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G Fillion

Publications and source records attributed to G Fillion.

At least 19 recordsLinked to original sources
PubMed1992

Improved brain delivery of AZT using a glycosyl phosphotriester prodrug.

The concentration of AZT in mice plasma and brain was measured using HPLC after an ingestion of 20 mg/kg of AZT or the molar equivalent of hexadecyl 2-(alpha-D-mannopyranosidyl)ethyl 3'-azido-3'-deoxy-5'-thymidinyl phosphate 3. The results demonstrated the promising qualities of the prodrug 3 which gave AZT-5'-phosphate as the main metabolite: the total concentration of AZT derivatives detected in brain presented a peak of 156 nmol/g (5 nmol/g for AZT) at 1 h; the half-life was about 24 h (1 h for AZT) with an AUC of 4366 nmol h/g as compared to 4 nmol h/g for AZT. The lipophilic properties of 3 were confirmed by its in vitro transport of inside synaptosomes. The derivative 2-(alpha-D-mannopyranosidyl)ethyl 3'-azido-3'-deoxy-5'-thymidinyl phosphate (2) provided also a good delivery of AZT to the central nervous system, with values intermediate between those of AZT and 3.

Animals↗
PubMed1992

Inhibition of [3H] gamma-aminobutyric acid release from guinea-pig hippocampal synaptosomes by serotonergic agents.

We studied the effects of (m-trifluoromethyl-phenyl)piperazine (TFMPP) and quipazine on the K(+)-evoked [3H]GABA release from guinea-pig hippocampal synaptosomes loaded with [3H]GABA.TFMPP and quipazine inhibited the K(+)-evoked release of [3H]GABA dose-dependently (IC50 = 153 and 123 microM, respectively). Serotonergic antagonists such as methiothepin (0.1, 0.3 and 1 microM), ketanserin (0.1, 0.3 and 1 microM), dihydroergotamine (0.1 microM), metergoline (0.1 and 0.3 microM), methysergide (0.3 microM), propranolol (1 microM) and yohimbine (1 microM) did not significantly alter the inhibitory effect of TFMPP on [3H]GABA release suggesting that neither 5-HT1 nor 5-HT2 receptors are involved in this process. By contrast, the effect of TFMPP was diminished by selective 5-HT3 receptor antagonist: MDL 72222 (0.3 microM), tropisetron (0.3 and 1 microM), ondansetron (0.3 microM) and metoclopramide (1 microM). Tropisetron (1 microM) and ondansetron (0.3 microM) also inhibited significantly the quipazine effect whereas methiothepin (1 microM), dihydroergotamine (0.1 microM), yohimbine (1 microM) and ketanserin (1 microM) were ineffective on the quipazine inhibition of [3H]GABA release. Our results show a serotonergic modulatory effect on the K(+)-evoked [3H]GABA release from guinea-pig hippocampal synaptosomes by receptors which are neither 5-HT1, 5-HT2 or 5-HT4. They appear to be pharmacologically related to the 5-HT3 type but different from the 5-HT3 ionic channel receptors.

Animals↗
PubMed1992

Molecular cloning of two partial serotonin 5-HT1D receptor sequences in mouse and one in guinea pig.

The G protein coupled serotonin (5-HT) receptors, with seven membrane spanning domains, form a multigene family of which several members have been cloned and sequenced. The presence of 5-HT1D binding sites to our knowledge has not yet been reported in mouse. Here we describe the cloning and sequencing by the polymerase chain reaction (PCR) method of two 5-HT1D receptor sequences of the third cytoplasmic loop in mouse, strongly suggesting the existence of two 5-HT1D receptor genes, located on chromosome 4. A homologous sequence to one of them was cloned in guinea pig.

Animals↗
PubMed1991

Receptors for interleukin-1 (alpha and beta) in mouse brain: mapping and neuronal localization in hippocampus.

