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R Quirion

Publications and source records attributed to R Quirion.

At least 289 records · Page 16Linked to original sources
PubMed1989

Characterization of [3H]AF-DX 116 binding sites in the rat brain: evidence for heterogeneity of muscarinic-M2 receptor sites.

This study shows that [3H]AF-DX 116 binds specifically, saturably, and with high affinity to putative muscarinic-M2 receptor sites in the rat brain. In homogenates of the hippocampus, cerebral cortex, striatum, thalamus, and cerebellum, [3H]AF-DX 116 appears to bind two subpopulations of muscarinic sites: one class of higher affinity sites (Kd less than 4.0 nM) and one class of lower affinity sites (Kd greater than 50 nM, except in the cerebellum). The apparent maximal capacities (Bmax) of [3H]AF-DX 116 sites in forebrain tissues ranged between 34 and 69 fmol/mg protein for the higher affinity site, and between 197 and 451 fmol/mg protein for the lower affinity site. In cerebellar homogenates, the maximal capacity of [3H]AF-DX 116 binding sites was 10.4 +/- 0.4 (Kd = 1.9 +/- 0.2 nM) and 39.1 +/- 2.6 (Kd = 26 +/- 7 nM) fmol/mg protein for the higher and the lower affinity site, respectively. Determination of the Kd for the higher and lower affinity [3H]AF-DX 116 sites from association and dissociation constants yielded similar values to those obtained from the saturation data. The ligand selectivity pattern reveals that AF-DX 116 is more potent than (-)QNB greater than atropine greater than methoctramine greater than 4-DAMP greater than gallamine greater than NMS greater than carbamylcholine greater than oxotremorine greater than pirenzepine much greater than nicotine in competing for the higher affinity [3H]AF-DX 116 sites. With few exceptions, the pattern was similar for the lower affinity sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Quantitative autoradiographic distribution of [3H]AF-DX 116 muscarinic-M2 receptor binding sites in rat brain.

The distribution of muscarinic-M2 receptors in rat brain was investigated by in vitro autoradiography using [3H]AF-DX 116, a putative probe for the muscarinic-M2 receptor subtype. Incubation of rat brain coronal sections with 10 nM [3H]AF-DX 116 showed highest binding site densities in discrete areas such as the superior colliculus and certain thalamic and brainstem nuclei, similar to the distribution reported for [2H]acetylcholine/M2 sites. [3H]AF-DX 116 site densities were markedly lower in forebrain areas such as cortex, striatum, and hippocampus, in contrast to the distribution seen for [3H]pirenzepine-M1 binding sites, which were concentrated in these forebrain areas; however, differential patterns of labeling were observed for the two muscarinic-M2 probes, [3H]AF-DX 116 and [3H]acetylcholine, in the hippocampal formation. Although [3H]AF-DX 116 binding was broadly distributed in multiple subfields of the hippocampus, [3H]acetylcholine binding was discretely distributed in a manner resembling that of acetylcholinesterase staining. This suggests the existence of muscarinic-M2 subtypes in the CNS, especially in the hippocampal formation.

Animals↗
PubMed1989

Apparent absence of serotonin1B receptors in biopsied and post-mortem human brain.

In order to determine if post-mortem delays could account for the apparent absence of 5-HT1B sites reported in human brain, 5-HT1B binding parameters were determined in fresh and fresh-frozen cortical biopsies and compared to results obtained in post-mortem tissues. Binding parameters and in vitro receptor autoradiography were performed by using two different ligands which have been shown to label 5-HT1B sites, namely [3H]5-HT, in presence of 100 nM 8-OH-DPAT, and [125I]cyanopindolol, in presence of 10 microM (-)isoproterenol. No specific binding was detected with [125I] cyanopindolol in either fresh cortical biopsies or post-mortem tissues, suggesting that the apparent absence of 5-HT1B receptor sites reported earlier was not related to long post-mortem delays. Some specific labelling was seen with [3H]5-HT, in presence of 8-OH-DPAT. This binding, which is unlikely to be to the 5-HT1B type, could represent labelling to the 5-HT1D or 5-HT1E sites.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1989

A comparison of the effects of diazepam versus several typical and atypical anti-depressant drugs in an animal model of anxiety.

