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P M Laduron

Publications and source records attributed to P M Laduron.

At least 55 records · Page 3Linked to original sources
PubMed1990

Ethanol and opiate decrease the axonal transport of substance-P like immunoreactive material in rat vagus-nerves.

Since an enhanced retrograde axonal transport of receptor-bound opiate was observed in the ligated vagus nerves of rats treated chronically with alcohol, we decided to look at the anterograde axonal transport of substance P in the same experimental conditions and, after opiate administration. From 1 day up to 24 days' treatment with alcohol, we observed a decrease in the accumulation of substance P like immunoreactive material (SPLM) in rat ligated vagus nerves. Acute administration of lofentanil, an mu opiate agonist, caused the same reduction of anterograde axonal transport of SPLM and this effect could be prevented by naloxone. When naloxone or bezitramide, an opiate agonist, was given during the alcoholization period, the preference for alcohol in a choice test was reduced or prevented suggesting that opioid peptides are probably involved in chronic alcoholism. The present results support the idea that a common denominator could exist in drug addition and in chronic alcoholism and that substance P may be directly or indirectly involved.

Analgesics↗
PubMed1990

Retrograde axonal transport of neurotensin in the dopaminergic nigrostriatal pathway in the rat.

Although the existence of receptor transport has been clearly demonstrated in peripheral nerves, there is no clear cut evidence in the brain of such a process for neuropeptide receptors. Because of the localization of neurotensin receptors on dopaminergic terminals, the dopaminergic nigrostriatal pathway appears to be the system of choice for studying the axonal transport of neuropeptide receptors in the brain. When labelled neurotensin was injected into the rat striatum, a delayed accumulation of radioactivity in the ipsilateral substantia nigra was observed about 2 h after injection. An essential requirement to clearly observe this phenomenon was the pretreatment of animals with kelatorphan in order to prevent the labelled neurotensin degradation. The appearance of this labelling was prevented by injection of an excess of unlabelled neurotensin or of neurotensin 8-13, an active neurotensin fragment, but not by neurotensin 1-8, which had no affinity for neurotensin receptors. This process was saturable, microtubule-dependent and occurred only in mesostriatal and nigrostriatal dopaminergic neurons as identified after 6-hydroxydopamine lesion and by autoradiography. These results demonstrate that neurotensin was retrogradely transported by a process involving neurotensin receptors. The retrograde transport of receptor-bound neuropeptide may represent an important dynamic process which conveys information molecules from the synapse towards the cell body.

Animals↗
PubMed1990

Axonal transport of synaptic vesicles and muscarinic receptors: effect of protein synthesis inhibitors.

The effect of cycloheximide, a protein synthesis inhibitor, was studied on the axonal transport of noradrenergic synaptic vesicles and presynaptic muscarinic receptors, identified by in vitro binding of [3H]dihydrotetrabenazine and [3H]quinuclidinylbenzilate, respectively, in rat sciatic nerve. Cycloheximide (1.5 mg/kg) administered subcutaneously 2 h before ligation decreased by approximately 50% the accumulation of vesicles and receptors in the proximal segment above the ligature placed on the nerve; its action was detectable after a lag period of 10 h and disappeared 96 h after administration. Double ligatures were placed on the nerve at various time intervals between the first (distal) and the second (proximal) ligature, and the accumulation of vesicles and receptors proximal to the second ligature was measured; the first ligature diminished the accumulation above the second ligature. At an interval of 96 h between the first and the second ligature, cycloheximide completely prevented the accumulation of vesicles and receptors proximal to the second ligature. The effects of double ligatures and the response to cycloheximide treatment can best be explained on the assumption that an important proportion of synaptic vesicles and presynaptic receptors is being recycled in the nerve cell bodies after retrograde transport.

Animals↗
PubMed1990

Preferential decrease in dopamine utilization in prefrontal cortex by zopiclone, diazepam and zolpidem in unstressed rats.