Interleukin-I receptors were mapped and characterized in mouse brain by quantitative autoradiography using human recombinant [125I]interleukin-I alpha and [125I]interleukin-1 beta as ligands. Both ligands provide identical receptor mapping. In terms of specificity, interleukin-1 alpha and interleukin-1 beta were equally potent in binding competitions assays with either [125I]interleukin-1 alpha or [125I]interleukin-1 beta (EC50 11 pM). These receptors were shown to be highly concentrated in the dentate gyrus, in the choroid plexus at various levels of the brain, in the pituitary and in the meninges. They were also present at low concentrations in the cortex but undetectable in other brain structures. In the dentate gyrus, interleukin-1 receptors were localized on the granular and molecular layers (granule cells) when visualized on slides dipped in nuclear emulsion. Cellular localization of interleukin-1 receptors was assessed using selective lesion by colchicine. The complete loss of [125I]interleukin-1 binding in hippocampal areas where neurons were destroyed by colchicine demonstrates that interleukin-1 receptors are located on granule cells. Following lesion, sparse undestroyed cells, with glial cell morphology, also showed significant labelling. In conclusion, interleukin-1 receptors are located on the granule cells in the mouse dentate gyrus. These neurons may therefore be targets for neuromodulation by interleukin-1 and they may play a key role in the central effect of interleukin-1 as well as in the control of the immune response by the brain.

Animals↗
PubMed1991

Antagonism by antidepressant drugs of the inhibitory effect of trifluoromethylphenylpiperazine (TFMPP) on [3H]acetylcholine release in rat or guinea-pig hippocampal synaptosomes.

The effects of antidepressant drugs on the m-trifluoromethylphenylpiperazine (TFMPP)-induced inhibition of K(+)-evoked [3H]acetylcholine (3H-ACh) release were studied in rat or guinea-pig hippocampal synaptosomes. The serotonergic agonist TFMPP dose-dependently inhibited the K(+)-evoked release of 3H-ACh in rat hippocampus (IC50 = 53 microM). Chlorimipramine (5-500 nM), a typical tricyclic antidepressant, and minaprine (1-100 nM), an atypical antidepressant drug, partially antagonized the effect of TFMPP on 3H-ACh release in a dose-dependent manner. Other antidepressants (imipramine, citalopram, indalpine, fluoxetine, fluvoxamine, oxaprotiline, mianserine, nomifensine), at concentrations ranging from 10 to 500 nM, produced similar effects. Drugs with no antidepressant effect, such as chlorpromazine, clobazam, and cocaine (50, 100 and 500 nM), were without significant influence on the TFMPP effect. In guinea-pig hippocampal synaptosomes, minaprine (50 nM) also reduced the TFMPP-induced inhibition of 3H-ACh release, whilst clobazam (50 nM) was inactive. These results suggest that antidepressant drugs interact in vitro with heterologous serotonergic presynaptic receptors on cholinergic nerve terminals in rat and guinea-pig hippocampus.

Acetylcholine↗
PubMed1991

The inhibitory effect of trifluoromethylphenylpiperazine on [3H]acetylcholine release in guinea pig hippocampal synaptosomes is mediated by a 5-hydroxytryptamine1 receptor distinct from 1A, 1B, and 1C subtypes.