We examined the anxiolytic effects of a variety of anti-depressant drugs, administered either acutely or chronically, in an animal model of anxiety involving novelty-suppressed feeding in food-deprived rats. Following a single injection of desipramine (10 mg/kg) amitriptyline (10 mg/kg), mianserin (10 mg/kg), fluoxetine (10 mg/kg), buspirone (4 mg/kg), gepirone (4 mg/kg) or nomifensine (10 mg/kg), there was no decrease in the latency to begin eating in the novel environment such as occurred with diazepam (2 mg/kg). In fact, an increased latency was observed for desipramine, amitriptyline, fluoxetine, and nomifensine. In contrast, chronic (21 days) treatment with each of the above-mentioned drugs, except nomifensine, significantly reduced the latency to begin eating relative to vehicle controls. These findings suggest that a variety of tricyclic and novel anti-depressant drugs acquire anxiolytic properties following chronic administration.

Animals↗
PubMed1989

Receptor sites for atrial natriuretic factors in brain and associated structures: an overview.

1. Recent data have clearly shown the existence of specific receptor binding sites for atrial natriuretic factors (ANF) or polypeptides in mammalian brain tissues. 2. Ligand selectivity pattern and coupling to cGMP production suggest that brain ANF sites are similar to high-affinity/low-capacity sites found in various peripheral tissues (kidney, adrenal gland, blood vessels). These brain ANF sites possibly are of the B-ANP subtype. 3. High densities of ANF binding sites are found especially in areas of the central nervous system associated with the control of various cardiovascular parameters (such as the subfornical organ and area postrema). However, high densities of sites are also present in other regions such as the hippocampus, cerebellum, and thalamus in the brain of certain mammalian species, suggesting that brain ANF could act as a neuromodulator of noncardiovascular functions. 4. The density of brain ANF binding sites is modified in certain animal models of cardiovascular disorders and during postnatal ontogeny, demonstrating the plasticity of these sites in the central nervous system (CNS). 5. Specific ANF binding sites are also found in various other CNS-associated tissues such as the eye, pituitary gland, and adrenal medulla. In these tissues ANF appears to act as a modulator of fluid production and hormone release. 6. Thus, ANF-like peptides and ANF receptor sites are present in brain and various peripheral tissues, demonstrating the existence of a family of brain/heart peptides.

Animals↗
PubMed1989

Characterization and quantitative autoradiographic distribution of [3H]acetylcholine muscarinic receptors in mammalian brain. Apparent labelling of an M2-like receptor sub-type.

[3H]Acetylcholine receptor binding characteristics (under muscarinic conditions) have been investigated using membrane binding assays and in vitro receptor autoradiography. In rat, guinea-pig and monkey brain membrane preparations, [3H]acetylcholine binds with high affinity (25-50 nM) to an apparently single class of sites which is differentially distributed across brain regions. The ligand selectivity pattern reveals that the potency of (-)quinuclidinyl benzylate is greater than (greater than) atropine greater than scopolamine greater than oxotremorine greater than carbamylcholine greater than pirenzepine greater than methylcarbamyl-choline = nicotine in competing for [3H]acetylcholine binding sites, indicating that [3H]acetylcholine selectively binds to muscarinic sites under these incubation conditions. Moreover, the low potency of pirenzepine suggests that [3H]acetylcholine does not label a significant proportion of the M1 receptor sub-type but most likely binds to putative M2-like receptor sites. This hypothesis is also supported by the autoradiographic distribution of [3H]acetylcholine binding sites in all species studied here. High densities of [3H]acetylcholine binding sites are seen in various nuclei of the medulla and pons, certain thalamic nuclei, medial septum, laminae III, V and VI of the cortex and just above the pyramidal cell layer of the hippocampus. Such localization is much different from that seen with the non-selective antagonist [3H]quinuclidinyl benzylate and the selective M1 receptor ligand [3H]pirenzepine, although it resembles that of the selective M2 receptor antagonist [3H]AF-DX 116. Thus, [3H]acetylcholine apparently mostly binds with high affinity mainly to non-M1 muscarinic receptor types in mammalian brain tissues. Moreover, the ligand selectivity pattern and in vitro receptor autoradiographic data suggest that at low concentrations (10-20 nM) most of [3H]actylcholine labelled sites are of the M2-like receptor class.

