Search PubMed⌕ Search

Biomedical subjects

T Mennini

Publications and source records attributed to T Mennini.

At least 127 records · Page 7Linked to original sources
PubMed1990

Quantitative autoradiographical analysis of the age-related modulation of central dopamine D1 and D2 receptors.

Quantitative autoradiography of [3H]SCH 23390 and [3H](-)-sulpiride binding was performed in the brain of rats of various ages (3, 11 and 24 months) in order to study the changes in D1 and D2 receptor density with age. Binding of [3H]SCH 23390 in the caudate-putamen decreased progressively and markedly at rostral levels in 11- and 24- compared with 3-month-old rats (max. decrease -63%) while at caudal levels significant decrease was observed only in 24-month-old rats. [3H](-)-Sulpiride binding progressively decreased during aging in the caudate-putamen at rostral levels and the decrease was more pronounced laterally (-70% at 24 months), while at caudal levels no significant decrease was observed. D1 and D2 binding sites also decreased in the nucleus accumbens and olfactory tubercle of aged rats, while in the substantia nigra only the D1 receptors appeared to be modified with aging. No change was found in the entopeduncular nucleus, amygdala, frontoparietal, suprarinal-prefrontal and anterior cingulate cortex. The results indicate that the age-associated decrease of D1 and D2 receptors is not widespread, being confined to dopaminergic areas with high density of dopamine receptors.

Aging↗
PubMed1990

In-vivo radiolabelled oxiracetam binding to rat brain.

The in-vivo binding of [3H]oxiracetam has been studied in brain areas of rats examined 30 min after i.c.v. injection. Soluble radioactivity accounted for more than 90% of total radioactivity in all the structures considered and was not affected by co-injection with a 1000-fold excess of unlabelled oxiracetam. Both total and bound radioactivity showed a marked regional distribution, with highest concentrations in the septum, followed by the hippocampus; the cerebral cortex, striatum and cerebellum had the lower concentrations of radioactivity. Computer-assisted quantitative autoradiography with [14C]oxiracetam confirms these findings. Analysis of [3H]oxiracetam bound to membranes indicated that, after co-injection with a 1000-fold excess of unlabelled oxiracetam, there was a significant reduction of binding only in the septum, hippocampus and cerebral cortex. These results suggest that in those cerebral structures oxiracetam binds to saturable sites.

Animals↗
PubMed1990

Functional implications of decreased renal cortical atrial natriuretic peptide binding in experimental diabetes.

Glomerular hyperfiltration in streptozotocin-induced diabetes mellitus in rats may be mediated by atrial natriuretic peptide (ANP). We wanted to evaluate plasma levels of ANP and plasma volume in relation to renal ANP receptor density and affinity in rats 6 weeks after induction of diabetes. Plasma levels of immunoreactive ANP were significantly higher in hyperglycemic diabetic (75.2 +/- 8.3 pg/ml) than in control animals (34.7 +/- 8.1 pg/ml; p less than 0.01). Administration of insulin to keep diabetic rats normoglycemic normalized plasma levels of immunoreactive ANP (30.5 +/- 5.2 pg/ml). In contrast, plasma volume did not show significant differences among the groups (hyperglycemic diabetes, 46.6 +/- 3.8; normoglycemic diabetes, 42.4 +/- 3.2; controls, 43.2 +/- 2.0 ml/kg body wt). No correlation was found between plasma levels of immunoreactive ANP and plasma volume. By autoradiography a significant reduction in the number of renal cortical ANP receptors was observed in hyperglycemic diabetic rats as compared with controls. At variance, ANP receptor affinity did not change either in the cortex or in the medulla in hyperglycemic diabetics in comparison with control animals. The pathophysiological implication of cortical ANP receptor down-regulation was underscored by the blunted response of glomerular filtration rate to ANP infusion in diabetic animals as compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Deprivation of growth hormone-releasing hormone early in the rat's neonatal life permanently affects somatotropic function.

