Biomedical subjects

A Pazos

Publications and source records attributed to A Pazos.

At least 91 records · Page 5Linked to original sources

PubMed1988

Autoradiography of antidepressant binding sites in the human brain: localization using [3H]imipramine and [3H]paroxetine.

[3H]Imipramine and [3H]paroxetine were used to label sites associated with serotonin uptake mechanisms in post-mortem brain tissue from control subjects. The anatomical localization of these sites was examined by autoradiography and densities measured by microdensitometry. We found [3H]imipramine binding to increase with age in the cortex and amygdala, but to be independent of gender and post-mortem delay. Preliminary results indicate that the binding of both [3H]imipramine and [3H]paroxetine is diminished in the brain of patients treated with imipramine. The distribution of [3H]imipramine and [3H]paroxetine high-affinity binding sites was very similar, and correlated well with the distribution of serotonergic presynaptic markers in the brain. The highest densities of binding sites were found in the raphé nuclei and the midline thalamic nuclei. Other structures presenting high levels of binding were the substantia nigra, nucleus interpeduncularis, locus coeruleus, nucleus nervi hypoglossi, nucleus nervi facialis, mammillary bodies and other parts of the hypothalamus. In contrast, regions such as the neocortex, hippocampus, amygdala and cerebellum showed low densities of [3H]imipramine and [3H]paroxetine binding sites. This distribution seems to indicate that the ascending serotonergic pathways are the main site of action of antidepressants.

Aged↗

PubMed1987

[3H]ketanserin labels 5-HT2 receptors and alpha 1-adrenoceptors in human and pig brain membranes.

The binding characteristics of [3H]ketanserin (a reported selective radioligand for serotonin 5-HT2 receptors) and [125I]BE 2254 (which labels selectively alpha 1-adrenoceptors) were characterized in brain frontal cortex membranes of pig and man. Saturation experiments indicated that both radioligands label apparently a homogeneous class of binding sites in human and pig fontal cortex membranes. Competition experiments with [125I]BE 2254 using 17 agonists and antagonists showed monophasic and steep curves in human and pig frontal cortex membranes. The pharmacological profile of these sites is typical of alpha 1-adrenoceptors. In competition experiments with [3H]ketanserin, most of the tested compounds displayed shallow or biphasic curves. In particular, alpha 1-adrenoceptor-selective antagonists (prazosin, WB 4101, BE 2254...) displaced with nanomolar affinity about 15 and 40% of the specific [3H]ketanserin binding in human and pig frontal cortex membranes, respectively. The minor component of [3H]ketanserin binding correlated highly significantly with [125I]BE 2254 binding in both membrane preparations. The major component of [3H]ketanserin binding to pig and human frontal cortex membranes correlated significantly with [3H]ketanserin binding in rat brain cortex membranes (which is essentially to 5-HT2 receptors). The present data demonstrate that [3H]ketanserin in nanomolar concentrations binds significantly to alpha 1-adrenoceptors in human and pig frontal cortex membranes; this suggests a rather limited degree of selectivity of ketanserin for 5-HT2 receptors in pig and human tissues.

Adrenergic alpha-Antagonists↗

PubMed1987

Pharmacological characteristics and anatomical distribution of [3H]oxytocin-binding sites in the Wistar rat brain studied by autoradiography.

