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T Mennini

Publications and source records attributed to T Mennini.

At least 145 records · Page 8Linked to original sources
PubMed1987

Tianeptine, a selective enhancer of serotonin uptake in rat brain.

Tianeptine is a tricyclic agent provided with antidepressant activity in experimental models and in clinical trials. In vitro tianeptine and its two principal metabolites have no effects on monoamine uptake, release or neurotransmitter receptor binding. The biochemical effect of tianeptine in vivo after acute or repeated treatment indicates an enhanced serotonin uptake in cortex and hippocampus but not in mesencephalon, with no effect on noradrenaline or dopamine uptake. This enhanced serotonin uptake is not due to decrease in serotonin release, but is related to increase in the Vmax of the uptake carrier for serotonin. The fact that enhancers as well as inhibitors of serotonin uptake are provided with antidepressant activity challenge simple conclusion as to their mechanism of action. The possibility that increased serotonin uptake after repeated treatment may be related to the antidepressant activity exerted by these drugs, and drugs enhancing serotonin uptake might have antidepressant activity, with an earlier onset, is proposed.

Animals↗
PubMed1987

From fenfluramine racemate to d-fenfluramine. Specificity and potency of the effects on the serotoninergic system and food intake.

Experiments using the binding of various ligands for monoamines to rat brain membranes and synaptosomal preparations for studying monoamine uptake and release have shown that d-fenfluramine is more potent than the l isomer in inhibiting 5-HT uptake, whereas d-norfenfluramine preferentially releases 5-HT from a reserpine-insensitive compartment. Studies on brain monoamine metabolism in intact animals have shown that the d and l isomers of fenfluramine at relatively low doses have a specific action on brain 5-HT and catecholamines, respectively. Based on the different ability of metergoline and ritanserin to displace 5-HT2 binding to rat brain membranes and to antagonize d-fenfluramine's anorexia, evidence has been provided that d-fenfluramine preferentially uses 5-HT1 sites in the rat brain to cause anorexia in this animal species. Finally, characteristics, regional distribution, and pharmacological characterization of a high-affinity [3H]d-fenfluramine binding to rat brain membranes have been described. This binding appears to be different from 5-HT uptake sites ([3H]imipramine binding) and 5-HT receptors and is not regionally related to the endogenous levels of 5-HT in the rat brain. It is, however, preferentially displaced by some agents using 5-HT to cause anorexia in rats, raising the possibility that it is somewhat related to 5-HT mechanisms involved in feeding control.

Amines↗
PubMed1987

Diazepam and desmethyldiazepam differ in their affinities and efficacies at 'central' and 'peripheral' benzodiazepine receptors.

The in-vitro binding characteristics of three different ligands ([ 3H]Ro 15-1788, [3H]Ro 5-4864 and [3H]flunitrazepam) and the structural requirements for binding to 'central' and 'peripheral' benzodiazepine receptors have been evaluated in rat cerebral cortex, cerebellum and adrenal glands. [3H]Ro 15-1788 binding was detectable only in the brain. Clonazepam was the most potent inhibitor followed by diazepam and desmethyldiazepam, which showed the same affinity, and by premazepam; Ro 5-4864 did not show appreciable affinity. The same pattern was seen for [3H] flunitrazepam binding in brain areas while in adrenal gland the inhibition pattern was exactly superimposable on that with [3H]Ro 5-4864 in all the areas considered (Ro 5-4864 greater than diazepam greater than desmethyldiazepam greater than clonazepam greater than premazepam). These data confirm and extend previous reports. A methyl group in position 1 enhances the affinity for peripheral benzodiazepine binding sites which are labelled in the adrenal gland by [3H]Ro 5-4864 and [3H]flunitrazepam; in brain areas, [3H]flunitrazepam, like [3H]Ro 15-1788, selectively labels central binding sites. Methylation in position 1 did not change the affinity for these sites. Desmethyldiazepam is less active than diazepam as an anticonvulsant and in other tests. In-vivo experiments were therefore carried out to assess the 'intrinsic activity' of desmethyldiazepam: it appeared that this compound acts as a partial agonist at central benzodiazepine receptors.

Adrenal Glands↗
PubMed1986

Evidence of the involvement of dopamine in the analgesic effect of nefopam.

