piperidines and indalpine

Although relatively few drugs that specifically influence serotonin neurons have been used in humans, a wide variety of drugs has been used to modify serotonergic function in experimental animals. Several classes of agents increase serotonergic function. These include serotonin precursors (L-5-hydroxytryptophan and L-tryptophan) and monoamine oxidase inhibitors, which elevate serotonin stores; uptake inhibitors and releasers, which increase the concentration of serotonin in the synaptic cleft; and direct serotonin agonists, which mimic the action of serotonin on synaptic receptors. In addition, several kinds of drugs decrease serotonergic function, including serotonin depletors and agents that destroy serotonin neurons, as well as direct serotonin-receptor antagonists. The array of drugs now available improves the opportunities for clarifying the physiological roles of serotonin and gives promise of several therapeutic applications, including treatment of myoclonus.

Topics: Alanine; Brain; Citalopram; Clomipramine; Fenfluramine; Fluoxetine; Fluvoxamine; Humans; Monoamine Oxidase Inhibitors; Neurons; Oximes; p-Chloroamphetamine; Paroxetine; Piperidines; Propylamines; Receptors, Serotonin; Reserpine; Serotonin; Serotonin Antagonists; Synapses; Tetrabenazine; Zimeldine

Depression has been associated with a disturbance in serotonin function as reflected in platelet uptake of the transmitter as well as in CSF levels of its major metabolite, 5-hydroxyindoleacetic acid (5-HIAA). CSF 5-HIAA levels are subnormal in approximately 30% of melancholia patients. Early studies suggested that patients with a disturbed serotonin metabolism were less responsive to treatment with uptake inhibitors with a preferential action on noradrenaline neurons. Such findings encouraged the search for compounds with a selective effect on serotonin neurons. Although some classical antidepressants are potent inhibitors of serotonin uptake, they are not selective, since their metabolites, which appear to have antidepressant effects, inhibit noradrenaline uptake. The consistent findings of an increased risk for suicide in patients with low CSF 5-HIAA underlines the importance of exploring drugs that act on serotonin transmission. The biochemical effects of some serotonin uptake inhibitors and their clinical and research potential in depression are reviewed.

Topics: 5-Hydroxytryptophan; Alanine; Citalopram; Depressive Disorder; Fluoxetine; Fluvoxamine; Humans; Imipramine; Oximes; Paroxetine; Piperidines; Propylamines; Serotonin; Serotonin Antagonists; Trazodone; Zimeldine

The thyrotropin-releasing hormone (TRH) test was performed in 100 depressed patients, including 73 patients with a major depressive episode (MDE) according to DSM-III. Thirty-one patients subsequently received an antidepressant with a predominant serotoninergic action (indalpine or citalopram), and 27 patients received a noradrenergic antidepressant (maprotiline). The diagnostic value of the TRH test was not conclusive for any of the subgroups of depressed patients: MDE, MDE with melancholia or MDE in bipolar patients. Similarly, the value of the TRH test in the choice of antidepressant treatment according to the monoaminergic action was not convincing. These results are discussed in the light of the data of the international literature.

Topics: Adult; Aged; Bipolar Disorder; Citalopram; Depressive Disorder; Female; Humans; Male; Maprotiline; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Recurrence; Serotonin Antagonists; Thyrotropin; Thyrotropin-Releasing Hormone

Twelve healthy male volunteers were treated double-blind and cross-over with 4-(3-indolyl-2-ethyl)piperidine (indalpine), a selective 5-hydroxytryptamine uptake inhibitor with antidepressant and anxiolytic properties, and placebo for two weeks. Soon after starting the treatment with indalpine (50 mg/d) they felt subjectively mild sedative-like effects which were abolished when retested after two weeks' maintenance (150 mg/d). Objectively measured psychomotor performance (coordinative and reactive skills, standing steadiness, nystagmus, flicker recognition) was not, however, affected by indalpine. The only adverse effect attributable to indalpine was ejaculatory dysfunction which was spontaneously reported by 67% of the subjects. When alcohol (1 g/kg) was administered during the treatment periods most tests showed impairment. However, indalpine neither enhanced nor counteracted the effects of alcohol in this trial.

Topics: Adult; Attention; Breath Tests; Double-Blind Method; Emotions; Ethanol; Flicker Fusion; Humans; Male; Nystagmus, Physiologic; Piperidines; Postural Balance; Psychomotor Performance; Reaction Time; Serotonin Antagonists

After 1 mg DST, 25 major depressive patients (DSM-III) received at random either a specific inhibitor of noradrenaline reuptake (Maprotiline) or an inhibitor of serotonin reuptake (Indalpine or Citalopram). After at least 3 weeks of treatment, no difference was found in treatment response between suppressors and non suppressors. This study is unable to confirm the usefulness of the DST in selection of treatment according to its central activity on serotonin or noradrenaline-reuptake.