Oxytocin-binding sites were detected by autoradiography on rat brain sections incubated in the presence of the [3H]oxytocin. These sites were characterized pharmacologically using quantitative autoradiography. High pressure liquid chromatography controls of the incubation media indicated that labelling was due to the intact [3H]oxytocin molecule. Pharmacological analysis of different locations (central amygdaloid nucleus, ventral subiculum and ventromedial hypothalamic nucleus) showed that the sites detected had a high affinity for oxytocin and also for arginine-vasopressin. In contrast, some areas known to bind vasopressin intensely, such as suprachiasmatic and lateral septum nuclei, had little or no affinity for oxytocin. Autoradiographs revealed [3H]oxytocin-binding sites in already known brain areas (olfactory centres, ventral subiculum, central amygdaloid nucleus, bed nucleus of the stria terminalis) albeit with more extensive labelling of some of these formations, in particular, the amygdaloid complex. In addition, specific [3H]oxytocin-binding sites were found in areas not yet reported to bind oxytocin, such as the paraventricular thalamic and caudate nuclei. In the hypothalamus, specific binding sites were not detected in the supraoptic and paraventricular nuclei: the only structure labelled was the ventrolateral part of the ventromedial nucleus. Discrepancies between the concentrations of [3H]oxytocin-binding sites, the known distribution of oxytocin-containing endings and electrophysiological data indicate that autoradiography, under our conditions, apparently only reveals some of the oxytocin receptors in the brain. Thus, in the hypothalamus, no relationship can be established between the known effect of oxytocin on oxytocinergic magnocellular neurons and detection of specific [3H]oxytocin-binding sites. Autoradiography may reveal mainly oxytocin-binding sites in areas receiving diverse "parasynaptic" information, where oxytocin might play a modulatory role rather than exerting rapid, short-term effects of the neurotransmitter type.

Amygdala↗

PubMed1987

Serotonin receptors in the human brain--III. Autoradiographic mapping of serotonin-1 receptors.

The anatomical distribution of serotonin-1 receptors in human postmortem brain tissue was studied by quantitative light microscopic autoradiography. [3H]Serotonin was used to label all the subtypes of serotonin-1 sites (serotonin-1A, serotonin-1B, serotonin-1C). Serotonin-1A receptors were specifically labelled with [3H]8-hydroxy-2-[N,N-di-N-propyl-amino]tetralin, while [3H]mesulergine was used to identify serotonin-1C receptors. Receptor densities were quantified by means of a computer-assisted microdensitometric system. Confirming previous findings, serotonin-1A and serotonin-1C receptors were found in the human brain, while sites with the pharmacological characteristics of serotonin-1B binding sites could not be identified in this tissue. In addition, serotonin-1C receptors appeared to present differences in terms of pharmacology, depending on the brain area analysed. The distribution of both serotonin-1A and serotonin-1C receptor subtypes throughout the human brain was heterogeneous. High or very high densities of serotonin-1A receptors were found over the Ca1 field of the hippocampus, raphé nuclei, layers I and II of the cortex and some nuclei of the thalamus and amygdala. The claustrum, posterior hypothalamus, mesencephalic and pontine central grey matter and substantia gelatinosa of the cervical spinal cord, among others, presented intermediate concentrations of serotonin-1A receptors. In contrast, high densities of serotonin-1C receptors were present in the choroid plexus, substantia nigra, globus pallidus and ventromedial hypothalamus, while low or very low amounts of this receptor subtype were found in many other human brain areas. The anatomical distribution of serotonin-1A and serotonin-1C receptors is discussed taking into account the distribution of serotonergic neurons and fibres, the central functions in which serotonin appears to be involved and the characteristics of the neurological and psychiatric disorders where changes in brain serotonin-1 receptors have been reported.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1987

Serotonin receptors in the human brain--IV. Autoradiographic mapping of serotonin-2 receptors.

The anatomical distribution of serotonin-2 receptors in the human brain was studied by light microscopic autoradiography, using [3H]ketanserin as a ligand. The receptor densities were quantified by microdensitometry with the aid of a computer-assisted image-analysis system. A heterogeneous distribution of serotonin-2 receptor densities was found in the human brain. Very high concentrations were localized over layers III and V of several cortical areas, including the frontal, parietal, temporal and occipital lobes, the anterogenual cortex and the entorhinal area, as well as in the corpus mamillare of the hypothalamus. The claustrum, nucleus lateralis of the amygdala and some cortical layers also presented a high density of serotonin-2 receptors. Intermediate concentrations were found over the hippocampus, the caudatus, putamen and accumbens nuclei, and some nuclei of the amygdala, among other structures. Areas such as the thalamus, brain stem, cerebellum and spinal cord contained, in general, only low to very low densities of serotonin-2 receptors. A very high level of non-specific binding, which was not displaceable by any serotonin-2 compound, was found in some areas of the human brain, including the caudatus and putamen nuclei, the substantia nigra and the raphé nuclei. The distribution of serotonin-2 receptors in the human brain described herein is discussed in relation to the distribution of serotonergic innervation, the central effects which have been proposed to be serotonin-2-mediated, and the neuropathological characteristics of the diseases where a modification in the number of serotonin-2 receptors has been reported.