Acetylcholine↗
PubMed1989

Role of the central benzodiazepine receptor system in behavioral habituation to novelty.

In this article we report the results of two experiments examining the role of central benzodiazepine receptor sites in the response to novelty. Animals that were food deprived and presented with food in a novel environment showed long latencies before they began eating. Pretreatment with diazepam or preexposure to the "novel" environment for 1 hr/day for 4 or 7 days before testing in that environment dramatically reduced the latency to begin eating. Administration of either the "inverse agonist," FG-7142, or an antagonist, RO15-1788, of the central benzodiazepine receptor before testing completely reversed the effects of 7 days of preexposure to the novel environment. In home-cage feeding tests, FG-7142, but not RO15-1788, increased the latency to begin feeding in food-deprived animals. These findings indicate that FG-7142 is strongly anxiogenic, whereas RO15-1788 is not anxiogenic, yet both drugs are potent in reversing the effects of habituation. The results of these experiments suggest that the normal process of habituation to novelty may involve the release of an endogenous, anxiolytic compound (an agonist) that binds to a central benzodiazepine receptor, the effects of which are blocked by RO15-1788.

Animals↗
PubMed1989

Glutamate stimulation of [3H]dopamine release from dissociated cell cultures of rat ventral mesencephalon.

In dissociated cell cultures of fetal rat ventral mesencephalon preloaded with [3H]dopamine, glutamate (10(-5)-10(-3) M) stimulated the release of [3H]dopamine. Glutamate stimulation of [3H]dopamine release was Ca2+ dependent and was blocked by the glutamate antagonist, cis-2,3-piperidine dicarboxylic acid. Glutamate stimulation of [3H]dopamine release was not due to glutamate neurotoxicity because (1) glutamate did not cause release of a cytosolic marker, lactate dehydrogenase, and (2) preincubation of cultures with glutamate did not impair subsequent ability of the cells to take up or release [3H]dopamine. Thus, these dissociated cell cultures appear to provide a good model system to characterize glutamate stimulation of dopamine release. Release of [3H]dopamine from these cultures was stimulated by veratridine, an activator of voltage-sensitive Na+ channels, and this stimulation was blocked by tetrodotoxin. However, glutamate-stimulated [3H]dopamine release was not blocked by tetrodotoxin or Zn2+. Substitution of NaCl in the extracellular medium by sucrose, LiCl, or Na2SO4 had no effect on glutamate stimulation of [3H]dopamine release; however, release was inhibited when NaCl was replaced by choline chloride or N-methyl-D-glucamine HCl. Glutamate-stimulated [3H]-dopamine release was well maintained (60-82% of control) in the presence of Co2+, which blocks Ca2+ action potentials, and was unaffected by the local anesthetic, lidocaine. These results are discussed in terms of the receptor and ionic mechanisms involved in the stimulation of dopamine release by excitatory amino acids.

Animals↗
PubMed1989

Effect of chronic nicotine treatment on nicotinic autoreceptor function and N-[3H]methylcarbamylcholine binding sites in the rat brain.