The effect of the serotonergic receptor agonist 1-(m-trifluoromethylphenyl)piperazine (TFMPP) was studied on the K(+)-evoked [3H]acetylcholine [( 3H]ACh) release from guinea pig hippocampal synaptosomes loaded with [3H]choline. TFMPP (5-1,000 microM) inhibited the evoked ACh release in a dose-dependent manner (IC50 = 81.8 microM). The inhibitory effect of TFMPP was mimicked by CGS-12066B (10, 30, and 100 microM), a 5-hydroxytryptamine1B (5-HT1B)/5-HT1D receptor agonist; 1-(m-chlorophenyl)piperazine (100 microM), a 5-HT1C/5-HT1B receptor agonist; and 5-carboxamidotryptamine (10 microM), a nonselective 5-HT1 receptor agonist. 8-Hydroxy-2-(di-n-propylamino)tetralin (10 and 100 microM), a 5-HT1A receptor agonist, and quipazine (10 and 100 microM), a 5-HT2 receptor agonist, did not have any significant effect. Serotonergic antagonists, such as dihydroergotamine (0.1 and 1 microM), metergoline (0.1 microM), methysergide (0.5 and 1 microM), or yohimbine (1 and 10 microM), blocked the TFMPP effect dose-dependently. In contrast, methiotepine (0.3 and 1 microM), propranolol (1 microM), ketanserin (0.1 microM), mesulergine (0.1 microM), ICS 205930 (0.1 and 1 microM), and spiroperidol (1 and 7 microM) did not affect the TFMPP-induced inhibition of the evoked ACh release. These data suggest that, in guinea pig hippocampus, the K(+)-evoked ACh release is modulated by a 5-HT1 receptor distinct from the 5-HT1A, 5-HT1B, and 5-HT1C subtypes.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1990

GnRH receptors in rat brain, pituitary and testis; modulation following surgical and gonadotropin-releasing hormone agonist-induced castration.

The regulation of rat gonadotropin-releasing hormone (GnRH) receptors in male rat pituitary, hippocampus and testis was studied, in vivo, under steady-state conditions during treatment with D-Trp6 GnRH (triptorelin, slow-release form, at 300 micrograms/kg/month). GnRH receptors were characterized on tissue sections by quantitative autoradiography using 125I-GnRHa as a tracer. Castrating doses of triptorelin strongly down-regulated pituitary GnRH receptors (50% of reduction after 8 h, 80% on days 1-30); in contrast, only a transient decrease (20% at 8 h) was observed in the hippocampus with a rapid return to control levels. Triptorelin induced a marked (2-fold) increase in GnRH receptors in testicular interstitial tissue during 5 days with a return to control value by day 20. Administration of a GnRH antagonist (BIM 21009, 1 mg/kg/24 h) induced a rapid reduction of pituitary and testicular receptors to undetectable levels at 24 h, while hippocampal receptors were strongly reduced only. This indicates that GnRH receptors with similar pharmacology are differently controlled in various tissues and that brain receptors are likely to be also regulated by GnRH agonists and antagonists.

Animals↗
PubMed1989

Minaprine antagonises the serotonergic inhibitory effect of trifluoromethylphenylpiperazine (TFMPP) on acetylcholine release.

The serotonin agonist, m-trifluoromethylphenylpiperazine (TFMPP), inhibited the K+-evoked release of [3H]acetylcholine ([3H]ACh) from rat hippocampal synaptosomes. The inhibitory effect of TFMPP was blocked by the non-selective 5-HT1 antagonist, methiothepin, but was not affected by ketanserin, mesulergine or spiperone. The 5-HT3 antagonist, MDL 72222, slightly reversed the inhibitory effect. The antidepressant, minaprine, did not modify the basal release of [3H]ACh but it antagonised the inhibitory effect of TFMPP on the K+-evoked release. The maximal reversal was found at 0.3 microM minaprine. These results suggest that minaprine interacts with heterologous presynaptic 5-HT1B receptors. A new approach is thus opened to the study of the mechanism of action of antidepressant drugs.

Acetylcholine↗
PubMed1989

The effects of inorganic lead on the spontaneous and potassium-evoked release of 3H-5-HT from rat cortical synaptosome interaction with calcium.

Interaction of lead with the serotonergic system has been studied in vitro in rat brain synaptosomal fraction prepared from cortical tissue. Synaptosomes were loaded with 3H-5-HT and spontaneous and K+-evoked release of the amine was examined in the presence and the absence of calcium. It was shown that lead itself induced the release of 3H-5-HT (EC50 = 27 microM). This effect decreased (40%) in the presence of calcium without modification of the EC50. Moreover, lead markedly inhibited the K+-evoked release of 3H-5-HT observed in the presence of calcium. This effect was obtained either in the presence of lead or using synaptosomes pretreated with lead and washed. These results indicate that lead interferes with neuronal 5-HT release by mechanism(s) involving calcium.