This work investigated in rats whether passive immunization against the endogenous GHRF in the early postnatal period led to permanent alterations of somatotropic function, similar to those observed in several human growth disorders, e.g. constitutional growth delay (CGD). On postnatal days 1, 2, 4, 6, 8, and 10, rats were given an anti-GHRF-serum (GHRH-Ab, 100 microliters/rat, sc) and were tested 1, 30, and 60 days after this treatment for basal and GHRH-stimulated GH secretion both in vivo and in vitro. GHRH-Ab reduced both basal and GHRF-stimulated GH secretion at all intervals and induced marked and chronic impairment of growth rate. The following differences were observed in the GHRH-Ab treated rats compared to normal rabbit serum-treated controls: 1) GH biosynthesis (incorporation of L-[3H]leucine into the electrophoretic band of GH): reduction of about 70%, 1 day but not 30 days after treatment; 2) Pituitary weight: significant reduction in absolute weight (30-40%) at all posttreatment intervals, and relative weight, 1 and 30 days after treatment. 3) Pituitary GH concentration: significant reduction in GH content (about 40%) but not concentration, at all posttreatment intervals; 4) Percentage of somatotrophs (immunocytochemistry): about 40% reduction 1 day, but not 30 and 60 days after treatment; 5) Hypothalamic somatostatin messenger RNA (mRNA) levels in situ hybridization): selective reduction (40%) in the periventricular nucleus 1 day but not 30 days after treatment; 6) Hypothalamic somatostatin cell number (immunocytochemistry): no significant changes in any hypothalamic area at any interval; 7) Pituitary somatostatin binding (in situ autoradiography): significant reduction, 1 day and 30 days after treatment; 8) Somatostatin inhibition of GH release "in vitro": somatostatin effect on GH release was reduced 30 days after treatment. These and previous data indicate that: 1) Transient deprivation of GHRF in the immediate postnatal period of the rat leads to permanent impairment of growth rate and somatotropic function; 2) GHRF deficiency itself or through reduction of GH secretion impairs somatostatin functions temporarily in the hypothalamus and permanently in the pituitary; 3) This rat model may mimic some forms of growth disorders in humans and holds promise as useful tools for investigating the underlying pathophysiological mechanisms.

Animals↗
PubMed1989

Evidence that central 5-HT2 receptors do not play an important role in the anorectic activity of D-fenfluramine in the rat.

To gain information on the role of central 5-HT2 receptors in the reduction of food intake caused by D-fenfluramine in rats, different intraperitoneal doses of metergoline, a non-selective 5-HT receptor antagonist and ritanserin, a selective 5-HT2 receptor antagonist, were compared for their ability (a) to antagonize the anorectic effect of D-fenfluramine; (b) to occupy central 5-HT2 receptors in vivo (measured by the binding of [3H]spiperone in the frontal cortex) and (c) to affect the concentrations of D-fenfluramine and its active metabolite, D-norfenfluramine in brain. Metergoline dose-dependently reduced the effect of D-fenfluramine (2.5 mg/kg i.p.) on food intake, with complete antagonism at 1 mg/kg, a dose which occupies about 50% of cortical 5-HT2 receptors. Ritanserin, at a dose (0.5 mg/kg) causing 50% occupation of 5-HT2 receptors, had no effect on anorexia induced by D-fenfluramine and only partially prevented it at doses which caused maximum occupation of 5-HT2 receptors (1-2 mg/kg). Unlike 1 mg/kg metergoline, 1 mg/kg ritanserin significantly reduced the concentrations of D-norfenfluramine in the frontal cortex and hypothalamus of rats 30 min after injection of D-fenfluramine. The results suggest that 5-HT receptors, other than 5-HT2, possibly 5-HT1B, are involved in the anorectic effect of D-fenfluramine in food-deprived rats.

Animals↗
PubMed1989

Profile of in vitro binding affinities of neuroleptics at different rat brain receptors: cluster analysis comparison with pharmacological and clinical profiles.

