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Biomedical subjects

A Pazos

Publications and source records attributed to A Pazos.

At least 55 records · Page 3Linked to original sources
PubMed1995

Regulation of dihydropyridine-sensitive Ca++ channels during opioid tolerance and supersensitivity in rats.

The changes in cerebral dihydropyridine (DHP)-sensitive Ca++ channels (L-type) associated with tolerance and supersensitivity to the antinociceptive effect of the mu-opioid receptor agonist sufentanil were analyzed in rats. The tail-flick test was used to assess the nociceptive threshold. DHP binding and autoradiographic assays were performed with [3H]nimodipine and [3H]PN 200-110 [isopropyl 4-(2,1,3-benzoxadizol-4-yl)- 1,4-dihydro-2,6-dimethyl-5-methoxycarbonylpyridine-3-carboxylate], respectively. Chronic s.c. infusion of sufentanil (2 micrograms/hr) for 7 days induced tolerance (tolerance index, 5.6) in association with up-regulation of DHP binding sites in cerebral cortex membranes (+36%), as well as in brain sections. Animals were rendered hypersensitive to the antinociceptive effect of sufentanil by chronic and simultaneous infusion of sufentanil (2 micrograms/hr) and nimodipine (1 microgram/hr) for 7 days (potentiation index, 40 vs. tolerant). Under these conditions, a greater increase in the number of DHP binding sites was observed in cortex membranes (+71%), and more evidently in brain sections. In these animals, withdrawal of nimodipine for 48 hr returned the dose-response curve of sufentanil to the tolerant values, whereas Ca++ channels remained increased. The role of an increased influx through L-type channels in opioid tolerance is reinforced. Our results also suggest that, although changes in neuronal Ca++ fluxes are not the only underlying mechanism, the increase and the sustained blockade of Ca++ channels with nimodipine is essential for the expression of opioid supersensitivity.

Analgesics, Opioid↗
PubMed1995

Mu-opioid receptor regulation during opioid tolerance and supersensitivity in rat central nervous system.

We have analyzed by radiometric procedures in rat central nervous system the changes in the properties of mu-opioid receptors associated with tolerance and supersensitivity to the opioid agonist sufentanil. This study has used [3H]-[D-Ala2,MePhe4,Gly- (ol)5(2)]-enkephalin, a highly selective ligand, to label mu-opioid receptors in both membranes and tissue sections. The induction of opioid tolerance by chronic infusion for 7 days of high doses of sufentanil, a high efficacy agonist, produced mu-opioid receptor down-regulation, with a significant decrease in their density in both cortical (-67%) and spinal cord membranes (-55%) and no changes in the affinity constant. Autoradiographic studies showed an overall decrease of[3H]-Ala2,MePhe4,Gly-(ol)5(2)]-enkephalin binding in the somatosensory cortex (around -30%). When the dihydropyridine-Ca++ channel antagonist nimodipine was administered alone for 7 days, no significant changes in the density or affinity constant of mu-opioid receptors were observed. However, the chronic and simultaneous administration of nimodipine and sufentanil (7 days), induced a pronounced modification on the density of mu-opioid receptors of the rat central nervous system and blocked the down-regulation observed in sufentanil-treated (tolerant) rats. These neurochemical findings may account for the functional interaction we have observed previously in the analgesic studies between nimodipine and sufentanil. Our data strongly suggest a functional role of L-type Ca++ channels in the mediation of opioid tolerance and super-sensitivity.

Analgesics, Opioid↗
PubMed1994

Identification of beta-adrenoceptors in rat lymph nodes and spleen: an autoradiographic study.

The anatomical localization of beta 1 and beta 2-adrenoceptors was studied in rat lymphoid tissues by quantitative autoradiography using [125I]cyanopindolol as a ligand. In lymph nodes, a significant density of these receptors was found in the medullary cords and the interfollicular cortex, while only low densities were observed in the paracortex. No detectable binding appeared in the remaining areas. In the spleen, these receptors were mainly localized in the capsule, marginal zone of white pulp and red pulp, while the labelling over the white pulp was extremely low. The subtype beta 2 was predominant in both lymph nodes and spleen. The results suggest that beta-adrenoceptors are present in mature cells in lymphoid tissues and are probably not involved in homing mechanisms.