Adult↗

PubMed1987

The distribution of adenosine A1 receptors and 5'-nucleotidase in the brain of some commonly used experimental animals.

The distribution of adenosine A1 receptors was studied quantitatively in the brain of the rat, mouse, guinea-pig and cat, using in vitro autoradiography with [3H]N6-cyclohexyladenosine as ligand. Preliminary binding studies in brain sections from the guinea-pig and cat gave results similar to previous data from the rat and showed that the binding site had the pharmacological profile of an A1 receptor. The overall distribution of receptors was comparable in the species studied. The receptors were concentrated in the hippocampus, the cerebral cortex, some thalamic nuclei, the basal ganglia and the cerebellar cortex. The hypothalamus and the brainstem were sparse in receptors. Differences among species in receptor distribution and/or density were seen in some regions, e.g. the cerebral cortex, the striatum, the lateral geniculate nucleus and the cerebellar cortex. The autoradiograms were compared with adjacent sections stained for 5'-nucleotidase. There was in general a poor correlation between the distribution of A1 receptors and 5'-nucleotidase. Furthermore, there were marked differences between species in the distribution of the enzyme. The species differences observed in receptor localization may be of functional relevance.

5'-Nucleotidase↗

PubMed1987

Adenosine A1 receptors in the human brain: a quantitative autoradiographic study.

The distribution of adenosine A1 receptors in the human brain was studied by autoradiography in post mortem brain tissues from 26 subjects without reported neurological disease. N6-[3H]Cyclohexyl-adenosine was used as the ligand. For comparison, adjacent sections of some regions were examined histochemically for 5'-nucleotidase activity. The receptor sites were heterogeneously distributed throughout the CNS. The highest receptor densities were found in the stratum oriens, pyramidale and radiatum of the hippocampus. High densities were also found in the cerebral cortex and the striatum. In the thalamus there was a heterogeneous distribution of binding sites with a high density in structures such as the medial and anterior nucleus. Intermediate receptor densities were found in the accumbens, the olfactory tubercle and most parts of the amygdala among others. The hypothalamus had low receptor densities. In the brainstem and the spinal cord very low receptor concentrations were found. However, in some structures such as the substantia nigra, the colliculus superior and the substantia gelatinosa of the spinal cord a low level of binding could be measured. The cerebellar cortex showed low densities of receptors. Structures showing high levels of 5'-nucleotidase activity were the hippocampus, the striatum and parts of the cerebral cortex among other regions. In general there was a poor correlation between the localization of A1 receptors and the 5'-nucleotidase activity. Some regions, however, showed a similar distribution of these two markers. In general, the distribution of adenosine A1 receptors found in the human brain is comparable to that found in previous autoradiographic studies in the rat brain. However, some regional differences were observed in, for example, the cerebral cortex, the striatum and the cerebellar cortex. These differences may prove to be functionally relevant.

5'-Nucleotidase↗

PubMed1987

Beta-adrenergic binding sites in fetal rat central nervous system and pineal gland: their relation to other receptor sites.

Regional development of beta-adrenergic binding sites in the rat fetal central nervous system and pineal gland were studied in relation to the ontogeny of different drug and neurotransmitter binding sites. 3H-dihydroalprenolol labels the olfactory bulb very early in fetal life. A comparatively early development of binding sites is also seen for benzodiazepines during late gestation. 3H-serotonin, 3H-muscimol, 3H-GABA and 3H-(N)-methylscopolamine additionally label the olfactory bulb, revealing quite different patterns. Around gestational day 16, beta-adrenergic sites were found in the neocortex, then in choroid plexus and in the pineal gland. Besides beta-adrenergic, only 3H-flunitrazepam binding sites are detectable in the fetal eye, the latter with a more restricted regional distribution. In the fetal pineal, beta-adrenergic, muscarinic cholinergic and serotonergic binding sites appear at different times in gestation. In the neocortex a variety of binding site patterns develop. Two more general types can be distinguished: appearance along with caudorostral maturation of the brain and appearance within distinct brain regions, possibly related to local differentiation processes. The simultaneous onset of various binding sites in distinct areas of the fetal brain might result in higher sensitivity of individual brain areas to drugs.