Topics: Adult; Aged; Anthracenes; Citalopram; Depressive Disorder; Dexamethasone; Female; Humans; Male; Maprotiline; Middle Aged; Piperidines; Propylamines

Effects of an inhibitor of the uptake of noradrenaline (maprotiline, 75 and 150 mg) and two inhibitors of the uptake of 5-hydroxytryptamine (zimelidine, 100 and 200 mg; indalpine, 25 and 50 mg) on sleep were studied in healthy man. Maprotiline reduced the duration of rapid eye movement (REM) sleep and increased the duration of stage 2 sleep, and there was evidence of sedation the next day. Zimelidine and indalpine reduced the duration of REM sleep, but also reduced the total sleep time and increased wakefulness and stage 1 (drowsy) sleep. It is suggested that in acute studies, the effects of inhibition of uptake on sleep are likely to arise from presynaptic inhibition of release of transmitter, although other mechanisms cannot be excluded. Suppression of REM sleep is believed to be due to the balance between cholinergic and monoaminergic influences being disturbed rather than a specific effect arising from the modulation of a particular transmitter.

Topics: Adolescent; Adult; Double-Blind Method; Electroencephalography; Humans; Male; Maprotiline; Neurotransmitter Uptake Inhibitors; Norepinephrine; Piperidines; Psychomotor Performance; Serotonin; Sleep; Sleep, REM; Zimeldine

The potential value of pretreatment urinary 3-methoxy, 4-hydroxyphenylethyleneglycol (MHPG) levels to predict the therapeutic response to antidepressants was studied by measuring urinary MHPG output in 42 depressed inpatients treated with a selective inhibitor of serotonin (Indalpine) or noradrenaline (Maprotiline) reuptake. Among the 42 depressed inpatients there were 33 cases of major depressive episode. Patients were treated for at least 3 weeks, firstly with intravenous infusions of maprotiline or indalpine which have been administered at random. No difference in pretreatment urinary MHPG levels was found between the responders to indalpine (1.08 +/- 0.48 micrograms/24 h/mg of creatinine) and the responders to maprotiline (1.15 +/- 0.62 micrograms/24 h/mg of creatinine). However, there was a difference in the pretreatment levels of urinary MHPG between the non-responders to indalpine (0.56 +/- 0.28 microgram/24 h/mg of creatinine) and the non-responders to maprotiline (1.37 +/- 0.68 micrograms/24 h/mg of creatinine). No correlation between this biochemical parameter and HDRS score was found. These results indicate that, in this study, there is no obvious relationship between the pretreatment urinary MHPG levels in depressed patients and their therapeutic response to specific inhibitors of noradrenaline or serotonin reuptake. However, there was a positive trend towards a lower pretreatment MHPG level to be associated with lack of response to indalpine.

Topics: Adult; Age Factors; Anthracenes; Depression; Female; Glycols; Humans; Male; Maprotiline; Methoxyhydroxyphenylglycol; Middle Aged; Opium; Piperidines; Sex Factors

Indalpine 150 mg per day and mianserin 60 mg per day were compared in a double-blind study of 65 depressed out-patients: 52 patients completed the 4-week trial. At the end of four weeks there was no significant difference in antidepressant effect between the two drugs; but in the first two weeks, improvement in the mianserin-treated group was significantly greater than that in the indalpine group. The mianserin-treated group reported more side-effects of sedation (eg. drowsiness, clumsiness, heaviness of limbs etc.) and one patient on indalpine developed a mild leucopenia.

Topics: Adolescent; Adult; Aged; Antidepressive Agents; Bipolar Disorder; Clinical Trials as Topic; Depressive Disorder; Dibenzazepines; Double-Blind Method; Humans; Leukopenia; Mianserin; Middle Aged; Piperidines

In this double-bind randomized study involving 35 depressed female inpatients, Indalpine proved significantly superior to placebo on all the criteria used: Hamilton scales for depression and anxiety, clinician's vectorial ratings. Its rapid onset of action was further confirmed by the rapid appearance of significance relative to placebo: as early as the third day of treatment, that is, during the optimum placebo effect period. The results are all more valuable if one considers the magnitude of the placebo effect obtained with daily infusions of isotonic sodium chloride-dextros solution, the possible adjunction of a benzodiazepine and the availability of placebo tablets as an adjunct to the infusions upon request. Acceptabilité was found to be good, especially at the cardiovascular and cholinergic levels.

Topics: Adult; Brief Psychiatric Rating Scale; Clinical Trials as Topic; Depressive Disorder; Double-Blind Method; Female; Humans; Kinetics; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Random Allocation

The effects of indalpine (a selective 5-HT uptake inhibitor) on the threshold of lower limb nociceptive flexion reflexes were studied (double blind) in humans. After 3 days' administration, indalpine was found to exert a significant naloxone-reversible depression (threshold increased) of the nociceptive reflexes (naloxone and saline were tested double blind). In contrast, no change was found during treatment with placebo. The functional and therapeutic implications of these results are discussed.