It has been reported that N-methylcarbamylcholine (MCC), a nicotinic agonist, binds to central nicotinic receptors and causes an increase of acetylcholine (ACh) release from certain central cholinergic nerve terminals. The present experiments determine whether these two phenomena change in response to the chronic administration of nicotine, a procedure known to result in an increase in nicotinic binding sites. Chronic nicotine caused a brain region-specific up-regulation of [3H]MCC sites; binding increased in the frontal cortex, parietal cortex, striatum, and hippocampus, but not in the occipital cortex or cerebellum. The effect of nicotine was selective to nicotinic binding sites, because muscarinic sites, both M1 ([ 3H]pirenzepine) and M2 ([3H]ACh), were unaffected by chronic nicotine treatment. MCC increased the release of ACh from the frontal cortex and hippocampus by a calcium-dependent mechanism; MCC did not alter ACh release from striatum or occipital cortex of control animals. The MCC-induced increase in ACh release was not apparent in those animals which had been treated with nicotine. There was a partial recovery of nicotinic autoreceptor function when animals were allowed to recover (4 days) following chronic nicotine treatment, but the density of binding sites remained increased compared to control. Chronic nicotine did not change the potassium-evoked release of ACh from the frontal cortex or hippocampus, but decreased this measure from striatum. It also decreased the ACh content of the striatum, but not that of the cortex or the hippocampus; the activity of choline acetyltransferase was not altered in any of the regions tested.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1989

Presynaptic cholinergic mechanisms in the rat cerebellum: evidence for nicotinic, but not muscarinic autoreceptors.

The present study shows that N-[3H]methylcarbamylcholine ([3H]MCC) binds to a single population of high-affinity/low-density (KD = 5.0 nM; Bmax = 8.2 fmol/mg of protein) nicotinic binding sites in the rat cerebellum. Also, there exists a single class of high-affinity binding sites (KD = 4.8 nM; Bmax = 24.2 fmol/mg of protein) in the cerebellum for the M1 specific muscarinic ligand [3H]pirenzepine. In contrast, the M2 ligand, [3H]AF-DX 116, appears to bind to two classes of binding sites, i.e., a high-affinity (KD = 3 nM)/low-capacity (Bmax = 11.7 fmol/mg of protein) class, and a second class of lower affinity (KD = 28.4 nM) and higher capacity (Bmax = 36.3 fmol/mg of protein) sites. The putative M3 selective ligand [3H]4-diphenylacetoxy-N-methylpiperidine also binds to two distinct classes of binding sites in cerebellar homogenates, one of high affinity (KD = 0.5 nM)/low capacity (Bmax = 19.5 fmol/mg of protein) and one of low affinity (KD = 57.5 nM)/high capacity (Bmax = 140.6 fmol/mg of protein). In experiments which tested the effects of cholinergic drugs on acetylcholine release from cerebellar brain slices, the nicotinic agonist MCC enhanced spontaneous acetylcholine release in a concentration-dependent manner, and the maximal increase in acetylcholine release (59.0-68.0%) occurred at 10(-7) M. The effect of MCC to increase acetylcholine release was Ca2+-dependent and tetrodotoxin-insensitive, suggesting an action on cholinergic terminals. Also, the MCC-induced increase in acetylcholine release was effectively antagonized by dihydro-beta-erythroidine, d-tubocurarine, and kappa-bungarotoxin, but was insensitive to either atropine or alpha-bungarotoxin.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1989

Physiologic regulation and distribution of the renal vasopressin receptor.

