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Biomedical subjects

A Pazos

Publications and source records attributed to A Pazos.

At least 19 recordsLinked to original sources
PubMed1998

5-HT1B receptor binding in degenerative movement disorders.

Using [3H]sumatriptan as a radioligand, 5-hydroxytryptamine (5-HT)1B receptors were examined in posterior striatum and midbrain post-mortem tissue sections of 12 patients who had died from representative degenerative movement disorders as compared to nine controls. In the control human basal ganglia, the highest densities of [3H]sumatriptan binding were observed in the globus pallidus and substantia nigra. No significant change in the density of [3H]sumatriptan binding sites was found in the striatum and substantia nigra of the six Parkinson's disease brains. In the two brains from patients with progressive supranuclear palsy an increase was found in the densities of [3H]sumatriptan binding sites, most marked in the substantia nigra. In contrast, [3H]sumatriptan labelling was almost absent in the striatonigral degeneration brain and was markedly reduced in the three Huntington's disease brains. This study indicates that the status of 5-HT1B receptors is different in each degenerative movement disorder and suggests that human 5-HT1B receptors are located somatodendritically on GABAergic and peptidergic caudate-putamen neurons which project to the substantia nigra and globus pallidus, where these receptors are presynaptic.

Aged↗
PubMed1998

Selective increase of alpha2A-adrenoceptor agonist binding sites in brains of depressed suicide victims.

The alpha2A- and alpha2C-adrenoceptor subtypes were evaluated in postmortem brains from suicides with depression (n = 22), suicides with other diagnoses (n = 12), and controls (n = 26). Membrane assays with the antagonist [3H]RX821002 (2-[3H]methoxyidazoxan) suggested the presence of alpha2A-adrenoceptors in the frontal cortex and both alpha2C-adrenoceptors and alpha2A-adrenoceptors in the caudate. The proportions in caudate were similar in controls (alpha2A, 86%; alpha2C, 14%), depressed suicides (alpha2A, 91%; alpha2C, 9%), and suicides with other diagnoses (alpha2A, 88%; alpha2C, 12%). Autoradiography of [3H]RX821002 binding under alpha(2B/C)-adrenoceptor-masking conditions confirmed the similar densities of alpha2A-adrenoceptors in the cortex, hippocampus, and striatum from controls and suicides. In the frontal cortex of depressed suicides, competition of [3H]RX821002 binding by (-)-adrenaline revealed a greater proportion (61 +/- 9%) of alpha2A-adrenoceptors in the high-affinity conformation for agonists than in controls (39 +/- 5%). Simultaneous analysis with the agonists [3H]clonidine and [3H]UK14304 and the antagonist [3H]RX821002 in the same depressed suicides confirmed the enhanced alpha2A-adrenoceptor density when evaluated by agonist, but not by antagonist, radioligands. The results indicate that depression is associated with a selective increase in the high-affinity conformation of the brain alpha2A-adrenoceptors.

Adrenergic alpha-Agonists↗
PubMed1997

Are Wistar-Kyoto rats a genetic animal model of depression resistant to antidepressants?

Wistar-Kyoto rats are reported to be very passive in the forced swimming test. In addition, they did not respond to acute administration of either desipramine or 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). In the present experiment, it was studied whether or not they respond to acute and chronic administration of imipramine and the possible relationship to down-regulation of beta-adrenoceptors and 5-HT1 and 5-HT2 receptors. Sprague-Dawley and Brown-Norway rats were included in the study as it has been previously demonstrated that the two strains respond to acute desipramine and 8-OH-DPAT administration. Whereas acute administration of imipramine (15 mg/kg, three times in a 24 h period) significantly increased struggling and reduced immobility in Sprague-Dawley and Brown Norway rats, Wistar-Kyoto rats failed to respond to the drug. After chronic treatment with imipramine (13 days plus the acute imipramine treatment at the end of the treatment period), the three strains showed a positive response that was always significantly greater than the response to acute administration, but which was much lower in Wistar-Kyoto than in the other two strains. Down-regulation of both beta-adrenoceptors and 5-HT2 receptors was observed 24 h after the forced swimming test in acutely and chronically imipramine-treated rats of the three strains, except that in Sprague-Dawley rats beta-adrenoceptors did not change after acute imipramine. No significant decrease in 5-HT1 binding sites was observed in any strain. Acute imipramine administration caused a similar anorexia in Wistar-Kyoto as in the other strains and at least the same level of down-regulation of beta-adrenoceptors and 5-HT2 receptors. In addition, serum imipramine levels on the day after the last drug administration were higher in Wistar-Kyoto than in the other two strains. All these data suggest that the subsensitivity to imipramine observed in Wistar-Kyoto rats: (i) can not be primarily explained by pharmacokinetic differences, and (ii) does not appear to be related to the monoaminergic systems. Wistar-Kyoto rats might be therefore not only a good animal model of depressive-like (passive) behavior, but also a model of resistance to antidepressants which could be used to investigate the neurobiological basis of such resistance, which is also observed in some depressed patients.