Adrenergic beta-Antagonists↗
PubMed1994

Cholinergic markers in degenerative parkinsonism: autoradiographic demonstration of high-affinity choline uptake carrier hyperactivity.

[3H]Hemicholinium-3 ([3H]HC-3) binding, as a marker of the presynaptic high-affinity choline uptake carrier (HACU), and cholinergic muscarinic receptors were measured by autoradiography in several brain regions of levodopa-responsive parkinsonism and matched cases. A significant increase in the density of [3H]HC-3 binding sites was found in the striatum of parkinsonian brains, while there was a slight decrease in the parkinsonian hippocampus. Total, M1 and non-M1 muscarinic receptors remained unchanged in frontal cortex and striatum of parkinsonian brains as compared to controls. Total and non-M1 muscarinic receptors were significantly reduced in the parkinsonian hippocampus, whereas hippocampal M1 receptors were preserved. These data demonstrate a hyperactivity of the HACU, and thus of the acetylcholine synthesis, in parkinsonian brains probably compensatory of the loss of both dopaminergic terminals in the striatum and of basal forebrain neurons in the hippocampus. Our results emphasize the value of [3H]HC-3 binding in the study of the functional status of the cholinergic synapse in neurodegenerative disorders.

Aged↗
PubMed1994

Identification of alpha 2-adrenoceptors in rat lymph nodes and spleen: an autoradiographic study.

The anatomical localization and pharmacological characteristics of alpha 2-adrenoceptors were studied in rat lymphoid tissues by quantitative autoradiography with [3H]bromoxidine as a ligand. In lymph nodes, a significant density of these receptors was found in the capsule, interfollicular cortex and medullary cords, while only very low densities were observed in the paracortex and germinal centres. In the spleen, these receptors appeared to be mainly distributed in the marginal zone of white pulp as well as in the red pulp. These results suggest a role for alpha 2-adrenoceptors in the interaction between nervous and immune systems.

Animals↗
PubMed1994

Transient localization of 5-HT1A receptors in human cerebellum during development.

The appearance and distribution of 5-HT1A receptors in the human cerebellum during the ontogenetic development was studied in samples from a group of fetal, neonatal and adult cases, by means of quantitative autoradiography and membrane binding. [3H]8-OH-DPAT was used as a ligand. High densities of 5-HT1A receptors were found during the fetal and neonatal stages over the whole cerebellar cortex, with a slight predominance in the external part, in a band which included the molecular layer. In contrast, the adult cerebellum was nearly devoid of such sites. This finding supports a role for 5-HT1A receptors in the regulation of development in the human cerebellum.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1994

Changes in aminergic receptors in a PSP postmortem brain: correlation with pathological findings.

The state of different aminergic receptors was assessed, by quantitative autoradiography in tissue sections, in several representative brain regions from a typical progressive supranuclear palsy (PSP) patient and from 9 matched brains. The densities of muscarinic receptors were within control limits in most of the brain areas of this PSP brain. Serotonin1 receptors were clearly reduced only in areas with very relevant neuropathological damage, such as locus niger and globus pallidus. The density of D1 dopamine receptors in the caudate-putamen and frontal cortex of the patient was within control limits. By contrast, nigral D1 and striatal D2 dopamine receptors were dramatically reduced in the patient as compared to controls. Finally, alpha 2-adrenoceptors were clearly reduced in all the examined areas of this PSP patient as compared to control group. Both the potential role of these receptor changes in the pathophysiology of the clinical features of PSP and their correlation with the neuropathological findings of this PSP patient are discussed.

Aged↗
PubMed1994

Adrenergic receptors in the cerebellum of olivopontocerebellar atrophy.