Animals↗

PubMed1986

[125I]LSD labels 5-HT1C recognition sites in pig choroid plexus membranes. Comparison with [3H]mesulergine and [3H]5-HT binding.

The mammalian choroid plexus is enriched in a newly described serotonin recognition site, the 5-HT1C site. In order to further characterize these sites, the binding characteristics of [125I]LSD, [3H]mesulergine and [3H]serotonin to pig choroid plexus membranes were compared. These ligands labelled with high affinity a similar number of sites. The binding profiles of the sites labelled with these radioligands are indistinguishable as illustrated by highly significant correlation parameters. These sites are very similar to those labelled by N1-methyl-2-[125I]LSD in pig and rat choroid plexus membranes. The data demonstrate that these ligands label 5-HT1C recognition sites in pig and rat choroid plexus membranes.

Animals↗

PubMed1986

Serotonin-1C sites in the choroid plexus are not linked in a stimulatory or inhibitory way to adenylate cyclase.

The association of the serotonin recognition sites in the pig choroid plexus (5-HT-1C sites) with an adenylate cyclase was examined. The interaction of serotonin and mianserin with [3H]mesulergine binding was not affected by the stable GTP analogue GppNHp. The binding of [3H]serotonin to choroid plexus membranes was also unaffected by GppNHp while a dose-dependent decrease was observed in pig cortical and hippocampal membranes. The porcine choroid plexus contained a forskolin- and histamine-sensitive adenylate cyclase. Serotonin, however, was ineffective in this preparation. While forskolin-stimulated adenylate cyclase in the rat hippocampus was inhibited by serotonin forskolin-stimulated adenylate cyclase in the choroid plexus was insensitive to serotonin. These results indicate that the serotonin recognition sites in the choroid plexus are not linked in a stimulatory or inhibitory way to an adenylate cyclase, in contrast with other 5-HT-1 receptor subtypes.

Adenylyl Cyclases↗

PubMed1986

Serotonin receptors in the human brain. I. Characterization and autoradiographic localization of 5-HT1A recognition sites. Apparent absence of 5-HT1B recognition sites.

The presence, pharmacological properties and anatomical distribution of serotonin-1A and serotonin-1B receptor subtypes were studied in the human brain by both radioligand binding assays and autoradiographic procedures. Frontal cortices and hippocampi from human brains obtained at autopsy without evidence of neurological disease were used in this study. [3H]5-HT was used to label both 5-HT1A and 5-HT1B receptor subtypes. 5-HT1A receptors were selectively labeled by [3H]8-hydroxy-2[di-N-propylamino]tetralin, while 5-HT1B receptors were labeled by (-)-[125I]iodocyanopindolol ([125I]CYP) in the presence of 30 microM isoprenaline. The pharmacological profile of 5-HT1A receptors in human brain tissue was very similar to those previously found in rat and pig brain tissues. The general anatomical distribution of these sites was also similar to that found in the rat brain, although some differences were observed when analyzed at the microscopic level. In contrast to 5-HT1A receptors, it was not possible to identify 5-HT receptors having the pharmacological properties of 5-HT1B sites in the human brain, using either [3H]5-HT or [125I]CYP as ligands. The absence of identifiable 5-HT1B receptors in human brain preparations, a fact previously found in pig brain tissue, is discussed in terms of the existence of species differences in brain serotonin receptors.

Aged↗

PubMed1986

Serotonin receptors in the human brain. II. Characterization and autoradiographic localization of 5-HT1C and 5-HT2 recognition sites.