A series of 21 neuroleptics with different chemical structures (phenothiazines, thioxanthenes, dibenzodiazepines, butyrophenones, benzamides, etc.) was examined for their in vitro interactions with 12 neurotransmitter binding sites in the rat brain (alpha- and beta-noradrenergic, dopaminergic, muscarinic, serotoninergic, histaminic, and opioid receptors, calcium channels, and serotonin uptake binding sites). The biochemical profile obtained from the binding data was compared with reported pharmacological and clinical profiles for this class of compounds by cluster analysis. Cluster analysis on binding data classified the compounds in three main subgroups: benzamides, compounds with an affinity mainly for DA2 and 5-HT2 receptors and inactive at muscarinic receptors, and compounds with a high affinity for alpha 1-adrenergic receptors and muscarinic receptors. The main subgroups resulting from cluster analysis of previously published pharmacological and clinical data for neuroleptics contain compounds common to the present study, with some correlations. The results extend previous observations that a complete binding profile corresponds to the pharmacological and clinical profile of this class of compounds.

Animals↗
PubMed1989

Effects of aspartame and carbohydrate administration on human and rat plasma large neutral amino acid levels and rat brain amino acid and monoamine levels.

Thirty fasted human volunteers were given 0.83 and 8.3 mg aspartame/kg body weight alone, as part of a basal low carbohydrate meal (648 kcal, 10% carbohydrate) or as part of a high energy carbohydrate-rich meal (1290 kcal, 34% carbohydrate). Amino acid concentrations in plasma were determined before and 30, 60 and 180 min after the consumption of aspartame. Under these conditions, which mimic realistic aspartame consumption, aspartame had no significant effect on plasma concentration of any amino acid. In addition, the effect of aspartame alone or with carbohydrates on plasma and brain amino acid levels was studied in rats after acute or subacute (14 d) oral treatment. In subacute dosing experiments aspartame was included in the diet. Brain monoamine concentrations were also measured in the same animals. Plasma concentrations of large neutral amino acids were modified under acute conditions. In contrast, after subacute treatment no significant differences in plasma or brain amino acid concentrations or in brain monoamine concentrations were observed.

Amino Acids↗
PubMed1989

Pharmacology of amineptine: synthesis and updating.

Amineptine is a tricyclic antidepressant agent with the unique capacity to decrease selectively the uptake of dopamine (DA) without affecting the uptake of noradrenaline (NA) and serotonin (5HT). The effect is obtained both in vitro and in vivo by the use of suitable methodology. Amineptine can be differentiated from amphetamine both on the basis of pharmacological as well as biochemical parameters. In vivo, amineptine increases striatal homovanillic acid without affecting the levels of other metabolites of DA, namely, 3, 4, dihydrozoxyphenylacetic acid (DOPAC) and 3-methoxytyramine (3MT). However, by using relatively high doses of amineptine, the extracellular DOPAC level--assessed by the use of pulse voltammetry--was decreased preferentially in the nucleus accumbens but not in the striatum. Chronic treatment with amineptine, as with other antidepressant agents, induces a down-regulation of beta-adrenergic receptors. Amineptine enters the brain and its pharmacological effects are likely due to the unchanged drug rather than to its two main metabolites.

Animals↗
PubMed1989

In-vivo (+)-[3H]fenfluramine binding to rat brain: biochemical and autoradiographic studies.

The in-vivo binding of (+)-[3H]fenfluramine to rat brain regions is saturable, as shown by the inhibition curves obtained by co-injecting increasing concentrations of unlabelled (+)-fenfluramine: at 2.5 mg kg-1 the inhibition of total bound radioactivity was maximal in all regions. The regional distribution of (+)-[3H]fenfluramine specific binding sites (hypothalamus greater than striatum = cortex greater than brainstem greater than hippocampus greater than cerebellum) closely parallels the regional distribution of 5-hydroxytryptamine uptake. Computer-assisted quantitative autoradiography confirms these findings. The IC50 of (+)-fenfluramine for inhibition of its binding in-vivo is below 0.25 mg kg-1, compatible with the presence of high affinity sites. While the physiological role of (+)-[3H]fenfluramine binding sites in the brain, particularly in hypothalamic nuclei, is being investigated, it has been found that in-vivo labelling could also be obtained in the periphery, in lung and renal cortex. The possibility that this peripheral binding is due to the presence of blood platelets cannot be ruled out.