Using autoradiographic techniques we studied the changes that in adrenergic receptors occurred in the cerebellum of two olivopontocerebellar atrophy (OPCA) patients as compared with a control group. In OPCA cerebellum the densities of total beta-adrenoceptors were reduced along the cortex but increased in the white matter. Although mainly the beta 1 subtype was decreased along the cerebellar cortex, the increase of beta-receptors over the white matter was due to a selective raise in the beta 2 subtype. These findings suggest a postsynaptic neuronal location for the beta 1 subtype and a glial location for the beta 2-adrenoceptor. On the other hand, alpha 2-adrenoceptors were clearly reduced all along the cerebellar cortex of these OPCA brains, this probably being secondary to the loss of presynaptic adrenergic terminals arising from the locus coeruleus. These results help clarify both the subcellular location of adrenoceptors in human cerebellum and the neurochemical pathophysiology of OPCA.

Aged↗
PubMed1994

Selective cortical decrease of high-affinity choline uptake carrier in Alzheimer's disease: an autoradiographic study using 3H-hemicholinium-3.

3H-hemicholinium-3 (3H-HC-3) binding, a marker of the presynaptic high-affinity choline uptake carrier (HACU), was measured by autoradiography in several brain regions of 17 Alzheimer's disease (AD) patients and of 11 matched controls. A significant decrease in the density of 3H-HC-3 binding sites was found in entorhinal cortex, hippocampus and layers I-III of the frontal cortex. By contrast, in the caudate-putamen the number of 3H-HC-3 binding sites in AD cases was comparable to that of control striata. These data concur with previous results using classical presynaptic markers and reflect the loss in the activity of HACU, and, hence, in the synthesis of acetylcholine, that selectively occurs in cortical areas of AD brains due to the degeneration of presynaptic cholinergic terminals arising from the basal forebrain. However, the relatively low mean reduction in HACU in cortical areas (-40%), together with the apparent indemnity of this marker in certain severely demented AD cases, suggest that AD dementia cannot be explained simply by the loss of presynaptic terminals originating in the basal forebrain. These data seem to be a good explanation for the poor response to cholinergic replacement in AD.

Aged↗
PubMed1994

Synaptic vesicular monoamine transporter expression: distribution and pharmacologic profile.

The human vesicular monoamine transporter (hSVMT) cDNA predicts a protein of 515 amino acids that shares 92% amino acid identity with the rat cDNA. Northern analyses reveal expression of 4.3 kb SVMT mRNAs in rat hypothalamus, midbrain and brainstem, a 3 kb hSVMT mRNA in human brainstem and a 4.8 kb hSVMT mRNA in human hypothalamus. In situ hybridization documents significant SVMT expression in human nigra compacta neurons and in rat hypothalamic neurons whose distribution patterns are identical to those previously reported to display histaminergic markers. COS cell hSVMT expression yielded nanomolar affinities for tetrabenazine and reserpine, micromolar affinities for haloperidol, GBR12909, serotonin, mazindol, nomifensin and d-amphetamine, while dopamine, epinephrine, norepinephrine and histamine each displayed millimolar affinities. These observations extend the pharmacological characterization of hSVMT and studies of its distribution, and indicate likely physiological roles for SVMT in packaging monoamine transmitters including histamine.

Animals↗
PubMed1994

Autoradiographic demonstration of increased alpha 2-adrenoceptor agonist binding sites in the hippocampus and frontal cortex of depressed suicide victims.

To examine directly in the brain the status of alpha 2-adrenoceptors in major depression, the specific binding of the agonist [3H]UK 14304 was measured by quantitative receptor autoradiography in the hippocampus and frontal cortex of suicide victims (n = 17) with a retrospective diagnosis of depression (n = 7) or other psychiatric disorders (n = 10) as well as of matched control subjects (n = 9). In suicide victims, a significant increase in the number of alpha 2-adrenoceptors was found in the CA1 field (40%) and dentate gyrus (20%) of the hippocampus and in the external layers I (33%) and II (31%) of the frontal cortex, compared with that in matched controls. In depressed suicide victims, the increase in alpha 2-adrenoceptors in the CA1 field (57%) was significantly greater (24%, p < 0.05) than that observed in the group of suicide victims with other diagnoses (26%). In the same depressed suicide victims, the increase in cortical alpha 2-adrenoceptors was restricted to layer I (34%) and it was equivalent to that found in layer I (33%) of suicide victims with other diagnoses. The results indicate that suicide is associated with increases in the high-affinity state of brain alpha 2-adrenoceptors adrenoceptors and that there is a pronounced localized increase of this inhibitory receptor in the hippocampus of depressed suicide victims.