Animals↗
PubMed1989

In vitro effect of organic and inorganic mercury on the serotonergic system.

Interactions of organic (methyl mercury) and mineral (acetate, chloride, nitrate: Hg2+) mercury salts with the serotonergic systems were studied in vitro using synaptosomal fractions prepared from rat brain cortex preloaded with [3H]5-HT. In the absence of calcium, mercury salts induced a spontaneous release of the amine corresponding to a total depletion of the synaptosomal content. EC50 for the organic and mineral forms of the ion were 66 +/- 2 microM and 107 +/- 16 microM respectively. In the presence of calcium (2.4 mM) a similar pattern of release was observed except that an additional release was induced by mineral mercury at low concentration (EC50 = 8.4 +/- 1.3 microM) which corresponded to a maximal release of 18.6 +/- 3.5% of the synaptosomal content. Therefore, the latter release appears calcium-dependent. Parallelly, the effects of mercury salts have been examined on the binding of [3H]5-HT to its high affinity 5-HT1 sites; organic and mineral mercury inhibited the binding with IC50 of 27.8 +/- 3.2 microM respectively. These results show that mercury ions interact with the serotonergic system by different mechanisms depending on their concentrations and their ionic forms.

Animals↗
PubMed1988

Postnatal development of 5-HT1 receptors: [3H]5-HT binding sites and 5-HT induced adenylate cyclase activations in rat brain cortex.

The postnatal development of the 5-HT1 receptor system was studied in young rat brain cortex from birth to adulthood (14 successive ages). The high-affinity binding of [3H]5-HT was low at birth but developed markedly between the 8th and the 15th day postnatally. The basal adenylate cyclase activity produced 50 pmoles cAMP/mg protein/min at birth and increased from the 8th to the 15th day. 5-HT could stimulate the adenylate cyclase activity in adult rat brain cortex with two different affinity constants: Km = 1 nM and Km = 0.5 microM; these low- and high-affinity constants presumably correspond to 5-HT1A and 5-HT1non-A.non-B.non-C (5-HT1D) respectively. These two activities developed parallelly from the 14-15th to the 28th day. The 8-hydroxy-2-(di-n-propylamino-tetralin) (8-OH-DPAT)-induced activity described a curve similar to the one that corresponded to 10 microM 5-HT. These results establish that 5-HT1A and 5-HT1non-A.non-B.non-C receptors mainly develop during the synaptogenesis.

Adenylyl Cyclases↗
PubMed1988

5-Hydroxytryptamine stimulates two distinct adenylate cyclase activities in rat brain: high-affinity activation is related to a 5-HT1 subtype different from 5-HT1A, 5-HT1B, and 5-HT1C.