The presence, pharmacological properties and anatomical distribution of serotonin-1C and serotonin-2 receptor subtypes were studied in the human brain by both radioligand binding and autoradiographic procedures. Frontal cortex, hippocampus and choroid plexus from human brains obtained at autopsy without history of neurological diseases were used in this study. [3H]5-HT and [3H]mesulergine were used to label 5-HT1C recognition sites while [3H]ketanserin was used to label 5-HT2 receptors. The pharmacological profile of 5-HT1C sites which are very concentrated in the choroid plexus, was extremely similar to that of pig and rat 5-HT1C sites. These receptors were also detected in the hippocampus and the cortex from human brain. The general distribution of 5-HT1C sites in human and rat brain was similar although slight differences were observed. Human 5-HT2 receptors were concentrated in cortical areas but also found in the hippocampus. The pharmacological profile of these receptors was extremely similar in human and pig brain tissue, but differed in certain respects to that found in rat brain 5-HT2 receptors. The anatomical distribution of 5-HT2 receptors is similar in human and rat brain with some differences at the microscopic level. The importance of species differences in the development of 5-HT2 compounds is discussed.

Aged↗

PubMed1986

Central pressor effects induced by muscarinic receptor agonists: evidence for a predominant role of the M2 receptor subtype.

The cardiovascular effects induced in the rat by several muscarinic receptor agonists were studied. All the agonists produced a clear decrease in heart rate. This decrease appeared to be peripherally mediated, because it was antagonized by methylscopolamine. The effects on blood pressure varied depending on the presence of anaesthesia, previous treatments and the type of agonists tested. When peripheral muscarinic activity was blocked by administration of methylscopolamine, a dose-dependent hypertension was obtained following the injection of oxotremorine, arecoline and aceclidine, by both intraperitoneal and intracerebroventricular routes. The muscarinic receptor agonist RS 86 produced a slight increase in blood pressure but the increase was weaker than those observed with the agonists cited above. On the other hand, the muscarinic receptor agonists pilocarpine, AF-30 and McN-A-343, considered as partially M1-selective compounds, did not produce any effect on blood pressure. Moreover, the hypertension induced by oxotremorine was completely blocked by intracerebroventricular administration of the non-subtype-selective muscarinic receptor antagonist scopolamine but was unaffected by the M1-selective antagonist pirenzepine. We propose that the central hypertensive response induced by muscarinic receptor agonists in the unanaesthetized rat is, at least partially, mediated through the stimulation of the so-called M2 muscarinic receptor subtype.

Animals↗

PubMed1986

'Peripheral' benzodiazepine binding sites in human brain and kidney: autoradiographic studies.

Benzodiazepine (BZ) recognition sites of the 'peripheral' type were localized autoradiographically in human postmortem brain and kidney using [3H]Ro 5-4864. These sites presented a relatively homogeneous distribution. Areas such as the ependyma, choroid plexus and olfactory bulb, which in the rat are very rich in these binding sites, presented densities in the human brain which were about 1/10 of those seen in the rat. Human tissues presenting gliosis, such as the hippocampi from senile dementia patients, did not show a clear increase in the number of [3H]Ro 5-4864 sites, in contrast with the high densities found in rat brain areas presenting neurotoxin-induced gliosis. Intermediate densities of binding were seen in a human glioblastoma tumor. The human kidney also showed lower densities of peripheral BZ binding sites, when compared to the rat kidney. These results indicate that marked species differences exist in the densities of peripheral BZ sites and that caution has to be exerted when extrapolating data from the experimental animal to human.

Aged↗

PubMed1986

Evidence for species differences in 'peripheral' benzodiazepine receptors: an autoradiographic study.

The presence, density and distribution of 'peripheral' benzodiazepine (BZ)-binding sites was investigated by autoradiography in the brains of rats, mice, guinea pigs and cats and in some areas of the dog and monkey brains, using [3H]Ro 5-4864 as a ligand. Marked interspecies differences were found in the distribution and densities of these sites. Rats and mice presented a low density of binding uniformly distributed throughout the brain with high densities concentrated in the ependyma, choroid plexus and olfactory nerve layer of the olfactory bulb. In contrast, guinea pig and cat brains presented relatively high concentrations of peripheral BZ binding sites throughout the grey matter ependyma and choroid plexus, but low in the olfactory bulb. Monkey and dog brains presented low densities of peripheral BZ binding sites, including the choroid plexus.