Animals↗
PubMed1997

Autoradiographic distribution of M1, M2, M3, and M4 muscarinic receptor subtypes in Alzheimer's disease.

We studied the autoradiographic densities of all pharmacologically characterised muscarinic receptors (MR) in frontal, temporal, and visual cortex, hippocampal formation, and striatum in autopsied brains from 19 histopathologically verified patients of Alzheimer's disease (AD) and in matched controls. Almost all (16 of 19) of the AD cases were severe. In AD brains, total MR, M1, and M3 MR subtypes were found to be significantly decreased in entorhinal cortex and in most hippocampal strata. Total MR and M1 receptors were also significantly reduced in visual area and in frontal cortex of AD brains, respectively. M2 receptors were significantly reduced over hippocampal formation but increased significantly in striatum of AD brains as compared with controls. M3 receptors in AD were in the range of controls in neocortex and striatum, whereas the M4 receptor subtype was also preserved in all brain regions in AD brains when compared with controls. This is the first autoradiographic study analysing the distribution of all MR subtypes in AD brains. These changes in MR densities concur with the general pattern of neuronal degeneration occurring in AD brains and partly explain the poor response of AD cognitive decline to present cholinergic supplementation therapies. Although M3 and M4 MR were labelled with nonselective approaches, the preservation of M4 and to a lesser degree M3 MR subtypes in AD brains could open an alternative way for the symptomatic therapy of AD dementia.

Aged↗
PubMed1997

125I-galanin binding sites in Alzheimer's disease: increases in hippocampal subfields and a decrease in the caudate nucleus.

Using iodinated human galanin and autoradiography, galanin binding sites were studied in cortical and hippocampal areas and in some brainstem nuclei in the brains of eight patients with senile dementia of the Alzheimer type (SDAT) and of nine matched control cases. The highest density of binding sites was found in the substantia nigra with a less intense labeling in the hippocampus and cortical regions. In the SDAT cases a significant increase in number of galanin binding sites was found in some hippocampal areas, a decrease in the caudate nucleus, and no significant changes in frontal and entorhinal cortices. These findings suggest that some central galanin systems may be deranged in SDAT.

Aged↗
PubMed1997

Identification and characterization of a new serotonergic recognition site with high affinity for 5-carboxamidotryptamine in mammalian brain.

We analyzed the existence of an additional serotonin (5-HT) receptor subtype, sensitive to 5-carboxamidotryptamine, in the mammalian brain. Radioligand binding studies with [3H]5-HT were carried out in rat, guinea pig, and human brain membranes, in the presence of unlabeled drugs to mask the binding to all known 5-HT receptors, with the exception of 5-HT1E sites. Under these conditions, unlabeled 5-carboxamidotryptamine still showed a biphasic competition curve with a nanomolar affinity component. Saturation studies with 5-[3H]carboxamidotryptamine were carried out in the presence of (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin, mesulergine, and ergotamine, to mask the binding to all receptors known to be labeled by 5-carboxamidotryptamine. These studies showed the existence in cortex and hippocampus from guinea pig and human brain of a remaining binding site with high affinity (pK(D) = 7.8-8.1) and a unique pharmacological profile. 5-HT and 5-carboxamidotryptamine showed nanomolar affinity, whereas 5-methoxytryptamine recognized this binding site with intermediate affinity. Other drugs exhibited low or very low potency in inhibiting this binding. The addition of 5'-guanylylimidodiphosphate significantly reduced the number of binding sites labeled by 5-[3H]carboxamidotryptamine, in the presence of the masking drugs described above, indicating the interaction with a GTP-binding protein. Preliminary autoradiographic studies in human brain appear to indicate that this 5-HT binding site is present in areas such as the globus pallidus, neocortex, and hippocampus, among others.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1997

A comparative study of alpha2- and beta-adrenoceptor distribution in pigeon and chick brain.