This study has compared the effects of a cyclopyrrolone, zopiclone, a benzodiazepine, diazepam, and an imidazopyridine, zolpidem, on dopamine (DA) and DOPAC levels, and DA utilization (DOPAC/DA ratio) in rat striatum and prefrontal cortex. The endogenous levels of DA were significantly increased by both zopiclone (2.5, 10 and 40 mg kg-1 p.o.) and diazepam (10 and 40 mg kg-1 p.o.) in the prefrontal cortex, whereas striatal DA content was significantly increased only with the highest dose of diazepam (40 mg kg-1 p.o.). Diazepam (10 and 40 mg kg-1 p.o.) decreased cortical level of DOPAC more markedly than striatal levels, whereas zopiclone (40 mg kg-1 p.o.) only slightly decreased striatal DOPAC levels. Zopiclone and diazepam dose-dependently decreased DA utilization, an effect which was more marked in prefrontal cortex than in striatum. This result was confirmed with zolpidem, another benzodiazepine ligand. Zopiclone was most potent at decreasing DA utilization at the cortical level. The diazepam-induced decreases in DA metabolism and utilization were antagonized by Ro 15-1788, suggesting that the effects seen were mediated by specific benzodiazepine receptors. Thus, our results clearly show that ligands acting on the benzodiazepine receptor GABA receptor chloride ionophore complex can decrease the utilization of dopamine in unstressed rats. The preferential decrease in cortical DA utilization induced by benzodiazepine ligands may be compared to the well-known activation by stress of the mesocortical DAergic system.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1989

Photoaffinity labeling of the monoamine transporter of bovine chromaffin granules and other monoamine storage vesicles using 7-azido-8-[125I]iodoketanserin.

An iodinated azido derivative of ketanserin, 7-azido-8-[125I]iodoketanserin ( [125I]AZIK), has been used to label the monoamine transporter of bovine chromaffin granule membranes by the technique of photoaffinity labeling. In the dark, this derivative was found to bind reversibly to the membranes, with an equilibrium dissociation constant estimated to be 6 nM at 0 degrees C. As for ketanserin, binding occurred at the tetrabenazine site: (i) [125I]AZIK was displaced efficiently from its binding site by tetrabenazine, ketanserin, and 7-azidoketanserin, whereas serotonin, which is a substrate for the transporter but has a low affinity for tetrabenazine binding site, was a poor displacer; pipamperone and pyrilamine, two antagonists of respectively serotonin S2 and histamine H1 receptors, were inactive. (ii) 7-Azidoketanserin was a competitive inhibitor of [3H]dihydrotetrabenazine binding, and it inhibited the ATP-dependent uptake of serotonin by chromaffin granule ghosts. Irradiation of [125I]AZIK with long-wavelength UV light, followed by electrophoresis on sodium dodecyl sulfate/polyacrylamide gels and autoradiography, revealed irreversible labeling of a membrane component with an apparent molecular weight of 73,000. Tetrabenazine inhibited the labeling of this 73-kDa band in a manner parallel to the binding of [125I]AZIK in the dark. Such a labeling is totally compatible with previous results obtained through photolabeling with a tetrabenazine derivative or by target size analysis. Moreover, preliminary experiments showed that [125I]AZIK can label the tetrabenazine binding sites of various sources including rat striatum, rabbit platelets, human pheochromocytoma, and human adrenal medulla. Therefore, this molecule appears to be an excellent probe to label the monoamine transporter of different amine storage vesicles even without purification.

Absorption↗
PubMed1989

Riluzole antagonizes the anxiogenic properties of the beta-carboline FG 7142 in rats.

The possible anxiolytic activity of riluzole, a drug which interferes with glutamic acid neurotransmission, was studied in rats using operant conflict procedures. In both "anxiolytic" and "anxiogenic" procedures, riluzole alone did not possess any anticonflict or proconflict effect at doses of 2 and 4 mg/kg PO. Riluzole over the same dose-range was able to antagonize the well known proconflict effect of the beta-carboline derivative FG 7142, an inverse agonist at the GABA-benzodiazepine-chloride ionophore receptor complex. This effect could be related to the possible interaction of riluzole with glutamic acid neurotransmission, since it has been demonstrated previously that beta-carbolines such as DMCM and beta-CCM were able to deplete the levels of aspartic and glutamic acids in rodent cortex, perhaps by enhancing release of amino acid neurotransmitters. If one subscribes to the hypothesis that the anxiety induced by beta-carboline derivatives is related to depression, riluzole might be of value in the treatment of anxiety related to depression.

Animals↗
PubMed1989

High affinity acceptor sites in guinea pig brain for [3H]52770 RP, a PAF antagonist.

[3H]52770 RP, a PAF antagonist, was found to bind with high affinity and in a reversible manner on specific and saturable binding sites in guinea pig cortical membranes. Scatchard analysis revealed the presence of one class of binding sites with an equilibrium dissociation constant of 0.38 nM and a Bmax of 1190 fmol/mg protein. However, these binding sites did not correspond to the PAF receptors described with this ligand in platelet plasma membranes; indeed, PAF and its analogs were unable to displace [3H]52770 RP binding in guinea pig brain. Therefore, one may conclude that [3H]52770 RP in guinea pig brain labels acceptor or recognition sites, rather than true receptor sites.

Animals↗
PubMed1989

Riluzole, a novel antiglutamate, prevents memory loss and hippocampal neuronal damage in ischemic gerbils.