Topics: Adult; Electrophysiology; Endorphins; Female; Humans; Male; Naloxone; Nociceptors; Piperidines; Reflex; Serotonin; Serotonin Antagonists

A spectrofluorometric assay has been developed for the measurement of LM 5008, a novel antidepressant, in biological fluids. A buccal absorption study in 12 healthy subjects showed increased uptake of LM 5008 under higher pH conditions. Single dose administration of 25 mg orally to 3 volunteers showed peak levels after 2 to 3 hours. Pharmacodynamic studies in 12 volunteers comparing 25 mg LM 5008, 1 mg atropine and placebo showed that pupil diameter increased significantly after LM 5008 compared with atropine and placebo, but no other significant anticholinergic effect was demonstrated. Atropine showed a significant decrease in saliva production and in eccrine sweating and a significant increase in dryness of the mouth and in pupil diameter compared with placebo. The distance of the near point tended to increase during atropine treatment but only significantly at 6 hours. LM 5008 produced no significant change in these measurements.

Topics: Adult; Antidepressive Agents; Double-Blind Method; Female; Heart Rate; Humans; Male; Parasympatholytics; Piperidines; Pupil; Saliva; Salivation; Sweating

Effects of experience with Pavlovian autoshaping procedures on lever-press autoshaping conditioned response (CR) performance and 3H-8-OH-DPAT-labeled binding of 5-HT(1a) receptors as well as 125I-LSD-labeled binding of 5-HT(2a) receptors were evaluated in four groups of male Long-Evans hooded rats. Two groups of rats (Group Paired High CR and Group Paired Low CR) received Pavlovian autoshaping procedures wherein the presentation of a lever (conditioned stimulus, CS) was followed by the response-independent presentation of food (unconditioned stimulus, US). Rats in Group Paired High CR (n=12) showed more rapid CR acquisition and higher asymptotic levels of lever-press autoshaping CR performance relative to rats in Group Low CR (n=12). Group Omission (n=9) received autoshaping with an omission contingency, such that performing the lever-press autoshaping CR resulted in the cancellation the food US, while Group Random (n=9) received presentations of lever CS and food US randomly with respect to one another. Though Groups Omission and Random did not differ in lever-press autoshaping CR performance, Group Omission showed significantly lower levels of 3H-8-OH-DPAT-labeled 5-HT(1a) binding in post-synaptic areas (frontal cortex, septum, caudate putamen), as well as significantly higher plasma corticosterone levels than Group Random. In addition, Group Random showed higher levels of 3H-8-OH-DPAT-labeled 5-HT(1a) binding in pre-synaptic somatodendritic autoreceptors on dorsal raphe nucleus relative to each of the other three groups. Autoradiographic analysis of 125I-LSD-labeled 5-HT(2a) receptor binding revealed no significant differences between Groups Paired High CR and Paired Low CR or between Groups Omission and Random in any brain regions.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Anti-Anxiety Agents; Autoradiography; Brain Chemistry; Buspirone; Central Nervous System Depressants; Conditioning, Classical; Corticosterone; Ethanol; Iodine Radioisotopes; Lysergic Acid Diethylamide; Male; Piperidines; Rats; Rats, Long-Evans; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Selective Serotonin Reuptake Inhibitors; Serotonin Receptor Agonists; Zimeldine

The design and synthesis of a novel series of indole derivatives (9) having dual 5-HT transporter reuptake and 5-HT(1A) antagonist activity are described.

Topics: Antidepressive Agents, Second-Generation; Carrier Proteins; Drug Design; Humans; Indicators and Reagents; Jurkat Cells; Kinetics; Membrane Glycoproteins; Membrane Transport Proteins; Nerve Tissue Proteins; Piperidines; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Selective Serotonin Reuptake Inhibitors; Serotonin Antagonists; Serotonin Plasma Membrane Transport Proteins; Structure-Activity Relationship

1. The effects of apomorphine (APO) administration on DA system activity were assessed by measuring dopamine metabolite levels (HVA) in several circumstances. 2. Pretreatment with IMI reduced the effect of APO on HVA levels. 3. Pretreatments with either IDE or DMI did not reduce the effect of APO on HVA levels. 4. Reductions of either NE and 5-HT levels after DSP4 and pCPA restored the effect of APO after IMI pretreatment.

Topics: Animals; Apomorphine; Benzylamines; Corpus Striatum; Fenclonine; Homovanillic Acid; Imipramine; In Vitro Techniques; Male; Norepinephrine; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Serotonin; Serotonin Antagonists

In the treatment of depression, when antidepressant drug choice is made according to alterations of erythrocyte membrane transport of L-tyrosine and L-tryptophan in the individual patient, the clinical results are superior to those obtained when drugs are prescribed according to the physician's judgment. This is demonstrated by comparing three experimental groups: I, 100 patients treated in relation to their L-tyrosine and L-tryptophan transport; II, 30 patients treated according to the clinician's experience; III, 38 subjects treated against the L-tyrosine and L-tryptophan transport indications. In these groups, the frequency of patients improved by more than 70% is 77%, 47%, and 16%, respectively.

