Biomedical subjects

T Mennini

Publications and source records attributed to T Mennini.

At least 91 records · Page 5Linked to original sources

PubMed1994

Potential antidepressant properties of SR 57746A, a novel compound with selectivity and high affinity for 5-HT1A receptors.

SR 57746A, 4-(3-trifluoromethylphenyl)-N-[2-(naphth-2-yl)ethyl]-1,2,3,6- tetrahydropyridine HCl, was studied for its specific 5-HT1A receptor agonist action and antidepressant-like effects in the rat. The compound showed a high affinity for 5-HT1A specific binding sites in the rat hippocampus (IC50 3 nM), moderate affinity (10(-7)-10(-6) M) for dopamine D2 receptor, 5-HT uptake, 5-HT2 and alpha 1-adrenoceptor binding sites and practically no effect on binding sites of monoamine, GABAA, benzodiazepine and histamine receptors. It inhibited forskolin-stimulated adenylate cyclase activity in rat hippocampal membranes at concentrations of 10(-6) and 10(-5) M. The effect of 10(-6) M SR 57746A on forskolin-stimulated adenylate cyclase activity was completely antagonized by 10(-6) M (-)-propranolol. Administered per os as a three-dose course to rats, SR 57746A significantly increased struggling in the forced swimming test at doses from 0.3 to 3 mg/kg. Single doses had no such effect. The effect of a three-dose course with 1 mg/kg SR 57746A on rats' struggling was antagonized by pretreatment with 5 mg/kg i.p. metergoline, a non-selective 5-HT receptor antagonist, and by 20 mg/kg i.p. (-)-propranolol, an antagonist at 5-HT1 receptors. Three oral doses of 100 mg/kg parachlorophenylalanine, an inhibitor of 5-HT synthesis, and 100 mg/kg i.p. (+/-)-sulpiride, an antagonist at dopamine D2 receptors, also antagonized the effect of SR 57746A in the forced swimming test. The results show that SR 57746A has selectivity and high affinity for 5-HT1A receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗

PubMed1994

[3H](+)-pentazocine binding to rat brain sigma 1 receptors.

[3H](+)-Pentazocine binding has been characterized in the rat brain. It binds to a single population of binding sites with affinity of about 7 nM and density of 280 fmol/mg protein. [3H](+)-Pentazocine binding is not enriched in the crude synaptic membrane, being about 1/6 of what we found in the crude membrane preparation. The binding, like that for other sigma ligands, was enriched in the microsomal and nuclear fractions. The inhibition by haloperidol, proadifen and d-fenfluramine was the same in the crude synaptic membrane, nuclear and microsomal fractions, suggesting that [3H](+)-pentazocine binds to a homogeneous protein in the different subcellular fractions. Our pharmacological characterization using 45 different drugs suggests that the [3H](+)-pentazocine binding site in rat brain differs from other sigma ligands, like N-propyl-3-(3-hydroxyphenyl)piperidine ([3H](+)-3PPP), N,N'-di(o-tolyl)guanidine ([3H]DTG) and (+)-N-allylnormetazocine ([3H](+)-SKF10,047). [3H](+)-Pentazocine binding in rat brain is inhibited by sigma compounds and some cytochrome P450 ligands, like proadifen and 1-[2-[bis(4-fluoro-phenyl) methoxy]ethyl]-4-[3-phenylpropyl] piperazine (GBR 12909), although with considerably lower potency than reported for other sigma ligands. Other inhibitors are some serotonin uptake blockers or their metabolites and phenylalkylamines.

Animals↗

PubMed1994

Brain uptake and distribution of the potential memory enhancer CL 275,838 and its main metabolites in rats: relationship between brain concentrations and in vitro potencies on neurotransmitter mechanisms.