Adrenergic alpha-Agonists↗
PubMed1993

Blockade of GABA receptors in superior colliculus protects against focally evoked limbic motor seizures.

Blockade of GABA receptors in the rat superior colliculus (SC) has been shown to protect against maximal electroshock-induced tonic convulsions and spontaneous generalized non-convulsive seizures. In the present study, we determined that blockade of GABA receptors in SC could also protect against focally evoked limbic motor seizures. Limbic motor seizures were induced by the unilateral focal application of bicuculline methiodide into area tempestas (AT), an epileptogenic site in the deep prepiriform cortex. Control rats (receiving bilateral infusions of saline into SC) all exhibited convulsive seizures following bicuculline in AT. Rats pretreated (5 min before) with bicuculline (50 pmol) bilaterally in the deep layers of the SC, were protected against the AT-evoked convulsive seizures. Unilateral application of bicuculline in the deep SC or bilateral application in the superficial layers of the SC did not alter the convulsive response to bicuculline in AT. These results indicate that the anticonvulsant action of GABA blockade in SC is not limited to tonic convulsive seizures but extends to the clonic manifestations evoked by seizures originating in forebrain limbic circuits. Given that the deep layers of SC receive inputs from GABA neurons in substantia nigra and that suppression of the activity of nigral neurons is anticonvulsant against a variety of seizures (including those evoked from AT), it is likely that the anticonvulsant action of bicuculline in SC is due to interference with the influence of a nigrotectal GABAergic projection.

Animals↗
PubMed1993

Autoradiographic mapping of 5-HT1 receptors in the guinea-pig brain with particular reference to the 5-HT1D receptor sites.

The anatomical distribution of 5-HT1 receptors in the guinea-pig brain was studied by means of in vitro quantitative autoradiography using [3H]-5-HT as ligand. The relative presence of the subtypes of the 5-HT1 binding site was investigated by adding selective concentrations of 8-OH-DPAT, (-)21,009, mesulergine and 5-CT. In addition, differentiation of 5-HT1D receptors was achieved by incubation of the tissues with [3H]-5-HT in the presence of 100 nmol/l 8-OH-DPAT together with 100 nmol/l mesulergine. Areas presenting high densities of 5-HT1A receptors included the neocortex (internal layers), hippocampal formation (dentate gyrus, CA1 field), septum and raphe nuclei, while 5-HT1C sites accounted for most of the [3H]-5-HT binding to the choroid plexus. Non 5-HT1A-non 5-HT1C sites (mainly 5-HT1D and, also probably, 5-HT1E receptors) were clearly predominant in the guinea-pig brain. These sites were mainly present in the neocortex (external layers), basal ganglia, hypothalamus and midbrain (substantia nigra, superior colliculus). As previously described, sites with the properties of 5-HT1B receptors could not be clearly identified in the guinea-pig brain. The present results, in addition to providing a detailed map of the 5-HT1 receptors in the guinea-pig brain, indicate that the guinea-pig is a useful laboratory animal for the study of 5-HT1D receptors.

Animals↗
PubMed1993

Autoradiographic demonstration of loss of alpha 2-adrenoceptors in progressive supranuclear palsy: preliminary report.

