P o/b. This relationship was valid over a range of 5 orders of magnitude. These data are interpreted as indicating that the TBZ-binding site is hydrophobic and is in equilibrium with the ligand present in the membrane phase, and that substrates and TBZ derivatives are characterized by an equal intrinsic affinity for this site of about 1 microM. The 3-fold difference in affinity observed between alpha- and beta-diastereoisomers of TBZOH was accounted for by a similar difference in apparent P o/b. Reserpine, haloperidol, and chlorpromazine have much lower intrinsic affinity for the TBZ-binding site.

Amines↗
PubMed1988

Ketanserin binds to the monoamine transporter of chromaffin granules and of synaptic vesicles.

[3H]Ketanserin binding studies were performed on purified chromaffin granule membranes. Binding was found to occur on one class of sites and was temperature dependent. At 30 degrees the equilibrium dissociation constant KD was 45 nM. At 0 degrees, a KD value of 6 nM and a half-life of dissociation of 40 sec were measured. Methysergide, an antagonist of 5-hydroxytryptamine2 (5-HT2) receptors structurally unrelated to ketanserin, did not displace ketanserin binding. Tetrabenazine, an inhibitor of the monoamine transporter of chromaffin granules, displaced [3H]ketanserin binding. Conversely, ketanserin inhibited the binding of [3H] dihydrotetrabenazine, a ligand that specifically binds to the monoamine transporter. The inhibition was of the competitive type, indicating that both drugs bind to the same site. Ketanserin binding did not depend upon ATP-induced energization of chromaffin granules. ATP-dependent 5-HT uptake by chromaffin granule ghosts was inhibited by ketanserin with an IC50 value of 70 nM. A series of ketanserin derivatives were tested for their ability to displace [3H]dihydrotetrabenazine; EC50 values differed by more than 2 orders of magnitude and were not correlated to affinities on 5-HT2 receptors. In mouse brain, [3H]ketanserin was found to bind to methysergide-sensitive and to tetrabenazine-sensitive sites. In the striatum, tetrabenazine-sensitive sites represented a larger fraction than the methysergide-sensitive ones, whereas the reverse was true in the frontal cortex. It is concluded that nonspecific displaceable binding sites of [3H]ketanserin previously described in the striatum are tetrabenazine binding sites associated with the synaptic vesicle monoamine transporter.

Animals↗
PubMed1987

Inactivation of the catecholamine transporter during the preparation of chromaffin granule membrane 'ghosts'.

The activity of the catecholamine transporter of chromaffin granules and the binding to these vesicles of reserpine, a transporter inhibitor, decrease during ghost preparation. In contrast, the number of binding sites of dihydrotetrabenazine, another transporter ligand, is constant. Dihydrotetrabenazine thus binds to an inactive transporter whereas reserpine binds only to active vesicles. Inactivation occurs during lysis of the granules, possibly because of an incomplete resealing. The turnover number of the transporter, determined by dividing the uptake activity by the density of dihydrotetrabenazine binding sites, has a maximal value (140 molecules/min) in intact granules. The reserpine to dihydrotetrabenazine binding ratio (10-25%) is an estimate of the proportion of correctly resealed vesicles.

Adrenal Medulla↗
PubMed1987

Axonal transport of the synaptic vesicle monoamine carrier identified by [3H]dihydrotetrabenazine binding in rat sciatic nerve.

The monoamine carrier of noradrenergic synaptic vesicles was assayed in the rat sciatic nerve by in vitro binding of [3H]dihydrotetrabenazine. The number of binding sites increased with time on both sides of a ligature, indicating fast anterograde and retrograde axoplasmic transports of comparable amplitude. Anterogradely and retrogradely transported binding sites had similar pharmacological properties, which were characteristic of binding to the monoamine carrier embedded within a lipid bilayer. Contrary to the secreted synaptic vesicle matrix constituents, the intrinsic monoamine carrier assayed by [3H]dihydrotetrabenazine binding is a marker adapted to retrograde transport studies.

Animals↗
PubMed1987

Characterization of the vesicular monoamine transporter in cultured rat sympathetic neurons: persistence upon induction of cholinergic phenotypic traits.

The binding of [3H]dihydrotetrabenazine ([3H]TBZOH), a specific ligand of the reserpine-sensitive monoamine transporter in brain and adrenal medulla storage vesicles, has been measured in cultured sympathetic neurons from newborn rat in relation to their neurotransmitter phenotype. As shown previously, neurons cultured in the absence of muscle-conditioned medium displayed high activities in catecholamine synthesizing enzymes and low levels of choline acetyltransferase, and neurons cultured in conditioned medium displayed the reverse pattern (J. P. Swerts, A. Le Van Thai, A. Vigny, and M. J. Weber, Dev. Biol. 100, 1-11, 1983). The density of [3H]TBZOH binding sites as well as their subcellular distribution were identical in both types of cultures. Two other structures rich in choline acetyltransferase, the electric organ of Torpedo and the ciliary ganglion of the chick embryo did not contain measurable amounts of [3H]TBZOH binding sites, suggesting that the monoamine transporter is not an ubiquitous component of cholinergic synaptic vesicles. These data suggest that the synthesis of the monoamine transporter in sympathetic neurons is not coregulated with the syntheses of the three norpinephrine synthesizing enzymes. It is proposed that the same population of synaptic vesicles can accumulate acetylcholine or catecholamine, depending only upon which neurotransmitter synthesizing enzymes are expressed by sympathetic neurons.

Amines↗
PubMed1987

Rat adrenal medulla: levels of chromogranins, enkephalins, dopamine beta-hydroxylase and of the amine transporter are changed by nervous activity and hypophysectomy.

The levels of several constituents of chromaffin granules were determined in rat adrenal medulla after treatment with insulin or reserpine and after hypophysectomy. Insulin treatment induced increased levels of enkephalins, dopamine beta-hydroxylase, the amine carrier and of chromogranin B whereas catecholamines, cytochrome b-561 and chromagranin A remained slightly below control levels. Administration of reserpine led to similar changes with the exception of the enkephalins which increased much less. After hypophysectomy, chromogranin A was reduced to low levels; dopamine beta-hydroxylase, the amine carrier and catecholamines showed an intermediate reduction, whereas the other components remained at control levels. We can conclude that nervous stimulation of the adrenal medulla (by insulin and reserpine) induces the synthesis of enkephalins, dopamine beta-hydroxylase, the amine carrier and chromogranin B whereas the level of chromogranin A apparently depends on corticosteroids. Thus, major components of the secretory content and the membranes of chromaffin granules are regulated separately, which allows the biogenesis of chromaffin granules with a significantly altered composition.

Adrenal Medulla↗
PubMed1986

The regionalization of [3H]dihydrotetrabenazine binding sites in the mouse brain and its relationship to the distribution of monoamines and their metabolites.

[3H]Dihydrotetrabenazine binding was measured in 8 areas of the mouse brain. In all areas, binding occurred on a homogeneous class of sites (Kd approximately equal to 2.6 nM). The density of [3H]dihydrotetrabenazine binding sites strongly varied between the different brain structures; it was compared to endogenous levels of biogenic monoamines and their metabolites: the density is independent of the nature of the monoamine and of neuronal activity, but is highly correlated to the total amount of monoamines present in each structure.

3,4-Dihydroxyphenylacetic Acid↗