Topics: Adult; Aged; Antidepressive Agents; Depressive Disorder; Erythrocyte Membrane; Female; Fluvoxamine; Humans; Imipramine; Male; Mianserin; Middle Aged; Monoamine Oxidase Inhibitors; Oximes; Piperidines; Receptors, Adrenergic; Receptors, Serotonin; Tryptophan; Tyrosine

Differential scanning calorimetry was used to study the interaction of a membrane model with two neuromediators [noradrenaline and 5-hydroxytryptamine (Serotonin)] and four antidepressant drugs (imipramine, indalpine, citalopram, and milnacipran), known to be uptake inhibitors of these neuromediators. The study was carried out on dipalmitoyl phosphatidylcholine liposomes, a bilayer phospholipid system taken as a simplified model of biological membranes. Analysis of the thermograms led us to classify the molecules according to their lipophilic action, as in the conventional measurement of the water-octanol partition coefficient, and also enabled us to precisely determine their location along the phospholipid bilayer. A hypothesis based on this localization is put forward concerning the competitive, or otherwise, character of the blocking of uptake of the neuromediators. The extreme cases of interaction and localization of imipramine and milnacipran, a new antidepressant, relative to the bilayer are also analyzed in terms of side effects.

Topics: 1,2-Dipalmitoylphosphatidylcholine; Antidepressive Agents; Buffers; Calorimetry, Differential Scanning; Chemical Phenomena; Chemistry, Physical; Cyclopropanes; Imipramine; Membranes, Artificial; Milnacipran; Models, Theoretical; Norepinephrine; Octanols; Piperidines; Serotonin; Solubility; Temperature

An investigation of the site of interaction of a variety of tricyclic and nontricyclic 5-HT uptake inhibitors with the neuronal sodium-dependent 5-HT transporter was undertaken. The dissociation of [3H]paroxetine binding induced by indalpine (10 microM), SL 81.0385 (10 microM), fluoxetine (10 microM), citalopram (10 microM), paroxetine (0.15 microM), imipramine (10 microM) and 5-HT (50 microM) produced monophasic dissociation curves and gave t1/2 values of dissociation similar to that induced by dilution alone. In inhibition studies of [3H]paroxetine binding with citalopram, imipramine and 5-HT, increases in the concentration of [3H]radioligand used led to parallel rightward shifts of the inhibition curves with no diminution of the maximum degree of inhibition (Imax). "Schild-type" analyses of the data obtained from the inhibition curves with these 3 compounds gave slopes close to unity. In chemical modification studies, treatment of membrane fractions with N-ethylmaleimide led to a pronounded reduction in specific [3H]paroxetine binding. Preincubation of these membranes with SL 81.0385, fluoxetine, imipramine, tryptamine and 5-HT provided significant protection against this NEM-induced inactivation. The above findings are interpreted to provide evidence for a common or at least overlapping binding site for the tricyclic and nontricyclic 5-HT uptake inhibitors with the substrate recognition site of the neuronal sodium-dependent 5-HT transporter.

Topics: Animals; Antidepressive Agents, Tricyclic; Binding Sites; Binding, Competitive; Biological Transport; Cerebral Cortex; Citalopram; Dose-Response Relationship, Drug; Ethylmaleimide; Fluoxetine; Imipramine; Male; Neurons; Paroxetine; Piperidines; Rats; Rats, Inbred Strains; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Sodium

Extracellular levels of endogenous serotonin (5-HT) and its major metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were measured in the caudate-putamen of anesthetized and awake rats using intracerebral microdialysis coupled to HPLC with fluorimetric detection. A dialysis probe (of the loop type) was perfused with Ringer solution at 2 microliters/min, and samples collected every 30 or 60 min. Basal indole levels were followed for up to 4 days in both intact and 5,7-dihydroxytryptamine (5,7-DHT) lesioned animals. Immediately after the probe implantation, the striatal 5-HT levels were about 10 times higher than the steady-state levels that were reached after 7-8 h of perfusion. The steady-state baseline levels, which amounted to 22.5 fmol/30 min sampling time, remained stable for 4 days. In 5,7-DHT-denervated animals, the steady-state levels of 5-HT, measured during the second day after probe implantation, were below the limit of detection (less than 10 fmol/60 min). However, during the first 6 h post-implantation, the 5-HT output was as high as in intact animals, which suggests that the high 5-HT levels recovered in association with probe implantation were blood-derived. As a consequence, all other experiments were started after a delay of at least 12 h after implantation of the dialysis probe. In awake, freely moving animals, the steady-state 5-HT levels were about 60% higher than in halothane-anesthetized animals, whereas 5-HIAA was unaffected by anesthesia. KCl (60 and 100 mM) added to the perfusion fluid produced a sharp increase in 5-HT output that was eight-fold at the 60 mM concentration and 21-fold at the 100 mM concentration. In contrast, 5-HIAA output dropped by 43 and 54%, respectively. In 5,7-DHT-lesioned animals, the KCl-evoked (100 mM) release represented less than 5% of the peak values obtained for the intact striata. Omission of Ca2+ from the perfusion fluid resulted in a 70% reduction in baseline 5-HT output, whereas the 5-HIAA levels remained unchanged. High concentrations of tetrodotoxin (TTX) added to the perfusion medium (5-50 microM) resulted in quite variable results. At a lower concentration (1 microM), however, TTX produced a 50% reduction in baseline 5-HT release, whereas the 5-HIAA output remained unchanged. The 5-HT reuptake blocker, indalpine, increased the extracellular levels of 5-HT sixfold when added to the perfusion medium (1 microM), and threefold when given intraperitoneally (5 mg/kg). By contrast, the 5-HIAA level remai