We assessed, by quantitative autoradiography in tissue sections, the density of alpha 2-adrenoceptors in several representative brain regions from a typical progressive supranuclear palsy (PSP) patient and in 9 matched brains. The full agonist 3H-bromoxidine was used as a ligand. The density of alpha 2-receptors was dramatically reduced in all the examined brain areas of this PSP patient as compared to the control group. The locus ceruleus degeneration observed here is the most plausible explanation for this loss of alpha 2-receptors. Our data show that abnormalities in the noradrenergic system may justify some clinical features of the PSP clinical picture, this supporting the idea of further study of the clinical effects of noradrenergic drugs in PSP.

Adrenergic alpha-Agonists↗
PubMed1993

Lindane administration to the rat induces modifications in the regional cerebral binding of [3H]Muscimol, [3H]-flunitrazepam, and t-[35S]butylbicyclophosphorothionate: an autoradiographic study.

The effect of lindane administration on the specific binding of ligands to different sites on the GABAA receptor-ionophore complex was studied in the rat brain by receptor mapping autoradiography. [3H]Muscimol (Mus), [3H]flunitrazepam (Flu), and t-[35S]butylbicyclophosphorothionate (TBPS) were used as specific ligands of GABA, benzodiazepine, and picrotoxinin binding sites, respectively. Rats received a single oral dose of 30 mg/kg lindane and they were classified into two groups according to the absence or presence of convulsions. Vehicle-treated groups acted as controls. The effect of the xenobiotic on ligand binding was measured in different brain areas and nuclei 12 min or 5 h after its administration. Lindane induced a generalized decrease in [35S]TBPS binding, which was present shortly after dosing. In addition, [3H]Flu binding was increased in lindane-treated animals, this modification also appearing shortly after administration but diminishing during the studied time. Finally, lindane induced a decrease in [3H]Mus binding, which became more evident over time. These modifications were observed both in the presence and in the absence of convulsions. However, an increase in [3H]-Mus binding was detected shortly after lindane-induced convulsions. The observed decrease in [35S]TBPS binding is in agreement with the postulated action of lindane at the picrotoxinin binding site of the GABAA receptor chloride channel. The effects observed on the binding of [3H]Flu and [3H]Mus may be secondary to the action of lindane as an allosteric antagonist of the GABAA receptor.

Animals↗
PubMed1992

Modification of muscarinic acetylcholine receptors in the rat brain following chronic immobilization stress: an autoradiographic study.

The modifications of rat brain muscarinic acetylcholine receptors induced by chronic immobilization stress lasting 10 min/daily or 2 h/daily for 3, 7 or 21 days were analyzed by quantitative in vitro autoradiography. [3H]N-Methylscopolamine ([3H]NMS) was used as ligand. Chronic immobilization stress for 10 min/day did not produce any significant change in the properties of [3H]NMS binding sites throughout the rat brain. In contrast, 2 h/day immobilization caused a significant increase in the maximal number of muscarinic receptors (Bmax) in several brain areas such as the cortical layers, the CA1 field of the hippocampus and caudate-putamen, among others. Affinity values (Kd) were not modified. These results suggest that chronic immobilization stress induces supersensitivity of muscarinic receptors in certain cholinergic pathways in rat brain, the pattern of response being different to that previously found for acute stress.

Animals↗
PubMed1992

A rodent model of focally evoked self-sustaining status epilepticus.

We describe a novel model of status epilepticus produced by the focal application of bicuculline methiodide into the deep prepiriform cortex of rats pretreated with lithium chloride. Three out of eight rats pretreated with one dose of lithium (3 mmol/kg) 24 h prior to induction of seizures by focal bicuculline, and eight out of 12 rats pretreated with two doses of lithium (at 24 and 48 h) prior to seizure induction, exhibited continual uninterrupted convulsive seizure activity (status epilepticus) lasting between 10 min and > 2 h. This status epilepticus which was manifest both behaviorally and electroencephalographically, was sensitive to reversal by diazepam (5 mg/kg i.p.) given as long as 2 h after the onset of sustained status epilepticus. Pilocarpine (25 mg/kg) pretreatment also predisposed to status epilepticus in response to the focal application of bicuculline, but diazepam (5 or 10 mg/kg i.p.) was ineffective in suppressing the status epilepticus in the presence of pilocarpine.

Animals↗