The involvement of brain monoamines in the mechanism of action of nefopam, a new analgesic, was investigated in rats. The study was designed to evaluate the effect of various means of impairing monoaminergic transmission on nefopam analgesia as measured with the hot plate method. Pretreatment with reserpine (2 mg/kg) significantly reduced the antinociceptive action of nefopam (40 mg/kg), indicating that the interaction of this drug with the monoaminergic systems is important for its effects. A role for serotonin (5-HT) or norepinephrine (NE) was ruled out by the fact that selective depletion of 5-HT (using 5,7-dihydroxytryptamine) or NE (using DSP-4 or FLA-63) did not affect nefopam analgesia. A significant reduction of the effect of nefopam was found in rats pretreated with 6-hydroxydopamine (6-OHDA). Also 6-OHDA plus desipramine, which selectively depleted brain DA, markedly reduced the antinociceptive effect of nefopam. The data strongly suggest that a critical dopaminergic synapse is involved in the mechanism by which nefopam inhibits nociceptive responses in rats.

5,7-Dihydroxytryptamine↗
PubMed1986

Localization of GABAA and GABAB receptor subtypes on serotonergic neurons.

The effect of selective destruction of serotonin (5-HT)-containing neurons with 5,7-dihydroxytryptamine (5,7-DHT) on [3H] muscimol and (-)-[3H]baclofen binding was investigated in various rat brain regions. Ten days after intracerebroventricular 5,7-DHT, serotonin levels and [3H]imipramine binding were markedly decreased. 5,7-DHT reduced [3H]muscimol binding only in the mesencephalon, and (-)-[3H]baclofen binding was unmodified in all the areas considered. These results suggest that except in the mesencephalon GABA receptors may not be localized on serotonergic nerve terminals.

5,7-Dihydroxytryptamine↗
PubMed1986

Neurochemical mechanism of action of drugs which modify feeding via the serotoninergic system.

The neurochemical mechanisms by which drugs acting on central serotoninergic system modify feeding were reviewed. Fenfluramine, a clinically effective appetite suppressant, releases serotonin from nerve terminals and inhibits its reuptake, and considerable evidence suggests that these effects mediate its anorectic activity. The D isomer of fenfluramine is particularly specific in affecting serotonin mechanisms and causing anorexia. Transmitters other than serotonin such as acetylcholine, catecholamines and GABA are also affected by systemic administration of fenfluramine, but some of these effects are secondary to fenfluramine's action on serotoninergic mechanisms. Moreover, there is no evidence that these brain substances are involved in fenfluramine's ability to cause anorexia. Several studies with drugs affecting different serotonin mechanisms such as release and uptake or mimicking the action of serotonin at post-synaptic receptors suggest that increase serotonin release and direct stimulation of postsynaptic receptors are the most effective mechanisms for causing depression of food intake, although inhibition of serotonin uptake may also contribute in appropriate conditions. Development of serotonin receptor hyposensitivity and, in some instances, decreased serotonin levels may lead to tolerance to the anorectic activity of drugs enhancing serotonin transmission, the degree of this depending critically on the type of effect on serotonin mechanisms and intensity and duration of serotonin receptor activation. Recent evidence suggests that a decrease in serotonin function causes stimulation of feeding. This may lead to development of new strategies for the treatment of clinical anorexias.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1986

Effect of long term amineptine treatment on pre- and postsynaptic mechanisms in rat brain.