The kinetics, brain uptake and distribution of CL 275,838, a potential memory enhancer, and its main metabolites (II and IV) were evaluated in rats after intraperitoneal doses of 5, 10 and 20 mg/kg. Brain maximum concentrations (Cmax) of the three compounds after pharmacologically active doses were then related to the in vitro concentrations affecting some monoaminergic and amino acid receptor sites to examine the relative importance of these neurotransmitter systems in the pharmacological actions of CL 275,838. After 10 mg/kg CL 275,838, the unchanged compound rapidly entered the brain and distributed almost uniformly in various regions inside the blood-brain barrier. Its disappearance from brain and plasma was almost parallel with a comparable elimination half-life (t 1/2) of about 2 h. Metabolite II entered the brain and equilibrated with plasma more slowly than the parent compound, achieving mean Cmax (0.2 microM) within 3 h of dosing. Metabolite IV was rapidly detected in rat brain but hardly amounted to 10% (0.1 microM) of the parent compound Cmax (1 microM). There was a linear relationship between dose and plasma and brain concentrations of the three compounds up to 20 mg/kg CL 275,838. At micromolar concentrations the parent compound had affinity for serotonin (5-HT) uptake sites, 5-HT2 and dopamine (DA2) receptors. Only at much higher concentrations than those achieved in vivo after pharmacologically active doses did it increase the binding of 3H-glutamate to NMDA (N-methyl-D-aspartate) receptors. Metabolite II has a similar neurochemical profile.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Solubilization and characterization of d-fenfluramine binding sites from bovine cerebral cortex.

Stable d-Fenfluramine binding activity was obtained in high yields, in cholate extracts of bovine cerebral cortex crude membrane preparations. Dissociation constant (Kd 17 nM), stereoselectivity and the rank order of potencies of various serotonin uptake inhibitors were similar to those measured in native membranes. The inhibitory effect of Na+ ions was also maintained in the soluble state, since the presence of 100 mM Na+ leads to an even greater reduction of the binding than in membrane-associated binding sites. Photoaffinity labeling of soluble binding sites with p-[125I]d-Fenfluramine has led to the identification of a single specific band of molecular weight around 40-50 kDa. This suggests that d-Fenfluramine binding sites are separate molecular entities from the serotonin transporter, that belongs to a family of integral membrane proteins of 68-73 kDa molecular weight.

Affinity Labels↗

PubMed1994

Involvement of P-type Ca2+ channels in the K(+)- and d-fenfluramine-induced [3H]5-HT release from rat hippocampal synaptosomes.

The Ca2(+)-dependent [3H]5-HT release induced by depolarization or by 0.5 microM d-fenfluramine in rat hippocampal synaptosomes, was significantly reduced (35-42%) by three different P-type Ca2+ channels blockers (omega-Agatoxin-IVA, 100 nM, funnel-web spider toxin, FTX, 0.05 microliters/ml, and its synthetic analogue, sFTX, 1 mM), indicating the major role of these channels in the Ca2+ influx preceding neurotransmitter release.

Animals↗

PubMed1994

Does GFAP mRNA and mitochondrial benzodiazepine receptor binding detect serotonergic neuronal degeneration in rat?

Intracerebroventricularly (ICV) injected 5,7-dihydroxytryptamine (5,7-DHT), which reduced by 70-90% forebrain serotonin levels, significantly raised glial fibrillary acidic protein (GFAP) mRNA levels in the hippocampus and nucleus raphe dorsalis 5 days but not 15 days after the lesion. A significant increase of mitochondrial benzodiazepine receptors (MBR), measured by binding autoradiography of 3H-PK 11195, was found in the nucleus raphe dorsalis 5 and 15 days after the ICV 5,7-DHT and also in the hippocampus, ventral tegmental area, and substantia nigra at 15 days. No significant effect was observed in the striatum and cortex for either GFAP mRNA or MBR binding. Unlike the ICV route, bilateral injection of 5,7-DHT into the medial forebrain bundle, which caused a 65-90% reduction of serotonin levels in different forebrain regions, significantly raised GFAP mRNA and MBR binding only at the site of injection with no effect in hippocampus, striatum, and cortex. MBR binding slightly increased in the nucleus raphe dorsalis 15 days after the lesion. High doses of d-fenfluramine (10 mg/kg intraperitoneally twice daily for 4 days) caused 80-90% reduction of serotonin levels 5 days after the last injection but did not change the GFAP mRNA or the MBR binding in any of the brain regions considered. These findings suggest that the effect of 5,7-DHT on microglial and glial markers is probably related to a nonspecific interaction with other neuronal systems besides the serotonin or to direct interaction with glial cells; the use of these parameters for detecting selective degeneration of serotonin axons presents some obvious limitations.