The neuroprotective effects of riluzole, a novel antiglutamate, has been demonstrated in a model of ischemia induced in female Mongolian gerbils by transient bilateral carotid occlusion. Riluzole was administered at a dose of 4 mg/kg, i.p., just before, 4 hr after, and for the 14 d following the transient bilateral carotid occlusion (10 min). The functional sequelae of ischemic damage were assessed using a memory test (passive avoidance) and the extent of neuronal damage by histological examination and quantitative autoradiography of muscarinic cholinergic receptors in the hippocampus. The performance of the ischemic gerbils in the memory test was about half that of control animals. This memory deficit was completely reversed in animals treated with riluzole. This protective effect of riluzole was confirmed by histological and autoradiographic studies. The neuronal degeneration of CA1 pyramidal cells in the hippocampus observed in the ischemic group was not seen in the riluzole-treated animals, which resembled the control group. This neuronal degeneration in the CA1 area was confirmed by a quantitative measurement of muscarinic receptors: The binding was decreased by a third in the lacunosum moleculare, the stratum oriens, and the stratum radiatum. By contrast in riluzole-treated gerbils, this decrease was reversed by 50%. Finally, a clear-cut correlation was found between the deficit in the memory test and the decrease in muscarinic receptor binding in the CA1 fields. These results are compatible with the idea that glutamic acid may be involved in the neuronal degeneration of the hippocampus following ischemia, and could be foreseeable.(ABSTRACT TRUNCATED AT 250 WORDS)

Amnesia↗
PubMed1988

[3H]GBR 12935 binding to dopamine uptake sites: subcellular localization and reduction in Parkinson's disease and progressive supranuclear palsy.

[3H]GBR 12935 bound with high affinity to dopamine uptake sites in rat striatum where a close parallelism was observed between the subcellular localization profiles for [3H]dopamine uptake and [3H]GBR 12935 specific binding. Using the same ligand, we characterized the dopamine uptake sites in human striatum: the mean KD value was 3.2 nM and the specific binding was inhibited by several dopamine uptake blockers but with slightly lower affinities than those observed in the rat. The subcellular localization profile revealed a synaptosomal enrichment of the specific binding in human striatum. [3H]GBR 12935 binding was decreased in the putamen and caudate nucleus of subjects with Parkinson's disease (33 and 46% of control values, respectively) and progressive supranuclear palsy (38 and 57% of control values, respectively). It is very unlikely that the remaining binding sites in both diseases correspond to piperazine acceptor sites that are not involved in dopamine uptake. However, we cannot exclude the possibility that some of these remaining dopamine transporter sites are not functional, since the reduction in [3H]GBR 12935 specific binding was less marked than the decrease in the dopamine content of the same areas.

Animals↗
PubMed1988

In vivo determination of the profile of benzodiazepine ligands by comparing the inhibition of 3H-Ro 15-1788 binding to the modulation of cGMP levels in mouse cerebellum.

The in vivo effects of various benzodiazepine (BZD) ligands belonging to different chemical families were studied comparatively in mouse cerebellum using displacement of 3H-Ro 15-1788 binding and cGMP content as biochemical tools. It was possible to differentiate four classes of compounds with regard to these biochemical parameters. The first class of compounds such as diazepam and suriclone induced a net effect on in vivo 3H-Ro 15-1788 binding and a dose-dependent decrease of cGMP levels. A second class of drugs such as ZK 91296 and CGS 9896 showed in vivo activities in displacement studies but relatively small or moderate activities on cGMP levels. A third class was represented by Ro 15-1788 itself which prevented dose-dependently the in vivo 3H-Ro 15-1788 binding but was devoid of effect on cGMP levels. Finally, a fourth class of compounds (CGS 8216, FG 7142, beta-CCM and DMCM) showed in vivo displacement of 3H-Ro 15-1788 with concomitant increase of cGMP levels. The first class of compounds represents full agonists, the second class, partial agonists, the third class, the antagonist Ro-15-1788 itself, and the fourth class corresponds to inverse agonists. Thus it is proposed to use 3H-Ro 15-1788 binding and cGMP levels to differentiate in vivo BZD ligands acting on the BZD receptor/GABA receptor/chloride ionophore complex.

Animals↗
PubMed1988

Riluzole, a glutamate antagonist, enhances slow wave and REM sleep in rats.

Riluzole is a drug that interferes with glutamate neurotransmitters. We studied the sleep pattern of rats treated orally with riluzole at doses ranging from 0.5 to 8 mg/kg. Duration of slow wave sleep and rapid eye movement sleep was found to increase in a dose-dependent manner from 1 mg/kg, at the expense of awakeness. These data suggest that glutamate neurotransmission may be involved in the regulation of sleep. Riluzole can be of interest as sleep modulator, in particular in psychiatric disorders.