The pharmacological properties and anatomical distribution of alpha2-, beta1- and beta2-adrenoceptors in pigeon and chick brains were studied by both homogenate binding and tissue section autoradiography. [3H]Bromoxidine (alpha2-adrenoceptor-), [3H]CGP 12177 (beta-adrenoceptor) and [125I]cyanopindolol (beta-adrenoceptor) were used as radioligands. In both species, [3H]bromoxidine binding to avian brain tissue showed a pharmacological profile similar to that previously reported for alpha2-adrenoceptors in mammals. Regarding the anatomical distribution, the areas with the highest densities of alpha2-adrenoceptors in the pigeon brain included the hyperstriatum, nuclei septalis, tectum opticum and some brainstem nuclei. Most beta-adrenoceptors found in tissue membranes and sections from chick and pigeon brain were of the beta2 subtype, in contrast to what has been reported in the mammalian brain, where the beta1 subtype is predominant. A striking difference was found between the two species regarding the densities of these receptors: while pigeon brain was extremely rich in [125I]cyanopindolol binding throughout the brain (mainly cerebellum) in the pigeon, the levels of labelling in the chick brain were much lower; the exception was the cerebellum, which displayed a higher density than other parts of the brain in both species. Overall, our results support the proposed anatomical equivalences between a number of structures in the avian and mammalian encephalon.

Adrenergic alpha-Agonists↗
PubMed1996

The subtype-selective alpha 2-adrenoceptor antagonists BRL 44408 and ARC 239 also recognize 5-HT1A receptors in the rat brain.

Several alpha 2-adrenoceptor compounds have been reported to recognize 5-HT1A receptors. The interaction of the alpha 2A/D- and alpha 2B/C-adrenoceptor antagonists BRL 44408 (2-[2H-(1-methyl-1,3-dihydroisoindole) methyl]-4,5-dihydroimidazole) and ARC 239 (2-[2-[4-(o-methoxyphenyl)piperazin-1-yl] ethyl]-4,4-dimethyl-1,3-(2H,4H)-isoquinolinedione) with 5-HT1A receptors was evaluated in rat brain. Competition experiments in cortex with both compounds against the specific binding of the 5-HT1A receptor radioligand [3H]8-OH-DPAT (8-hydroxy-2-(n-dipropyl-amine)-tetralin) yielded Ki values in the nanomolar range, fairly close to their previously reported affinities for alpha 2-adrenoceptors. Similar Ki values were obtained under alpha 2-adrenoceptor masking conditions by competition assays of these compounds against the alpha 2-adrenoceptor and 5-HT1A receptor radioligand [3H]RX 821002 (2-methoxy idazoxan) specific binding in hippocampus. The results indicate that BRL 44408 and ARC 239 recognize 5-HT1A receptors in addition to alpha 2-adrenoceptors. The fact should be considered when using these compounds to study alpha 2-adrenoceptor subtypes.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed1996

Alpha 2-adrenoceptor subtypes in the human brain: a pharmacological delineation of [3H]RX-821002 binding to membranes and tissue sections.

In order to study the characterization and localization of [3H]RX-821002 (2-methoxy-idazoxan) binding to alpha 2-adrenoceptor subtypes in several regions of the human brain, we have carried out competition studies using both autoradiography and membrane binding assays. The alpha 2A-adrenoceptor subtype was found to be predominant in the different layers of the frontal cortex, cerebellum and hippocampal formation, while in the neostriatum it was the non-alpha 2A- (alpha 2B- and alpha 2C-) adrenoceptor subtype. In the frontal cortex, in addition to binding to the alpha 2A-adrenoceptor subtype, [3H]RX-821002 bound also to a small portion of alpha 2B- and alpha 2C-adrenoceptors in layer III, and to an unidentified binding site in the external layers. In the hippocampus, both alpha 2A- and non-alpha 2A- (alpha 2B- and alpha 2C-) adrenoceptors were labelled in the dentate gyrus and the CA1 field, together with 5-HT1A receptors. 5-HT1A receptors were labelled predominantly in the stratum pyramidale layer. These results, in addition to delineate the relative presence of alpha 2-adrenoceptor subtypes, indicate that caution is needed when analyzing RX 821002 binding to human brain tissue.