Animals↗
PubMed1989

Reduction of food intake by manipulation of central serotonin. Current experimental results.

Serotonergic anorectics are correctly defined only if they enhance 5-HT transmission and have their anorectic effects inhibited by drugs that block 5-HT receptors. Fenfluramine, the prototype indirect 5-HT agonist, and its metabolite, norfenfluramine, act as 5-HT releasers and uptake inhibitors and are both more effective in the dextro form. They lack the stimulant activity and do not cause hyperthermia or stereotypical behaviour as is characteristic of amphetamines. The anorectic effect of those drugs is attenuated by metergoline, a 5-HT receptor antagonist, in animals and man; 5-HT uptake inhibitors such as fluoxetine, zimelidine, SL 810385, and sertraline also cause anorexia, but only sertraline antagonism by metergoline has been reported. The effect of serotonergic anorectics on 5-HT release has been poorly investigated. Quipazine and RU-24969 cause anorexia by acting directly on 5-HT post-synaptic receptors. Serotonergic nerve terminals take up [3H]-D-fenfluramine and bind with high affinity in rat brain; uptake, an active process, appears to occur at a different site than binding, which is not affected by ouabain or low temperature. Anorexia is probably induced by interaction with 5-HT1B receptors in the rat; the human equivalent of this receptor is not known, but the 5-HT1D type is a likely candidate.

Animals↗
PubMed1988

Different components of 3H-imipramine binding in rat brain membranes: relation to serotonin uptake sites.

In the present paper we confirm and extend previous studies showing heterogeneous 3H-imipramine (3H-IMI) binding sites. Inhibition curves of various drugs (serotonin, imipramine, desmethyl-imipramine, d-fenfluramine, d-norfenfluramine and indalpine, a potent serotonin uptake inhibitor) obtained using 2 nM 3H-IMI and in presence of 120 mM NaCl, confirmed the presence of at least three 3H-IMI binding sites: two of these (high and low affinities) were serotonin-insensitive while the third one was selectively inhibited by serotonin and indalpine with nanomolar affinities. Moreover, this last component was found to be selectively modulated by chronic imipramine treatment thus suggesting a closer relation to serotonin uptake mechanism. These data indicate that the use of a more selective inhibitors of the serotonin-sensitive component (like indalpine or serotonin itself) to define non specific 3H-IMI, may be of help in understanding its relation with serotonin uptake system.

Animals↗
PubMed1988

Nigral dopamine autoreceptors are exclusively of the D2 type: quantitative autoradiography of [125I]iodosulpride and [125I]SCH 23982 in adjacent brain sections.

The effect of unilateral 6-hydroxydopamine lesions of the medial forebrain bundle on the specific binding of [125I]iodosulpride and [125I]SCH 23982 in the rat substantia nigra was determined by quantitative autoradiography of adjacent sections. The specific binding of [125I]iodosulpride was reduced by 40-70% on the lesioned side in the substantia nigra pars compacta, reticulata, lateralis and in the ventral tegmental area. In contrast, the specific [125I]SCH 23982 binding was unchanged in all subdivisions of the substantia nigra. The results indicate that dopamine autoreceptors are present in the substantia nigra and in the ventral tegmental area and that they are exclusively of the D2 type.

Animals↗
PubMed1988

Catecholamine receptor binding in rat kidney: effect of aging.