Topics: 5,7-Dihydroxytryptamine; Anesthesia; Animals; Brain; Calcium; Caudate Nucleus; Chromatography, High Pressure Liquid; Denervation; Dialysis; Female; Halothane; Hydroxyindoleacetic Acid; Neurons; Piperidines; Potassium Chloride; Putamen; Rats; Rats, Inbred Strains; Serotonin; Serotonin Antagonists; Tetrodotoxin

The mechanism of the increase in heart rate caused by 5-hydroxytryptamine (5-HT) in the spinal guinea-pig was investigated. Administration of 5-HT (15, 30, 60 and 120 micrograms.kg-1 i.v.) elicited dose dependent increases in heart rate. The responses to 5-HT were not modified by methiothepin (0.5 and 1.5 mg.kg-1), ketanserin (0.5-4.5 mg.kg-1) or MDL 72222 (0.5-4.5 mg.kg-1) but were antagonized by the beta-adrenoceptor antagonists, propranolol (0.1-1 mg.kg-1) or atenolol (0.5-4.5 mg.kg-1). Indalpine, which is known to interfere with the uptake of 5-HT by nerve terminals and blood platelets, significantly reduced the effects of 5-HT at a dose (5 mg.kg-1) that also affected the tachycardia elicited by tyramine. The increase in heart rate caused by tyramine in reserpinized animals was attenuated and, unlike normal animals where the responses to 5-HT remained constant after repeated administration, there was a quickly developing tachyphylaxis to 5-HT. These results show that the increase in heart rate elicited by 5-HT in spinal guinea-pigs is not mediated by any of the currently characterized 5-HT receptors ('5-HT1-like', 5-HT2 and 5-HT3), and that a major part of the tachycardia seems to be mediated by a release of catecholamines by a mechanism similar, though perhaps not identical, to that for tyramine. Another as yet unidentified mechanism could be involved besides though perhaps not identical, to that for tyramine. Another as yet unidentified mechanism could be involved besides this action.

Topics: Adrenergic beta-Antagonists; Animals; Atenolol; Decerebrate State; Female; Guinea Pigs; Heart Rate; In Vitro Techniques; Isoproterenol; Male; Piperidines; Propranolol; Reserpine; Serotonin; Serotonin Antagonists; Tyramine

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.

Topics: Animals; Binding Sites; Brain; Cell Membrane; Fenfluramine; Imipramine; Male; Norfenfluramine; Piperidines; Rats; Serotonin; Serotonin Antagonists

SR 95191 [3-(2-morpholino-ethyl-amino)-4-cyano-6-phenyl-pyridazine], a novel compound, has been shown in preliminary experiments to inhibit type A monoamine oxidase (MAO). This report describes the activities of SR 95191 in behavioral experiments in mice and rats and shows that SR 95191 has the profile of a selective type A MAO inhibitor (MAOI). Moreover, SR 95191 also possesses dopamine (DA) stimulant properties. The activities of SR 95191 were compared to those of the MAOIs moclobemide, clorgyline, pargyline and l-deprenyl, as well as to those of the antidepressant drugs imipramine, nomifensine and indalpine and to those of the DAergic drugs (+)-amphetamine and apomorphine. SR 95191 p.o. antagonized the effects of reserpine in mice and rats, decreased immobility in the mouse despair test, antagonized haloperidol-induced catalepsy in rats and potentiated 5-hydroxytryptophan in mice and rats with an overall potency which was half that of imipramine. SR 95191, like moclobemide, did not potentiate yohimbine-induced lethality and did not antagonize oxotremorine-induced tremor. Like selective type A MAOIs, SR 95191 potentiated 5-hydroxytryptophan-induced tremor without affecting beta-phenethylamine-induced stereotypies in mice. SR 95191 did not antagonize 3-hydroxy-4-methyl-alpha-phenylethylamine-induced hyperthermia. Like all DA stimulant drugs, SR 95191 induced stereotypies in rats, which were blocked by haloperidol and alpha-methylparatyrosine, and induced contralateral turning in mice with a unilateral striatal 6-hydroxydopamine lesion. Based on these results, it is postulated that SR 95191 has a unique profile of activity combining the properties of a selective type A MAO inhibitor and those of an atypical DAergic drug.