Adrenergic alpha-Antagonists↗
PubMed1996

Effects of freezing storage time on the density of muscarinic receptors in the human postmortem brain: an autoradiographic study in control and Alzheimer's disease brain tissues.

The effect of sex, age (range = 41-84 years), postmortem delay (range = 1-71 h) and freezing storage time (FST) (range = 8-75 months) at -25 degrees C on the density of muscarinic receptors (MR) was examined in tissue sections of several representative areas of 41 postmortem brains from adult patients who had died from non-neurological disorders using [3H]N-methylscopolamine as a ligand. Neither age, sex nor postmortem delay determined significant changes in the density of MR in frontal and entorhinal cortex, hippocampus and striatum. By contrast, FST significantly decreased the densities of MR in frontal and entorhinal cortex, pyramidal layer of CA1 and CA3 fields at the hippocampus and over caudate nucleus. This reduction in MR densities did not reach statistical significance, for any region, when FST was less than 39 months. Although there was a tendency towards a decrease, no significant changes were observed in putamen and over hippocampal dentate gyrus. FST (range = 11-78 months) also significantly decreased the densities of MR in the same regions of postmortem brains from 18 patients who had died with a clinico-pathological diagnosis of Alzheimer's disease (AD). Even though there was a general tendency towards a decrease (between 7% in the caudate and 30% in the dentate gyrus at the hippocampus), no significant differences could be seen in MR densities between control and AD cases, except in the hilus in the dentate gyrus (P < 0.022), when brains were matched for FST. From the present results it is clear that control and diseased brains must also be matched for FST as well as for other factors such as sex, age and postmortem delay. It is possible that differences in FST could in part account for the variability of the reported results measuring MR in control and AD brains. At least for MR, FST shorter than three years would seem to be acceptable when performing this kind of studies.

Adult↗
PubMed1996

Autoradiographic evidence of mu-opioid receptors down-regulation after prenatal stress in offspring rat brain.

In order to visualize neuroanatomical alterations in specific brain regions, light microscopy autoradiography was carried out on offspring (postnatal day 10) from female rats stressed in different periods of gestation and controls. Group 1 was subjected to restraint stress from day 2 to 6; group 2, from day 7 to 11; group 3, from day 12 to 16; group 4, from day 2 to 16. Group 2 showed pronounce decreases in mu-opioid receptor density in different brain regions. The decrease in mu-opioid receptor density was less marked in the group 1, 3 and 4. Present data suggest that the prenatal stress induce down-regulation of mu-receptors in different brain regions.

Analgesics↗
PubMed1996

[3H]Sumatriptan binding sites in human brain: regional-dependent labelling of 5-HT1D and 5-HT1F receptors.

The general properties of [3H]sumatriptan binding sites in postmortem human brain tissue sections are described. High concentrations of autoradiographic grains were seen in globus pallidus = substantia nigra > cortex > putamen > hippocampus. While 5-HT (5-hydroxytryptamine) displaced in all regions more than 90% of [3H]sumatriptan binding, the level of binding inhibited by 5-CT (5-carboxamidotryptamine) varied in each region. Although the binding inhibited by 5-CT in some regions such as globus pallidus and substantia nigra was equivalent to that obtained with 5-HT, in cortical areas, such as frontal cortex and hippocampus, a substantial level of binding insensitive to 5-CT was seen. In addition, in membrane binding assays, 10 nM metergoline displaced most [3H]sumatriptan specific binding in striatum and only 16% in frontal cortex. In the human brain sumatriptan binds to at least two 5-HT1 receptors, 5-HT1D and 5-HT1F.