The effect of amineptine and its two metabolites on monoamine uptake, release and receptor binding was studied in vitro. Amineptine and its two metabolites did not displace labelled ligands for known neurotransmitters and drug receptor sites. Amineptine and its two metabolites did not influence [3H]-5-hydroxytryptamine ([3H]-5-HT) uptake or release by rat brain synaptosomes. Amineptine inhibited [3H]-dopamine and [3H]-noradrenaline ([3H]-NA) accumulation, with IC50 values of 1.4 and 10 microM, respectively. The effect was retained, though with lower efficacy, by the two metabolites. Amineptine released [3H]-dopamine from preloaded synaptosomes. Metabolite 1 had no effect on catecholamine release, and metabolite 2 was about half as active as the parent compound on [3H]-dopamine release. The releasing effect of amineptine on [3H]-dopamine was potentiated by reserpine pretreatment, suggesting that the drug acts on the cytoplasmic neurotransmitter pool. Chronic treatment with amineptine (20 mg kg-1, twice daily for 15 days followed by a 3 days drug withdrawal period) resulted in a decrease of [3H]-spiperone binding sites in striatum, and of [3H]-dihyroalprenolol and [3H]-clonidine in cortex. Chronic treatment with amineptine reduced basal [3H]-dopamine accumulation in striatal synaptosomes, without affecting [3H]-NA or [3H]-5-HT accumulation. The adaptive changes in the pre- and postsynaptic dopamine mechanisms observed after long term treatment with amineptine are consistent with the drug acting as an indirect dopamine agonist. The down regulation of beta- and alpha 2-noradrenoceptors observed after long term amineptine treatment may play a role in the antidepressant activity of the drug.

Animals↗
PubMed1986

Allosteric inhibition as a model to explain flatter displacement curves in binding experiments: application to "heterogeneous" serotonin receptors.

Flattened or biphasic inhibition curves are usually interpreted by postulating the presence of two sites which are labelled with the same affinity by the ligand and can be recognized using the appropriate inhibitor with different selective affinities. We found that a priori this type of curve, can be equally fitted by another model, the allosteric model, on account of the mathematical equivalence of the two model functions when the 3H-ligand concentration is kept constant (i.e. inhibition experiments). A new approach consisting of three-dimensional analysis of the experimental data (3H-ligand binding as a function of ligand and inhibitor concentrations, simultaneously) permitted a statistical discrimination between the two models. The examples, used as tool for the present study, are the flattened or biphasic inhibition curves obtained by displacing 3H-serotonin with the neuroleptic spiperone. The results are discussed in relation to the general interpretation of this type of "anomalous" binding data and to the specific field of serotonergic receptor subtypes.

Allosteric Regulation↗
PubMed1986

Neurochemical effects of buspirone in rat hippocampus: evidence for selective activation of 5HT neurons.

The effect of buspirone on neurotransmitter systems in rat hippocampus has been evaluated in vitro and in vivo. In vitro buspirone does not affect the specific binding of 3H-flunitrazepam, 3H-GABA, 3H-dexetimide, but displaces 3H-5HT binding with nanomolar affinity. Oral administration of buspirone does not modify the hippocampal concentrations of GABA, acetylcholine, choline and of 3H-flunitrazepam specifically bound in vivo, but results in a dose-dependent reduction of 5HIAA and noradrenaline concentrations. While the effect on noradrenaline is also obtained in striatum of buspirone-treated animals, the effect on 5HIAA shows a regional specificity. The in vitro and in vivo data suggest that buspirone specifically activates 5HT neurons in hippocampus, and are compared with those obtained with diazepam.

Animals↗
PubMed1985

In vivo stereospecific [3H]spiperone binding in rat brain: characteristics, regional distribution, kinetics and pharmacological properties.

The time course of [3H]spiperone distribution in the three major pools (specifically and non-specifically membrane-bound and soluble) of different brain areas, was studied in rats given a tracer amount of the drug. In addition, the stereospecificity, dissociation kinetics and pharmacological nature of the in vivo bound [3H]spiperone were investigated. The data show that [3H]spiperone binding sites in the striatum, olfactory tubercles and hypophysis differ clearly from those of the cortical regions. In the prevalently dopaminergic areas the amount of ligand bound to membranes is, up to 24 h post-treatment, proportional to the total 3H present. However a more correct analysis of the data was obtained in all the experiments when membrane-bound was measured instead of total radioactivity. Thus assay of the in vivo specifically bound [3H]spiperone appears essential for a correct evaluation of the density, affinity, regional distribution, pharmacological nature and kinetics of the drug-receptor interaction.

Animals↗
PubMed1985

Anorectic effect of fenfluramine isomers and metabolites: relationship between brain levels and in vitro potencies on serotonergic mechanisms.

A study of the possible molecular mechanisms of action by which the isomers and metabolites of fenfluramine increase serotonin transmission, leading to anorectic activity, is presented. The actual brain levels of fenfluramine and norfenfluramine isomers after administration of equi-anorectic doses to rats are compared with their potencies in affecting serotonergic mechanisms in vitro. Isomers and metabolites of fenfluramine can have the same pharmacological action by influencing serotonin uptake, release and binding in a quantitatively different manner.