Previous studies suggest that circulating levels of vasopressin (AVP) influence the responsiveness of the kidney to AVP. To determine how changes in renal AVP receptors and adenylate cyclase (AC) contribute to such altered responsiveness, we analyzed AVP receptors and AVP-sensitive AC in kidneys from Sprague-Dawley, Long-Evans and homozygous Brattleboro rats. In autoradiographic studies, the distribution of [3H]AVP binding sites was similar in all groups, corresponding to the location of AVP-sensitive AC: collecting ducts greater than outer medullary collecting ducts greater than medullary thick ascending limb greater than cortical collecting ducts. No differences in AVP receptor affinity or content were observed in kidney medullary membranes from Sprague-Dawley, Long-Evans or Brattleboro rats (KD = 0.8, 0.9, and 0.7 nM; Bmax = 116 +/- 9, 95 +/- 11 and 98 +/- 6 fmol/mg). Basal and AVP-stimulated AC activities were lower in kidney membranes from Brattleboro rats compared with Sprague-Dawley and Long-Evans animals (basal = 28 +/- 4, 40 +/- 4 and 38 +/- 3 pmol cAMP/mg/min; EDmax = 57 +/- 5, 80 +/- 7 and 71 +/- 2 pmol cAMP/mg/min) with no change in ED50. In 48-hour water-deprived Sprague-Dawley rats, AVP receptors were decreased from 116 +/- 9 to 58 +/- 2 fmol/mg, suggesting that AVP receptors are down-regulated by elevated AVP blood levels. The absence of changes in basal or AVP-stimulated AC in dehydrated rats indicates that receptor-AC coupling is normal and that maximum AC activation can occur with partial receptor occupancy. The data also indicate that impaired renal responsiveness to AVP in Brattleboro rats is not due to down-regulation of AVP receptors.

Adenylyl Cyclases↗
PubMed1989

Structure-activity profile of calcitonin gene-related peptide in peripheral and brain tissues. Evidence for receptor multiplicity.

The radioligand binding characteristics and in vitro biological activities of human calcitonin gene-related peptide (hCGRP) homologs, analogs and fragments have been tested in a variety of preparations in order to determine the structural requirements of the calcitonin gene-related peptide (CGRP) receptor. The ligand selectivity profile observed in this study suggests that [125I] hCGRP binding sites present in rat brain and spleen are similar. The high affinity of the analogs [Cys(ACM)2.7]hCGRP and cyclo2.7 [Asp2, Lys7]hCGRP indicates that the disulfide bridge between positions 2 and 7 is not essential for the binding of the ligand to the CGRP receptor. On the other hand, the lack of affinity of various N-terminal fragments in the binding assays demonstrates the importance of amino acids 9-37 in maintaining appropriate receptor recognition. The existence of CGRP receptor subtypes is supported by data obtained in various in vitro bioassays. For example, the linear analog, [Cys(ACM)2.7]hCGRP, which retained high potency in the rat vas deferens bioassay displayed no agonistic activity in the right and left guinea pig atrial preparations. Additionally, the C-terminal fragment hCGRP 12-37 possessed some antagonist properties in atrial but not vas deferens preparations. Thus, it appears that it is possible to differentiate between CGRP receptor subtypes on the basis of differential agonistic (e.g.[Cys(ACM)2.7]hCGRP) and antagonistic (e.g., hCGRP 12-37) potencies in various isolated tissues. Moreover, the weak but significant antagonistic properties of hCGRP 12-37 may be most useful in order to design more potent CGRP receptor antagonists.

Animals↗
PubMed1989

Characterization and possible role of growth factor and lymphokine receptors in the regulation of cholinergic function in the mammalian brain.

Using in vitro receptor autoradiographic techniques, we characterized the distribution of various growth factor (GF) and lymphokine receptors in the rat brain. In neonatal brain, specific insulin-like GF-1 (IGF-1) and epidermal GF (EGF) sites were observed in various regions. In particular, dense [125I]IGF-1 and [125I]EGF labelling was seen in the hippocampal formation. In the adult (3-month old) rat brain, a broader distribution of IGF-1 sites was apparent, whereas few EGF sites were visualized. As in the neonate, the adult hippocampus was enriched with IGF-1 binding sites. In addition, high levels of interleukin-2 (IL-2) binding sites were detected in the hippocampus of the adult rat. Exogenous IGF-1, EGF, and IL-2 significantly reduced the potassium (25 mM)-evoked release of acetylcholine (ACh) from slices of rat hippocampus. The GF effects were restricted to the adult hippocampus; neither IGF-1 nor EGF altered ACh release from slices of immature (6- and 18-day old) rat brain. Moreover, the GF and IL-2-mediated effects on ACh release appear to be specific to the hippocampus. For example, ACh release from frontal cortex or striatum was not significantly affected by either GFs or IL-2. In summary, our results suggest that in the rat hippocampus, IGF-1, EGF, and IL-2 may be important modulators of cholinergic activity.