5,7-Dihydroxytryptamine↗

PubMed1994

Differential effects of 5,7-dihydroxytryptamine-induced serotoninergic degeneration of 5-HT1A receptors and 5-HT uptake sites in the rat brain.

The time-course of 5,7-dihydroxytryptamine-induced lesions (2, 5 and 14 days after i.c.v. injection of 150 micrograms) and the effects of acute reserpine treatment (10 mg/kg, i.p., one or 5 days before scheduled death), were evaluated by autoradiography of [3H]paroxetine binding sites in the rat brain. Reserpine had no significant effect on [3H]paroxetine binding, indicating that the depletion of serotonin is not sufficient per se to alter the serotonin uptake sites in any region. Two days after the 5,7-dihydroxytryptamine lesion, [3H]paroxetine binding was already decreased in the majority of brain regions. In the caudate putamen these binding sites were significantly decreased only 14 days after the lesion, whereas the ventral tegmental area (or the enclosed median forebrain bundle), the dorsal raphe (mainly the ventral portion) and the median raphe maintained their high density of serotonin uptake sites even after 14 days. Results were similar using [3H]citalopram as ligand for the serotonin uptake sites, in the brains of rats lesioned 5 days before death; an exception was the ventral portion of the dorsal raphe, where there was a significant increase with [3H]paroxetine and a decrease with [3H]citalopram binding. In adjacent sections of the same brains we also measured [3H]8-OH-DPAT binding, confirming that it completely disappears in the dorsal raphe after the lesion. Thus, considering the extent of serotonin cell body degeneration, there appears to be a paradoxical mismatch between the excessive loss of [3H]8-OH-DPAT binding and the resistance of [3H]citalopram or [3H]paroxetine binding in the dorsal raphe, suggesting that the two binding sites may undergo adaptive regulation in surviving neurons.

5,7-Dihydroxytryptamine↗

PubMed1994

Novel benzodioxopiperazines acting as antagonists at postsynaptic 5-HT1A receptors and as agonists at 5-HT1A autoreceptors: a comparative pharmacological characterization with proposed 5-HT1A antagonists.

The novel benzodioxopiperazines [4-(benzodioxan-5-yl)1-[2- (benzocyclobutane-1-yl)ethyl]piperazine] (S 14489), [4-(benzodioxan-5-yl)1-(indan-2-yl)piperazine)] (S 15535) and [4-(benzodioxan-5-yl)1-[2(indan-1-yl)ethyl]piperazine (S15931) competitively displaced the binding of [3H]-8-OH-DPAT at serotonin (5-HT)1A receptors with affinities (pKis) of 9.2, 8.8 and 8.9, respectively. These values compared favorably with those of the structurally related eltoprazine (8.0) and the proposed 5-HT1A antagonists NAN-190 (9.2), MDL 73005 EF (8.9), SDZ 216-525 (8.8), BMY 7378 (8.7), (-)-tertatolol (8.1), (-)-alprenolol (7.7), WAY 100,135 (7.5) and spiperone (6.9). The affinities of S 14489, S 15535 and S 15931 for other 5-HT receptor types (5-HT1B, 5-HT1C, 5-HT1D, 5-HT2 and 5-HT3) were about 50 to 1000-fold lower. The spontaneous tail-flicks, flat-body posture and hypothermia mediated by an action of the 5-HT1A agonist 8-OH-DPAT at postsynaptic 5-HT1A receptors were dose-dependently and completely antagonized by S 14489, S 15535 and S15931 at doses of 0.63 to 10.0 and 2.5 to 40.0 mg/kg for s.c. and oral administration, respectively. They did not induce these responses alone, and in their presence, dose-response curves for 8-OH-DPAT were shifted in parallel to the right without loss of maximal effect. By contrast, eltoprazine, MDL 73005 EF, BMY 7378 and NAN-190 behaved as "partial" agonists and only incompletely antagonized the actions of 8-OH-DPAT in these tests. At 5-HT1A autoreceptors, S 14489, S 15535 and S 15931 acted as agonists in inhibiting striatal 5-hydroxytryptophan accumulation (0.16-2.5 mg/kg, s.c.) and in abolishing the electrical activity of the dorsal raphe nucleus (0.005-0.100 mg/kg, i.v.). Eltoprazine, BMY 7378, NAN-190 and MDL 73005 EF also behaved as agonists at these 5-HT1A autoreceptors, whereas WAY 100,135, spiperone, (-)-tertatolol, (-)-alprenolol and SDZ 216-525 inhibited neither accumulation nor firing. WAY 100,135 and spiperone antagonized the inhibition of DRN firing induced by S 14489, S 15535 and S 15931. The affinity of 15535 for dopamine D1 and D2 receptors, as well as for beta-, alpha 1- and alpha 2-adrenoceptors, was > 100-fold lower than its affinity for 5-HT1A receptors. Further, in vivo, at doses of 10.0 to 40.0 mg/kg, s.c., it showed minimal activity in tests of dopamine D2 (and D1) receptor-mediated activity. Similarly, in vivo, S 15535 was weakly active in a test of alpha 1-adrenoceptor-mediated activity.(ABSTRACT TRUNCATED AT 400 WORDS)