Animals↗
PubMed1985

In vivo interaction of premazepam with benzodiazepine receptors: relation to its pharmacological effects.

The study of in vivo occupancy of benzodiazepine receptors in rat hippocampus and cerebellum indicates that premazepam reaches only about 70% and 80% occupancy respectively within the dose range used for pharmacological tests in rats. Moreover, at equiactive doses (antileptazol ED50), more brain receptors are occupied by premazepam than by other benzodiazepines, suggesting that premazepam may act as a partial agonist at benzodiazepine receptors, with intrinsic activity lower in cerebellum than in hippocampus. These results may explain the lack of sedative and ataxic properties of premazepam.

Animals↗
PubMed1985

Enhancement of diazepam activities induced by denzimol in mice.

Denzimol, a new anticonvulsant drug, enhances the depressant and antimetrazol activities of diazepam in mice, in a dose and time-dependent fashion. The depressant and anticonvulsant activities of phenobarbital were not affected by Denzimol. It is suggested that Denzimol induces an increase in the number of the benzodiazepine receptors, and that such increase might be responsible for the enhancement of the diazepam's activities.

Animals↗
PubMed1984

Effects of denzimol on benzodiazepine receptors in the CNS: relationship between the enhancement of diazepam activity and benzodiazepine binding sites induced by denzimol in the rat.

Denzimol, a new anticonvulsant drug with a pharmacological profile similar to that of phenytoin, enhances the ataxic and antimetrazol activity of diazepam in rats without affecting its activity against picrotoxin-induced seizures. In vivo and ex vivo denzimol enhances the binding of 3H-flunitrazepam in cortex and in hippocampus but not in cerebellum. The possibility of this increase in the number of benzodiazepine binding sites contributing in some way to enhancement of the depressive and anticonvulsant activity of diazepam is discussed.

Animals↗
PubMed1984

Diazepam increases membrane fluidity of rat hippocampus synaptosomes.

Diazepam in vitro produced a concentration-dependent increase of membrane fluidity in crude synaptic membranes from rat hippocampus, but not cerebellum. Similar effects were obtained with higher concentrations of Ro 15-1788 and PK 11195, while zopiclone was completely inactive. In vivo acute treatment with diazepam and Ro 15-1788 gave results similar to those in vitro. The specific benzodiazepine antagonist also significantly increased membrane fluidity and was not able to reverse diazepam's effect. The data are discussed in terms of a possible role of protein kinase inhibition by the drugs not mediated by the 'central' or 'peripheral' type of benzodiazepine receptors.

Animals↗
PubMed1984

In vitro interaction of premazepam with benzodiazepine receptors in rat brain regions.

Premazepam (PRZ) in vitro competitively displaced 3H-diazepam (DIA), 3H-flunitrazepam (FLU) and 3H-RO 15-1788 from their binding sites on rat brain synaptosomes, with a potency intermediate to other benzodiazepines (BDZs), and Hill coefficients near 1 in different brain regions. Incubation at 37 degrees C reduced premazepam's affinity for BDZ receptors to a lower extent than other benzodiazepines and had no effect on the Hill coefficient. The IC50 of PRZ on 3H-RO 15-1788 and 3H-FLU binding was markedly reduced by GABA in rat cortex, like those of reference classical BDZs, but was GABA-independent in the cerebellum. The IC50 of the BDZ antagonist, RO 15-1788 was unaffected by GABA in both brain areas. The possibility that PRZ behaves as a partial agonist in the cortex and as an antagonist in the cerebellum is discussed.

Animals↗
PubMed1984

Increased number of brain benzodiazepine receptors after in-vivo administration of estazolam to rats.

Estazolam significantly increased the Kd of [3H]flunitrazepam in-vitro, like other benzodiazepines (BDZs) acting competitively at the receptor site. At variance with other BDZs, estazolam significantly raised the Bmax for [3H]flunitrazepam, at concentrations lower than its Ki for BDZ receptors. This effect may be responsible for the observed increase in [3H]diazepam binding after in-vivo administration of estazolam to rats.

Animals↗