Topics: 5-Hydroxytryptophan; Amphetamines; Animals; Antidepressive Agents; Behavior, Animal; Benzamides; Body Temperature; Catalepsy; Clorgyline; Drug Interactions; Female; Haloperidol; Imipramine; Levodopa; Male; Mice; Moclobemide; Monoamine Oxidase Inhibitors; Motor Activity; Nomifensine; Oxotremorine; Pargyline; Piperidines; Pyridazines; Rats; Rats, Inbred Strains; Reserpine; Selegiline; Stereotyped Behavior

Topics: Animals; Brain Chemistry; Chromatography, High Pressure Liquid; Electrochemistry; Male; Mice; Microchemistry; Piperidines

Plasma levels of free and conjugated 3,4-dihydroxyphenylethyleneglycol (DOPEG), the main deaminated metabolite of norepinephrine, were assayed in 48 depressed patients before initiating a treatment with either maprotiline, an inhibitor of norepinephrine reuptake, or indalpine, a specific inhibitor of serotonin reuptake. The two groups of depressed patients were comparable. The therapeutic effect was evaluated by using the Hamilton Rating Scale for Depression. No difference in pretreatment plasma free and conjugated DOPEG levels was found between the responders and the nonresponders to maprotiline or indalpine. Neither was there any difference in the pretreatment levels of plasma free DOPEG between the two groups of responders and the two groups of nonresponders to either drug. Finally, there was no difference in the therapeutic response to maprotiline or to indalpine between the patients with high and low plasma DOPEG levels before treatment. These results indicate that there is no relationship between the initial plasma levels of DOPEG in depressed patients and their therapeutic response to a norepinephrine or a serotonin reuptake blocker.

Topics: Adult; Aged; Anthracenes; Depression; Female; Glycols; Humans; Male; Maprotiline; Methoxyhydroxyphenylglycol; Middle Aged; Piperidines

Both thresholds of nociceptive flexion reflex and pain sensation were studied in 6 normal subjects and in 6 patients with typical thalamic pain. In these patients, on the painful side, these thresholds were found increased (98 p. 100; 89 p. 100 respectively) compared to the normal side. Values obtained in this latter did not significantly differ from those observed in normal subjects. After 8 days of indalpine treatment, the nociceptive reflex threshold was furthered increased in the painful side while the pain threshold was not modified by this drug. In the normal side, changes observed after indalpine were similar to that obtained in normal subjects. All the indalpine-induced modifications were reversed by naloxone in both patients and normals. These results are discussed in the context of the possible mechanisms of thalamic hyperpathia.

Topics: Aged; Female; Humans; Male; Middle Aged; Naloxone; Pain; Pain Measurement; Piperidines; Reflex; Sensory Thresholds; Serotonin; Syndrome; Thalamic Diseases

This study investigated whether benzodiazepines reduce the capacity of animals to wait for food reward. Rats trained in a T-maze were allowed to choose between two magnitudes of reward: immediate, but small (two pellets) vs delayed, but large (eight pellets). The rats learned within ten sessions to select (80-100%) the arm leading to the largest reward. Separate groups of rats were then confined for 15, 30 or 60 s in the arm associated with the largest reward before gaining access to the spacially contiguous goal-box. The choice of the other arm was not followed by a period of waiting. Under these conditions, the frequency with which the small-reward arm was chosen increased linearly as a function of the duration of the waiting period. Diazepam (2-4 mg/kg IP) dose-dependently increased the number of times the small-reward arm was chosen during the sessions for which the waiting period was fixed at 15 or 30 s. Nitrazepam (2 mg/kg IP), chlordiazepoxide (16 mg/kg IP) and clobazam (16 mg/kg IP) had similar effects. The action of diazepam was counteracted by simultaneous administration of flumazepil (Ro 15-1788, 8 mg/kg PO). In the absence of confinement, these benzodiazepines, diazepam (4 mg/kg) excepted, did not modify selection of the large-reward arm. Conversely, the serotonin uptake blockers indalpine (2-4 mg/kg IP) and zimelidine (8-16 mg/kg IP) dose-dependently increased preference for the arm leading to the delayed (25 s) but large reward. These results suggest that benzodiazepines, perhaps by increasing impulsivity, render the animals less prone than controls to tolerate delayed access to reward.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anti-Anxiety Agents; Benzodiazepinones; Choice Behavior; Diazepam; Flumazenil; Male; Piperidines; Rats; Rats, Inbred Strains; Reward; Serotonin Antagonists; Synaptic Transmission; Zimeldine

The anxiolytic-sedative drugs thalidomide and supidimide inhibited spontaneous motor activity in rats. Both compounds inhibited the serotonin (5-HT) behavioural syndrome induced by tranylcypromine (TCP) plus L-tryptophan (TRP) or clorgyline plus the selective 5-HT uptake blocker, LM 5008 (4-[2-(3-indolyl)ethyl]piperidine) and delayed the behavioural effects of p-chloro-amphetamine, a releaser of 5-HT. The behavioural syndrome induced by the 5-HT agonist, 5-methoxy-N,N'-dimethyltryptamine (5-MeODMT) was unaffected by supidimide pretreatment. Thus supidimide does not possess 5-HT receptor antagonistic properties. This was further substantiated by the unaltered 5-HT-induced platelet aggregation in the presence of supidimide (10(-7)-10(-4) M). A decrease of 5-HT release into the synaptic cleft will lead to a diminished behavioural response to drugs that act presynaptically. Supidimide induced a greater increase in accumulation of brain 5-HT in TCP (5 mg/kg) plus TRP (100 mg/kg)-treated animals as compared to that in the corresponding controls. These data indicate that the behavioural and pharmacological actions of supidimide may be related to its inhibition of 5-HT release.