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

PubMed1993

Acute noise stress reduces [3H]5-hydroxytryptamine uptake in rat brain synaptosomes: protective effects of buspirone and tianeptine.

Acute noise stress decreased [3H]5-hydroxytryptamine ([3H]5-HT) uptake in synaptosomes from rat hypothalamus, hippocampus and cerebral cortex. The decrease was due to the maximum rate of [3H]5-HT uptake, which peaked 30 min after stress and partly returned to resting values within 4 h, with no changes in affinity (Km values). No changes in [3H]paroxetine binding and basal [3H]5-HT release were found in stressed rats. Tianeptine, given at the dose of 10 mg/kg 1 h before stress, counteracted the noise-induced decrease of 5-HT uptake, since it increased [3H]5-HT uptake in both resting and stressed animals, but did not prevent the rise in plasma corticosterone of stressed rats. Buspirone pretreatment had no effect on [3H]5-HT uptake in resting rats but prevented the noise-induced decrease in [3H]-HT uptake. Diazepam did not modify either the basal or the noise-induced reduction in [3H]5-HT uptake. The evidence that treatments reducing extrasynaptic 5-HT, by increasing its reuptake (tianeptine) or reducing its release (buspirone) in innervated regions are able to modify the stress-induced decrease in 5-HT uptake, further confirms the importance of serotonin in the mechanisms mediating neurochemical responses to stress.

Analysis of Variance↗

PubMed1993

Evidence of an exocytotic-like release of [3H]5-hydroxytryptamine induced by d-fenfluramine in rat hippocampal synaptosomes.

The monoamine releasing activity of d-fenfluramine was investigated with an in vitro model consisting of synaptosomes preloaded with the 3H-neurotransmitter and extensively washed in a superfusion apparatus before a 3-min exposure to d-fenfluramine. With this model, the drug-induced release is real and is not confused by inhibition of reuptake by the drug. d-Fenfluramine (0.5 microM) induced only [3H]5-hydroxytryptamine ([3H]5-HT) release from hippocampal synaptosomes whereas 10 microM also induced some overflow from hippocampal synaptosomes preloaded with [3H]noradrenaline or from striatal synaptosomes preloaded with [3H]dopamine, although the overflow was much lower than from 5-HTergic synaptosomes. We then focused on the [3H]5-HT release induced by 0.5 microM d-fenfluramine, which was previously shown to be Ca2+ dependent. The same finding was confirmed in the present study with other experimental protocols, indicating the requirement for extracellular Ca2+ ions. By measuring [3H]5-HT uptake into rat hippocampal synaptosomes we confirmed that Ca(2+)-ions are not required for the function of the 5-HT uptake carrier or for its interaction with d-fenfluramine. d-Fenfluramine-induced [3H]5-HT release was not altered by 1 microM nitrendipine (blocking the L-type Ca2+ channels) but was slightly decreased (20%) by 0.5 microM omega-conotoxin (blocking the N-type Ca2+ channels). It was also inhibited by 0.5 microM clonidine, interacting with alpha 2-adrenergic heteroreceptors, and by 10 nM tetanus toxin, known to affect the exocytosis of different neurotransmitters including 5-HT. These compounds had very similar effects on the Ca(2+)-dependent, exocytotic release of [3H]5-HT induced by depolarization, i.e. by 15 mM K+.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Tetanus toxin inhibits depolarization-induced [3H]serotonin release from rat brain cortex synaptosomes.