Animals↗

PubMed1986

Adenosine A1-receptors in human brain: characterization and autoradiographic visualization.

The characteristics and distribution of adenosine A1-receptors in human brain tissues were examined, using [3H]N6-cyclohexyladenosine ([3H]CHA) as a ligand. The binding of [3H]CHA had the pharmacological characteristics of an A1-receptor site and was similar to those of adenosine A1-receptors in rat brain tissue examined in parallel. Autoradiographic localization of adenosine A1-receptors in human brain tissues revealed a heterogeneous anatomical distribution with high levels, particularly in the hippocampal formation, striatum, neocortex and some thalamic nuclei. The distribution of receptors was similar to that seen in the rat brain. However, in some regions, as for example the cerebellar cortex, clear differences were seen.

Adenosine↗

PubMed1985

Beta-adrenoceptor subtypes in the human brain: autoradiographic localization.

The distribution and characteristics of beta-adrenoceptors in postmortem human brain was studied using quantitative autoradiographic techniques. 125I-Cyanopindolol was used as a ligand. High densities of beta-adrenoceptors were found in the caudate, putamen, different cortical areas and layers and the hippocampal formation. Low densities were present in other areas such as the thalamus, hypothalamus, midbrain and cerebellar cortex. Specific beta 1 and beta 2 antagonists were used to visualize and quantify separately the two subtypes of beta-adrenoceptors. Computer analysis of the competition curves obtained revealed that the putamen was enriched in beta 1 sites while the cerebellum contained predominantly beta 2 adrenoceptors. The regional distribution of beta-adrenoceptor subtypes was found to be similar to that seen in the rat brain.

Aged↗

PubMed1985

Quantitative autoradiographic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors.

The distribution of serotonin-1 (5-HT1) receptors in the rat brain was studied by light microscopic quantitative autoradiography. Receptors were labeled with [3H]serotonin (5-[3H]HT), 8-hydroxy-2-[N-dipropylamino-3H]tetralin (8-OH- [3H]DPAT), [3H]LSD and [3H]mesulergine, and the densities quantified by microdensitometry with the aid of a computer-assisted image-analysis system. Competition experiments for 5-[3H]HT binding by several serotonin-1 agonists led to the identification of brain areas enriched in each one of the three subtypes of 5-HT1 recognition sites already described (5-HT1A, 5-HT1B, 5-HT1C). The existence of these 'selective' areas allowed a detailed pharmacological characterization of these sites to be made in a more precise manner than has been attained in membrane-binding studies. While 5-[3H]HT labeled with nanomolar affinity all the 5-HT1 subtypes, the other 3H-labeled ligands labeled selectively 5-HT1A (8-OH-[3H]DPAT), 5-HT1C ([3H]mesulergine) and both of them ([3H]LSD). Very high concentrations of 5-HT1 receptors were localized in the choroid plexus, lateroseptal nucleus, globus pallidus and ventral pallidum, dentate gyrus, dorsal subiculum, olivary pretectal nucleus, substantia nigra, reticular and external layer of the entorhinal cortex. The different fields of the hippocampus (CA1-CA4), some nuclei of the amygdaloid complex, the hypothalamic nuclei and the dorsal raphé, among others, also presented high concentrations of sites. Areas containing intermediate densities of 5-HT1 receptors included the claustrum, olfactory tubercle, accumbens, central grey and lateral cerebellar nucleus. The nucleus caudate-putamen and the cortex, at the different levels studied, presented receptor densities ranging from intermediate to low. Finally, in other brain areas--pons, medulla, spinal cord--only low or very low concentrations of 5-HT1 receptors were found. From the areas strongly enriched in 5-HT1 sites, dentate gyrus and septal nucleus contained 5-HT1A sites, while globus pallidus, dorsal subiculum, substantia nigra and olivary pretectal nucleus were enriched in 5-HT1B. The sites in the choroid plexus, which presented the highest density of receptors in the rat brain, were of the 5-HT1C subtype. The distribution of 5-HT1 receptors reported here is discussed in correlation with the distribution of serotoninergic neurons and fibers, the related anatomical pathways and the effects which appear to be mediated by these sites.

Animals↗