Topics: Animals; Anti-Anxiety Agents; Brain; Catecholamines; Clorgyline; Dose-Response Relationship, Drug; Humans; In Vitro Techniques; Male; Methoxydimethyltryptamines; Monoamine Oxidase; Motor Activity; p-Chloroamphetamine; Piperidines; Platelet Aggregation; Rats; Rats, Inbred Strains; Serotonin; Serotonin Antagonists; Thalidomide; Tranylcypromine; Tryptophan

Administration of the serotonin-releasing drug fenfluramine to male rats caused a dose-dependent increase in both plasma prolactin and corticosterone levels. The effect of fenfluramine on prolactin was maximal at 30 min after injection, whereas the effect on plasma corticosterone levels reached a maximum 2 h after injection. In order to determine if the effect of fenfluramine on both hormones was mediated via serotonin release, rats were pretreated with the serotonin uptake inhibitors fluoxetine (10 mg/kg i.p.) or indalpine (10 mg/kg i.p.) 30 min prior to administration of fenfluramine (5 mg/kg i.p.). Both fluoxetine and indalpine inhibited the effect of fenfluramine on plasma prolactin levels, but did not modify the effect of fenfluramine on plasma corticosterone levels. Pretreatment of rats with the serotonin precursor L-tryptophan (100 mg/kg i.p.) potentiated the effect of a submaximal dose of fenfluramine (2 mg/kg i.p.) on plasma prolactin levels, but did not affect the corticosterone response. Depletion of serotonin stores by pretreatment with the serotonin inhibitor p-chlorophenylalanine (300 mg/kg i.p.; 72 h) did not significantly prevent the effect of fenfluramine on either hormone. There was a 34% inhibition of the effect of fenfluramine on plasma prolactin levels, but this effect was not statistically significant. The results of the experiments suggest that the effect of fenfluramine on prolactin secretion is mediated, at least in part, by a serotoninergic mechanism, but the effect on corticosterone secretion is not mediated via serotonin release.

Topics: Animals; Antidepressive Agents; Corticosterone; Fenclonine; Fenfluramine; Fluoxetine; Kinetics; Male; Piperidines; Prolactin; Propylamines; Rats; Rats, Inbred Strains; Serotonin; Tryptophan

Topics: Acute Disease; Agranulocytosis; Antidepressive Agents; Humans; Piperidines

Topics: Antidepressive Agents; Flushing; Humans; Male; Middle Aged; Piperidines

Administration of DL-fenfluramine to male rats caused an initial rise, followed by a sustained decrease in plasma renin activity. Both the increase, which reached a maximum at 30 min and the decrease, which was maximal at 4 hr after administration of fenfluramine, were dose-dependent. Pretreatment with either of the blockers of serotonin uptake, fluoxetine or indalpine blocked the increase in plasma renin activity induced by fenfluramine at 30 min, but did not affect the decrease at 4 hr after injection. Similarly, pretreatment with the inhibitor of the synthesis of serotonin, p-chlorophenylalanine methylester (PCPA) blocked the initial (30 min) but not the delayed (4 hr) effect of fenfluramine on plasma renin activity. The initial stimulation of secretion of renin by a submaximal dose (2 mg/kg, i.p.) of fenfluramine was potentiated by pretreatment with the precursor of serotonin L-tryptophan (100 mg/kg, i.p.). Pretreatment with the blocker of the uptake of norepinephrine, desipramine did not prevent the initial (30 min) effect but completely prevented the delayed (4 hr) effect of fenfluramine on plasma renin activity. These results suggest that the initial effect of fenfluramine is mediated via a serotonergic mechanism while the delayed, but long-lasting suppression of plasma renin activity, is mediated via a noradrenergic mechanism.

Topics: Animals; Blood Pressure; Desipramine; Dose-Response Relationship, Drug; Fenclonine; Fenfluramine; Fluoxetine; Heart Rate; Male; Norepinephrine; Piperidines; Rats; Rats, Inbred Strains; Renin; Serotonin; Serotonin Antagonists; Time Factors; Tryptophan

Dihydroxy-phenyl-ethylene-glycol (DOPEG or DHPG), a deaminated catabolite of noradrenaline formed after presynaptic re-uptake, is a good marker of metabolic activity in noradrenergic pathways. Plasma levels of free, conjugated and total DOPEG were measured by a radioenzymatic method in 45 patients with major depression selected according to the DSM 3 criteria and in 45 matched controls. A significant decrease in man DOPEG levels was observed in all depressive patients. A dexamethasone suppression test performed in these patients showed no difference in DOPEG levels between responders and non-responders, thus failing to support the hypothesis that subjects with low noradrenergic drive escape suppression. There was no correlation between plasma DOPEG levels and urinary excretion of methoxy-hydroxy-phenylglycol (MOPEG), another marker of noradrenaline metabolic activity. Thirty-one patients were treated with a specific monoaminergic antidepressant: maprotiline or indalpine; contrary to urinary MOPEG levels, plasma DOPEG levels had no predictive value concerning the response to this category of antidepressants. The various possible reasons for the fall in DOPEG observed in depressive patients are discussed.