The effects of tetanus toxin on depolarization-induced [3H]serotonin release from superfused rat brain cortex synaptosomes was investigated. Two hours' preincubation of the synaptosomes with tetanus toxin resulted in a concentration-dependent decrease of K(+)-stimulated release, with an IC50 of about 30 nM (4.5 micrograms/ml); this inhibitory effect was blocked by a previous incubation of the tetanus toxin with antitoxin serum. Tetanus toxin had no effect on reserpine-induced release, a model of Ca(2+)-independent release. These results indicate that tetanus toxin is able to alter the exocytotic machinery of serotoninergic terminals, in agreement with results obtained with other neurotransmitters. They also indicate that serotoninergic terminals possess the receptor for tetanus toxin. These findings are in line with in vivo observations suggesting a role for serotoninergic system in tetanus intoxication.

Animals↗

PubMed1993

Anorectic effect and brain concentrations of D-fenfluramine in the marmoset: relationship to the in vivo and in vitro effects on serotonergic mechanisms.

The present study investigated the anorectic activity of d-fenfluramine (d-F) and the relationship with brain levels of unchanged drug and its metabolite d-norfenfluramine (d-NF) in marmosets, relating them to neurochemical effects on the serotoninergic system. d-F and d-NF were equally active in reducing food intake (ED50 about 3 mg/kg, p.o.). However, the brain concentrations of the metabolite required to reduce food intake after synthetic d-NF were more than twice those after d-F, indicating that d-NF contributes to but does not completely explain the anorectic effect of d-F. At this dose d-F did not appreciably modify the serotonin (5-HT) and 5-hydroxyindoleacetic (5-HIAA) contents of the brain regions examined, except for a slight enhancement of 5-HIAA in hippocampus. In vitro in brain cortical synaptosomes d-F inhibited [3H]5-HT uptake more potently than d-NF, as in other species. d-F and d-NF showed similar potency in stimulating [3H]5-HT release, in a Ca++ dependent manner. The tritium released by d-F and d-NF appeared to be mainly unmetabolized [3H]5-HT. Like in other species the marmoset too has saturable and specific [3H]d-F binding sites, for which d-NF has lower affinity. d-F and d-NF have low affinities for 5-HT receptor subtypes, except that d-NF has appreciable affinity for 5-HT1C and 5-HT1D receptors. Unlike in rodents but similarly to primates in the striatum the pharmacology of 5-HT receptors seems to correspond to the 5-HT1D subtype.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

GABAA receptor impairment in the genetic absence epilepsy rats from Strasbourg (GAERS): an immunocytochemical and receptor binding autoradiographic study.

Some aspects of the GABA and cholinergic systems have been investigated in the cortex and thalamus of GAERS Wistar rats, a model of petit-mal epilepsy, and in a non-epileptic control strain. GABA and its synthetic enzyme, glutamic acid decarboxylase (GAD), were located by immunocytochemistry; the GABAA receptors were evaluated by autoradiography of GABA-enhanced 3H-flunitrazepam binding and by immunocytochemistry using specific antibodies against the beta 2-beta 3 subunits of GABAA receptor protein. GABA and GAD immunocytochemistry did not show up any difference in density or distribution of immunoreactive elements (fibers, terminals and neurons) between epileptic and control animals, but autoradiographic and immunocytochemical studies showed a decreased enhancement of 3H-flunitrazepam binding and of beta 2-beta 3 subunits of GABAA receptor in the sensorimotor cortex and anterior thalamic areas of the epileptic strain. No differences were found in benzodiazepine receptors in the two strains. GABAB receptors were measured as 3H-baclofen binding in a crude synaptic membrane preparation and there was no difference between epileptic and control animals. Choline acetyltransferase, the synthetic enzyme for acetylcholine, and muscarinic receptor subtypes (M1 and M2), visualized respectively by an immunocytochemical procedure and binding autoradiography, did not differ in epileptic and normal rats. The data suggest an impairment of the 'GABAA system' in restricted brain regions of epileptic rats, due to a reduction of receptor beta 2-beta 3 subunits and coupling to benzodiazepine receptors despite the normal synthesis and location of the neurotransmitter.