Binding to several receptors was compared in kidneys from 3- and 24-month-old rats. In crude membrane preparations of aged rat kidneys, the number of beta 2-adrenergic receptors was significantly reduced but the number of total beta-adrenoceptors was unchanged. The high-affinity alpha 1-adrenoceptor component was significantly reduced in old rats, whereas the low-affinity component was unchanged. The number of alpha 2-adrenoceptors showed a non-significant decrease. 3H-spiperone binding sites were similar in young and old rats. For each receptor binding the KD values were the same in young and old animals. The D1 dopamine receptor was significantly reduced in old rats. In our experiments, age-related changes of specific binding sites in the kidney were selective for some receptors studied and did not seem to be due to general aging-induced membrane modifications. Moreover, the renal and central receptors were sensitive to aging differently in the same animal model.

Aging↗
PubMed1988

Biochemical characterization of a new highly cardioselective beta-adrenoceptor antagonist.

P0160 (1-phenyl-3-(2-(3-(2-cyanophenoxy)-2-hydroxypropyl)amino) ethylhydantoin HCl) is an aryloxypropanolamine which contains a ureido group as part of the hydantoin ring. This molecule was synthesized to obtain a more cardioselective beta-adrenoceptor blocker. Preliminary data have shown that it is as potent as propranolol and four times more cardioselective than atenolol in pharmacological tests in-vitro and in the conscious rat. In the present study we evaluated the interaction of P0160 with beta-adrenoceptors by radioreceptor binding studies and by measuring adenylate cyclase activity coupled to beta-adrenoceptors. The data indicate that P0160 binds with nanomolar affinity to beta-adrenoceptors labelled with [3H]DHA in the rat heart, but with micromolar affinity in the rat lung. Its binding is stereospecific, the S-(-)isomer being 200 times more active than the R-(+) form. P0160's selectivity between cardiac beta 1- and beta 2-receptors was 1388, about 60 times that for metoprolol. Analysis of the thermodynamic characteristics of P0160's interaction with rat heart beta-adrenoceptors indicated antagonist properties of the same order of magnitude as propranolol, as confirmed by adenylate cyclase studies. These data indicate that P0160 is a potent, specific and selective beta 1-adrenoceptor antagonist, and give a molecular explanation for the cardioselective activity found in pharmacological tests.

Adenylyl Cyclases↗
PubMed1988

Progress in assessing the role of serotonin in the control of food intake.

There is evidence that serotonin inhibits food intake, particularly intake of carbohydrate and that induced by activation of catecholamine-containing neurons in different brain circuits. An agent that has contributed considerably to the hypothesis of a role of serotonin in feeding is fenfluramine, used as an anorexigenic drug in obese people. Experiments using synaptosomal preparations for studying monoamine uptake and release have shown that d-norfenfluramine preferentially releases serotonin from a reserpine-insensitive compartment. Studies on brain monoamine release and metabolism in intact animals have shown that d and l isomers of fenfluramine at relatively low doses have a specific action on brain serotonin and catecholamines, respectively. Several findings suggest that d-fenfluramine and d-norfenfluramine cause anorexia by increasing the availability of serotonin at postsynaptic receptors. Evidence has recently been provided that d-fenfluramine uses preferentially serotonin1 sites, particularly of the serotonin1B type, in the rat brain to cause anorexia in this animal species. Activation of serotonin1A sites by agents such as 8-OH-DPAT and buspirone instead has been shown to cause overeating. It is suggested that serotonin1B sites in the hypothalamus and serotonin1A sites in the serotonin neurons of the midbrain raphe nuclei mediate these effects. Evidence is provided that [3H]d-fenfluramine binding to rat brain membranes is different from serotonin uptake sites ([3H]imipramine binding) and serotonin receptors. It is, however, displaced by some drugs using serotonin to cause anorexia, raising the possibility that it is somewhat related to serotonin mechanisms involved in feeding control. These studies provide evidence that the serotoninergic system in the brain is a likely target for drugs affecting food intake and suggest new ways to develop novel and potent strategies for the treatment of clinical hyperphagia and anorexia.

Eating↗