5-HT binding sites of the 5-HT1 type are heterogeneous and appear to comprise several subtypes (5-HT1A, 5-HT1B and 5-HT1C); their physiological role is as yet unclear. The stimulation of adenylate cyclase induced by 5-HT has been investigated in membrane fractions prepared from rat brain cortex. Enzymatic activity was determined by measuring cAMP production with an HPLC technique. It was shown that 5-HT stimulates adenylate cyclase activity with 2 activation constants (Kact): one shows a high apparent affinity (Kact = 0.8 nM) and the other a lower apparent affinity (Kact = 0.30 microM). The latter activity, induced by micromolar concentrations of 5-HT, was inhibited by spiperone at concentrations that block 5-HT1A binding. 5-Methoxytryptamine, bufotenin, and LSD also had a stimulatory biphasic effect on adenylate cyclase activity, whereas trifluoromethylphenylpiperazine, 5-carboxyamidotryptamine, 8-hydroxy-(2-di-n-propylamino)tetralin, RU 24969 had a monophasic effect. Enzyme activation by drugs acting in the micromolar range was inhibited by spiperone (1 microM), suggesting a link between this activation and 5-HT1A sites. On the other hand, the high-affinity activation of the enzyme induced by 5-HT, 5-methoxytryptamine, bufotenin, LSD, and the activation induced by TFMPP were not inhibited by spiperone (1 microM), by propranolol (3 microM), or by mesulergine (0.1 microM), which selectively block 5-HT1A, 5-HT1B, and 5-HT1C sites. Inhibition was produced by dihydroergotamine, methysergide, cinanserin, and mianserin, but not by naloxone, phenoxybenzamine, and phentolamine. Therefore, these activations seem related to 5-HT1 receptors but not to 5-HT1A, 5-HT1B, or 5-HT1C sites. Accordingly, binding of [3H]5-HT to 5-HT1-like sites was examined in the presence of spiperone (1 microM) and propranolol (3 microM); in these conditions, a high-affinity site (KD = 3.4 nM) was indeed revealed. The relative potencies of a series of drugs that stimulate or inhibit the activation of the adenylate cyclase with a high affinity and their ability to inhibit this binding of [3H]5-HT showed a positive correlation, strongly suggesting a direct relation between this recognition site for 5-HT and the production of a second messenger (cAMP). Moreover, this potential receptor is shown to be heterogeneously distributed within the brain, and was localized postsynaptically at serotonergic synapses.

Adenylyl Cyclases↗
PubMed1988

Characterization and distribution of receptors for gonadotropin-releasing hormone in the rat hippocampus.

Distribution and properties of receptors for gonadotropin-releasing hormone (GnRH) were analyzed in the brain of adult male rats. Binding of the iodinated GnRH agonist Des-Gly10-(D-Ala6)-GnRH ethylamide was studied in hippocampus and anterior pituitary using three convergent approaches: quantitative autoradiography on frozen tissue, binding to fresh slices, and binding to crude membrane preparations. In all cases, binding was specific, saturable, and time, pH, and temperature dependent. Quantitative autoradiography revealed that the density of binding sites was high in the stratum oriens and stratum radiatum of the CA1-CA4 regions of Ammon's horn. The pyramidal cell layer was faintly labelled. Binding was almost undetectable in the dentate gyrus. The highest density of sites (Bmax = 11.6 +/- 1.0 fmol/mg protein) was observed in the stratum radiatum of the CA3 region. Under the same conditions the value obtained for pituitary tissues was 20.7 +/- 2.8 fmol/mg protein. Analysis of saturation curves indicated only one class of high-affinity sites for the hippocampus (CA3; Kd = 0.28 +/- 0.03 nM) and for the pituitary (Kd = 0.29 +/- 0.08 nM). Both native GnRH and GnRH antagonist were potent competitors of binding. Fresh slices and membrane preparations from whole hippocampus confirmed these autoradiographic data and yielded affinity constants of 0.28 +/- 0.01 and 0.52 +/- 0.08 nM, respectively. In addition, a very high binding density was present in the amygdaloid complex, while binding was barely detectable in the hypothalamus. These results demonstrate that high densities of specific GnRH receptors are present in areas concerned with the regulation of behavioral functions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Chronic beta-adrenergic stimulation increases in mice the sensitivity to methysergide and the number of cerebral high affinity serotonin binding sites (5-HT-1).

Reserpine administration in mice causes, among other effects an akinesia which can be reversed by the serotonin agonist-antagonist methysergide. The effect of methysergide is potentiated by clenbuterol, a beta-adrenergic agonist, which itself causes hypomotility. Potentiation is weak after a single injection of clenbuterol, but becomes much stronger after repeated administration for 12 days. This treatment also causes a 50% increase in the number of high affinity 5-HT-1 binding sites in the brain. This increase would explain the increased potency of methysergide against reserpine-induced akinesia. These results show that: a beta-adrenergic drug, clenbuterol modulates the serotoninergic system; this modulation takes its importance after chronic treatment only; this interrelation may be important in depressive illness since it is observed on a test used in the screening of antidepressant drugs.

Animals↗