Acetylcholine↗

PubMed1993

In-vivo binding of (+)-[3H]PN 200-110 to peripheral tissues and brain of spontaneously hypertensive rats: effect of lacidipine.

The time-course of dihydropyridine receptor occupancy by lacidipine and its relationship with pharmacological activity has been studied in spontaneously hypertensive rat (SHR), as measured by the inhibition of specific (+)-[3H]PN 200-110 binding in-vivo. After oral administration of doses active in reducing blood pressure, lacidipine did not show tissue target differences in respect to binding sites labelled by (+)-[3H]PN 200-110 in cerebral cortex, heart, ileum, bladder and thoracic aorta. The relative occupancy of receptors in heart 60 min after oral administration of 1 mg kg-1 lacidipine was 75%. After 12 h, when lacidipine was still effective in reducing blood pressure in SHR, a low (15%) but detectable proportion of receptors was still occupied by the drug. The percentage decrease of blood pressure was linear with the percentage of receptor occupancy obtained by different doses of lacidipine; that is, there was a close correspondence between ED25 for decrease in blood pressure (0.33 mg kg-1) and ED25 for inhibition of (+)-[3H]PN 200-110 specific binding in the heart (0.36 mg kg-1). The long-lasting effect of lacidipine on blood pressure might be explained by its selective interaction with dihydropyridine binding sites labelled in-vivo by (+)-[3H]PN 200-110.

Administration, Oral↗

PubMed1993

Further studies on alpha 2-adrenoceptor subtypes involved in the modulation of [3H]noradrenaline and [3H]5-hydroxytryptamine release from rat brain cortex synaptosomes.

Three selective alpha 2A- or alpha 2B-adrenergic antagonists (BRL-44408, BRL-41992 and imiloxan) were used in the present study designed to classify the presynaptic alpha 2-auto- and heteroreceptors in the rat brain cortex. The rank order of potency in antagonizing the inhibitory effect of (-)-noradrenaline or clonidine on the K(+)-induced [3H]noradrenaline and [3H]5-hydroxytryptamine (5-HT) release from superfused synaptosomes was BRL-44408 > or = BRL-41992 >> imiloxan. The same rank order was found for the affinities of these compounds for [3H]yohimbine binding in human platelet membranes, containing only alpha 2A-adrenoceptors, but does not correlate with the known affinities for alpha 2B-adrenoceptors (BRL-41992 > or = imiloxan > BRL-44408). These data support the conclusion that presynaptic alpha 2-auto- and heteroreceptors in rat brain cortex do not belong to the alpha 2B-subtype and suggest that the modulation of noradrenaline and 5-HT release may be mediated by the alpha 2A-subtype.

Adrenergic alpha-Antagonists↗

PubMed1993

Neurotoxicity of nonionic low-osmolar contrast media. A receptor binding study.

RATIONALE AND OBJECTIVES: The use of the newest nonionic, water-soluble, low-osmolar radiographic contrast media (CM) is still associated with occasional adverse reactions affecting the neural tissues. Because these CM display lipophilic potential in their interactions with biological membranes when diffusing within the brain parenchyma, they could affect neurotransmitter binding to the receptors. Two representative nonionic CM, iopamidol and iohexol, were studied to assess whether CM-related neurotoxicity derived from their interactions with specific receptors on neural membranes. METHODS: Binding assays were carried out in vitro on crude total membrane or crude synaptic membrane preparations from selected brain areas (cortex, striatum, hippocampus, cerebellum). The concentrations of CM and reference drugs that reduce specific binding of each ligand by 50% of its maximum value (IC50) were determined using radioligands to the receptors of the most common neurotransmitters in the central nervous system, including excitatory amino acids. RESULTS: Neither iopamidol nor iohexol inhibited the (3H) ligand binding to any kind of receptor up to very high concentrations (100 microM). CONCLUSIONS: The nonionic, low-osmolar CM did not influence the normal functions of neural membranes in our model. This suggests that occasional neurotoxic effects do not occur as a consequence of specific action on brain receptors. These CM may have an indirect, postmembrane site of action.