Animals↗
PubMed1988

Benzodiazepine receptors in normal human brain, in Parkinson's disease and in progressive supranuclear palsy.

Benzodiazepine receptors have been characterized in human brain. They have been localized mainly in the cerebral cortex and a synaptosomal enrichment was observed after brain fractionation by differential centrifugation. Benzodiazepine receptors were studied in Parkinson's disease and in progressive supranuclear palsy (PSP). In both diseases, the [3H]flunitrazepam specific binding was unchanged when compared to control groups (Bmax and KD values) except in the caudate nucleus of parkinsonian patients where an increase of the specific binding was observed. The subcellular distribution profile of benzodiazepine receptors in Parkinson's disease was similar to that of controls. gamma-Aminobutyric acid (GABA) still enhanced the [3H]flunitrazepam-specific binding (increase of binding affinity), indicating that the functional link between GABA and benzodiazepine receptors remained intact in Parkinson's disease. The present results suggest that benzodiazepine receptors in human striatum are localized on neuronal elements which do not degenerate in Parkinson's disease and PSP.

Aged↗
PubMed1988

Stereospecificity in binding studies. A useful criterion though insufficient to prove the presence of receptors.

In binding studies, stereospecificity is not a property restricted to receptor sites; indeed stereospecific binding has also been observed for acceptor sites. Therefore it does not represent a decisive criterion to make a binding site, a receptor site. However, in some well established cases, it can be useful especially when the difference between the active and inactive enantiomer exceeds 1000-fold as is the case for dexetimide and levetimide on muscarinic receptors. Stereospecific effect is also detectable with acceptor sites, e.g. spirodecanone sites, levocabastine displaceable neurotensin and, presumably, many other ones. Since the membrane is chiral (L-aminoacid) one should expect that non-specific displaceable binding would also display stereospecificity. In this regard, as most of the Scatchard plots reported throughout the literature are curvilinear, even if a straight line is drawn, one may assume that this is due to the presence of acceptor sites that are labelled by the ligand in addition to receptor sites. One cannot exclude the repetition of another "levocabastine story" with other neuropeptides. Hence, as the biochemical criteria like high affinity, saturability, reversibility and stereospecificity cannot differentiate a receptor from an acceptor (see Table 1), the most important and decisive criteria remain: (1) the drug displacement with compounds belonging to different pharmacological classes but mostly to different chemical classes, and (2) the functional correlates between the binding affinity and the potency in pharmacological or physiological tests in vitro or in vivo. When these points are fulfilled a binding site may be called a receptor site.

Animals↗
PubMed1988

Decrease of serotonin-S2 receptors in temporal cortex of patients with Parkinson's disease and progressive supranuclear palsy.

The number of serotonin-S2 receptors was decreased in the temporal cortex of patients with Parkinson's disease and progressive supranuclear palsy (PSP). There was no significant modification of these receptors in the frontal cortex or in the hippocampus and putamen in both diseases. The decrease in number of receptors in PSP was unexpected, because the cerebral cortex is thought to be spared in this disease. There was no correlation between the decrease in number of serotonin-S2 receptors and the degree of dementia in Parkinson's disease, suggesting that these receptors are not directly involved in the deterioration of cognitive functions.

Aged↗
PubMed1988

Different subcellular localization of neurotensin-receptor and neurotensin-acceptor sites in the rat brain dopaminergic system.

The subcellular localization of neurotensin-receptor sites (NT2 sites) and neurotensin-acceptor sites (NT1 sites) was studied in rat caudate-putamen by isopycnic centrifugation in sucrose density gradients. [3H]Neurotensin binding to NT2 sites occurred as a major peak at higher sucrose densities, colocalized with [3H]dopamine uptake, and as a small peak at a lower density; whereas binding to NT1 sites occurred as a single large peak at an intermediate density. 6-Hydroxydopamine lesions of the median forebrain bundle resulted in a total loss of NT2 sites in the caudate-putamen but did not affect NT2 sites in the nucleus accumbens and the olfactory tubercle. NT1 sites were not affected. Kainic acid injections into the rat caudate-putamen led to a partial decrease of NT1 sites in this region 5 days later. After a few weeks they returned to normal. Therefore NT2 sites are probably associated with presynaptic nigrostriatal dopaminergic terminals in the caudate-putamen but not in the nucleus accumbens and the olfactory tubercle. A possible association of NT1 sites with glial cells is suggested.

Animals↗
PubMed1988

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

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

Animals↗