Adult↗
PubMed1996

Differential regional distribution of AMPA receptor subunit messenger RNAs in the human spinal cord as visualized by in situ hybridization.

The electrophysiological characteristics of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors vary with their subunit composition. The establishment of the subunit distribution is an essential step in the understanding of the function of these receptors. In the spinal cord, AMPA receptors are involved in normal and, possibly, pathological processes. Using in situ hybridization histochemistry with radiolabelled oligonucleotides as probes, we have studied the distribution of AMPA receptor subunit messenger RNAs (spliced flip and flop variants of glutamate receptor subunits A-D) in the human post mortem spinal cord. Transcripts for flip variants were preferentially expressed in the superficial dorsal horn, with a dorsoventral decreasing gradient of the signals. Transcripts for flop variants were also abundantly present in all layers of the gray matter, with the highest signal being observed for glutamate receptor subunit Bflop. Accordingly, flop forms were predominant in areas other than the superficial dorsal horn. This differential distribution of transcripts in the dorsal horn suggests that the subunit composition of AMPA receptors varies with the afferent inputs; AMPA receptors on neurons in the superficial dorsal horn, where terminals of thin primary afferents conducting noxious information are located, contain more flip forms, whereas neurons in the deep dorsal horn, where thick primary afferents mediating innocuous stimuli terminate, have AMPA receptors which are mainly composed of flop forms of glutamate receptor subunits A and B. The relatively high abundance of glutamate receptor subunit B transcripts in the superficial laminae of the dorsal horn indicates that AMPA receptors in these laminae have lower Ca2+ permeability. In addition, the relative abundance of glutamate receptor subunits Bflip and Dflop may show that AMPA receptors in the superficial dorsal horn have slow desensitization, while those of motor neurons have rapid desensitization.

Adult↗
PubMed1996

Autoradiographic distribution of [3H]sumatriptan-binding sites in post-mortem human brain.

The anatomical distribution of [3H]sumatriptan-binding sites was analysed in brain tissue sections from 11 subjects. Relevant concentrations of [3H]sumatriptan-binding sites were seen in areas such as visual cortex > locus niger > globus pallidus > layers IV-V of the frontal cortex > subiculum > entorhinal cortex > nucleus tractus solitarius > nucleus trigeminalis caudalis. This distribution of [3H]sumatriptan-binding sites in the human brain shows some differences when compared with that of 5HT1D receptors, confirming that, besides 5HT1D, sumatriptan also binds to 5HT1F receptor subtype. Some species differences are evident between the distribution of [3H]sumatriptan-binding sites in the human brain and that reported for guinea-pig and rat brains, emphasizing that caution is needed in extrapolating experimental data from animals to humans. Furthermore, these data help to explain some of the therapeutic actions of sumatriptan. The remarkable levels of binding found in areas as nucleus tractus solitarius and nucleus trigeminalis caudalis suggest that in migraine attacks sumatriptan could exert its specific anti-emetic effects and, partly at least, induce analgesia by directly acting over these brain nuclei.

Adult↗
PubMed1996

Ontogenetic development of 5-HT1D receptors in human brain: an autoradiographic study.

The pattern of pre- and postnatal appearance of 5-HT1D receptors throughout the different areas of the human brain was studied by quantitative in vitro autoradiography, using [125I]GTI (serotonin O-carboxymethyl-glycyl-[125I]tyrosinamide) as a ligand. The anatomical distribution of 5-HT1D receptors in neonatal, infant and children's brain was in good agreement with that observed in the adult, the basal ganglia and substantia nigra being the most intensely labelled areas. The development of these receptors throughout the human brain was mainly postnatal: low densities of [125I]GTI binding sites were observed at the fetal/neonatal stage in most regions analyzed, in contrast with the high levels of labelling found in infant and children's brains. Indeed, in a number of regions, including the globus pallidus, substantia nigra and visual cortex, a peak of overexpression of 5-HT1D receptors was observed in the first decade of life. Such overexpression could support a regulatory role for 5-HT1D receptors in advanced periods of the CNS developmental process. Our results also indicate that the administration of drugs acting on 5-HT1D receptors during the early postnatal period of life could result in modifications of their properties, as these receptors are already functional in this period.

Adult↗