Animals↗

PubMed1993

Tertatolol, a new beta-blocker, is a serotonin (5-hydroxytryptamine1A) receptor antagonist in rat brain.

The interaction of tertatolol (d,l-hydroxy-2'-t-butylamino-3'propyloxy-8-thiochromane HCl) with 5-hydroxytryptamine (serotonin; 5-HT) receptors in several brain areas were investigated. Both ligand binding techniques and an electrophysiological approach were used. First, the affinity of tertatolol for different 5-HT receptor subtypes was measured, as assayed by a competition binding experiment using specific ligands in several brain areas. It was found that (-)-tertatolol binds to 5-HT1 receptor subtypes in rat brain, particularly the 5-HT1A subtype in the hippocampus (Ki = 5.9 nM). (-)-Tertatolol showed much lower affinity for 5-HT1B (Ki = 118.4 nM), 5-HT1C (Ki = 699.6 nM) and 5-HT2 (Ki = 678.6 nM) receptors. The binding of tertatolol to hippocampal 5-HT1A receptors was stereospecific in that the affinity of (+)-tertatolol to these receptors (Ki = 311.6 nM) was about 20 times lower as compared to that of (-)-tertatolol. There was no significant binding of tertatolol to 5-HT1D, 5-HT3, alpha-1 adrenergic receptors or to the serotonin uptake site. Electrophysiological techniques were used to study the effects of (-)-tertatolol on the activity of 5-HT-containing neurons in the rat dorsal raphe nucleus. Acute i.v. injection of (-)-tertatolol caused a slight increase in the basal firing rate of the majority of 5-HT neurons studied. Pretreatment with (-)-tertatolol (1 mg/kg i.v.) significantly reduced the inhibitory effect of 8-hydroxy-2-(di-n-proylamino) tetralin (0.25-64 micrograms/kg i.v.) on the firing rate of dorsal raphe nucleus 5-HT neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

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

PubMed1992

Hepatic protoporphyria is associated with a decrease in ligand binding for the mitochondrial benzodiazepine receptors in the liver.

Protoporphyrin IX (PP) and N-methylprotoporphyrin IX (N-MePP) added in vitro to liver membranes reduced dose-dependently the affinity of [3H]PK 11195 for the mitochondrial benzodiazepine receptors (MBRs), the latter being about 20 times more potent (Ki 4.5 and 0.25 microM). Preincubation of these two porphyrins with liver homogenates for 120 min at 4 degrees resulted in significant inhibition of [3H]PK 11195 binding even after repeated washings of the membranes due to the residual presence in the membranes of about 35 and 5% of PP and N-MePP, respectively. Thus, the hypothesis that an in vivo increase in the hepatic porphyrin content modifies the binding of the isoquinoline PK 11195 to the MBRs was investigated in an experimental model of protoporphyria. PP and N-MePP were allowed to accumulate in vivo through treatment with 3,5-diethoxycarbonyl-1, 4-dihydrocollidine (DDC) (100 mg/kg i.p., once), and rats were killed 5 h after treatment when hepatic porphyrin accumulation was marked (10-fold increase), PP predominating. In the liver, treatment reduced the affinity (Kd) of [3H]PK 11195 for MBRs (from 3.56 to 15.37 nM, P < 0.01) and the maximum number of binding sites (Bmax) (55% decrease, P < 0.05); the affinity (Ki) of RO 5-4864 for [3H]PK 11195 binding sites was also reduced (from 23.9 to 72.99 nM, P < 0.05). No significant differences were found in the brain cortex. Liver and brain diazepam binding inhibitor levels and plasma corticosterone levels were unchanged. The reduction in [3H]PK 11195 binding to MBRs in the liver of DDC-treated rats thus appears to be attributable to a specific effect of the DDC-induced formation of the two protoporphyrins; this conclusion suggests that in hepatic protoporphyria processes modulated by MBRs may be altered.

5-Aminolevulinate Synthetase↗