Animals↗
PubMed1989

Muscarinic receptor subtypes in human neurodegenerative disorders: focus on Alzheimer's disease.

Much evidence has clearly revealed the existence of marked cholinergic deficits in cortical and hippocampal areas in Alzheimer's disease. Although not necessarily of etiological origin, these deficits have been associated with learning and memory disabilities observed in this neurogenerative disorder. We report here that in addition to deficits in choline acetyltransferase (ChAT) activity, the maximal densities of high affinity [3H]acetylcholine and [3H]AF-DX 116 (possibly M2), but not M1 muscarinic receptor binding sites are decreased in cortex and hippocampus in Alzheimer's disease. Similar findings are also observed in Parkinson's disease with Alzheimer's type dementia. Additionally, animal studies suggest that a population of M2 receptors is presynaptically located on cholinergic nerve terminals where they can act as negative autoreceptors to decrease acetylcholine release. Interestingly, blockade of these sites facilitates acetylcholine release and learning in rats. This may be relevant for the design of more appropriate therapeutic approaches toward the treatment of certain symptoms of Alzheimer's disease.

Alzheimer Disease↗
PubMed1988

Evidence for the existence of three classes of neurokinin receptors in brain. Differential ontogeny of neurokinin-1, neurokinin-2 and neurokinin-3 binding sites in rat cerebral cortex.

The autoradiographic distribution of the 3 neurokinin (NK) receptor sub-types, NK-1, NK-2 and NK-3, was compared in rat cerebral cortex during post-natal development using [125I]Bolton-Hunter-substance P, (2-[125I]iodohistidyl1)neurokinin A and [125I]Bolton-Hunter-eledoisin as respective radioligands. Throughout brain development, NK-1 receptor sites are present in low densities with some enrichment seen in lamina III while NK-3 binding sites are concentrated in layers IV and V. However, it appears that NK-2 receptors are mostly expressed in lamina VI and only during the first two postnatal weeks. These results demonstrate further the existence and differential ontogeny of 3 classes of NK receptors in rat brain cortex.

Aging↗
PubMed1988

Glucocorticoid binding sites in human temporal cortex.

This work describes the presence of glucocorticoid binding sites in human temporal cortex obtained following partial lobectomy in two epileptic patients. Using [3H]dexamethasone as radioligand and cold cortisol or RU 28362 as competitor we found an apparent Kd of approximately 2.8 nM with a Bmax of approximately 34 fmol/mg protein. The order of potency of various unlabeled steroids to compete for [3H]dexamethasone binding was as follows: RU 28362 = RU 38486 = cortisol = dexamethasone greater than progesterone greater than spironolactone greater than estradiol. These data provide evidence for an intracellular mechanism by which circulating glucocorticoids might regulate neuronal function in the human cortex.

Adult↗
PubMed1988

Visualization of growth factor receptor sites in rat forebrain.

It is now known that various growth factors may also act in the central nervous system. Among them, it has recently been shown that epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) may possess trophic effects in the mammalian brain. We report here on the respective autoradiographic distribution of [125I]EGF and [125I]IGF-I receptor binding sites in the rat brain, both during ontogeny and in adulthood. It appears that [125I]EGF sites are mostly found in the rat forebrain during brain development. On the other hand, [125I]IGF-I sites are more widely distributed both during ontogeny and in adulthood. These results reveal the plasticity of the expression of EGF and IGF-I receptor sites in the mammalian brain. This could be relevant for the respective role of these two growth factors in the development and maintenance of neuronal function.

Aging↗