Topics: Adult; Antidepressive Agents; Brain; Depressive Disorder; Dexamethasone; Female; Glycols; Humans; Male; Maprotiline; Methoxyhydroxyphenylglycol; Middle Aged; Norepinephrine; Piperidines

Topics: Adult; Aged; Antidepressive Agents; Antidepressive Agents, Tricyclic; Depressive Disorder; Depressive Disorder, Major; Dibenzocycloheptenes; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Piperidines

The binding of [3H]indalpine (4-[2-(3-indolyl)]ethyl piperidine) to slide-mounted sections of rat brain has been characterized. This 5-hydroxytryptamine (5-HT) uptake blocker binds to sections with high affinity (KD approximately 1 nM). The binding is saturable, and can be displaced by the addition of clomipramine (1 microM). Other drugs inhibiting the uptake of 5-HT also have the capacity to inhibit the binding of [3H]indalpine. A significant correlation (r = 0.86) was found between the capacity of these compounds to inhibit the uptake of 5-HT and their potencies as inhibitors of [3H]indalpine binding. Binding was Na+ - and Cl- -dependent and was inhibited competitively by 5-HT. Furthermore, electrolytic lesions of the dorsal raphe or medial forebrain bundle, which cause a degeneration of 5-HT cell bodies and fibers, respectively, resulted in a 30-40% reduction in the binding of [3H]indalpine. [3H]Indalpine binds to the 5-HT uptake recognition sites in a different manner from imipramine-like compounds.

Topics: Animals; Antidepressive Agents; Antidepressive Agents, Tricyclic; Autoradiography; Binding Sites; Brain; Dopamine; Imipramine; Male; Medial Forebrain Bundle; Norepinephrine; Piperidines; Raphe Nuclei; Rats; Rats, Inbred Strains; Serotonin

Daily injection of triiodothyronine (T3) for 3 consecutive days dose dependently enhanced 1-5-HTP (4 mg/kg)-induced head twitches in mice. This effect was blocked by 1-penbutolol. Pretreatment with a sub-effective dose of T3 (0.06 mg/kg) markedly enhanced the ability of clenbuterol but not indalpine to potentiate the response to 1-5-HTP. Likewise, the effects of T3 were more pronounced on the desipramine- or maprotiline-induced potentiation of head-twitches than on the action of citalopram or clomipramine. These data suggest that the increased responsiveness to 1-5-HTP caused by T3 involves an indirect (noradrenalin-mediated) rather than a direct effect on serotonergic processes.

Topics: 5-Hydroxytryptophan; Animals; Antidepressive Agents; Clenbuterol; Dose-Response Relationship, Drug; Drug Synergism; Head; Male; Mice; Movement; Piperidines; Tremor; Triiodothyronine

Topics: Aged; Aggression; Animals; Antidepressive Agents; Chemical Phenomena; Chemistry; Depression; Drug Therapy, Combination; Female; Haplorhini; Humans; Male; Mental Disorders; Middle Aged; Obsessive-Compulsive Disorder; Phobic Disorders; Piperidines; Rabbits; Rats; Satiation; Serotonin Antagonists; Sexual Behavior

The authors report two cases of hepatitis and a case of pancreatitis associated with indalpine. In one case of hepatitis, onset was acute and the clinical presentation was suggestive of cholecystitis; in the other case, hepatitis was discovered by biological tests. In the two cases, hepatitis was mainly cytolytic. Outcome was favorable upon interruption of drug administration. Onset of pancreatitis was inconspicuous, with progressively increasing pain. The pancreatic lesions were diffuse and massive. After interruption of administration, outcome was eventually favorable. Elevated amylasemia was also noted in the two cases of hepatitis. It is suggested that transaminase and amylase activities should be monitored during indalpine therapy.

Topics: Aged; Antidepressive Agents; Chemical and Drug Induced Liver Injury; Female; Humans; Middle Aged; Pancreatitis; Piperidines

The localization of binding sites for [3H]indalpine to sections of rat brain was studied by a quantitative autoradiographic technique. Binding sites for this specific neuronal 5-hydroxytryptamine (5-HT) uptake inhibitor are concentrated in areas rich in 5-HT neuronal cell bodies, fibers, and synaptic terminals. One of the most interesting features of this regional distribution is the very high density of these sites found in the dorsal raphe, substantia nigra, ventral tegmental area, and locus ceruleus. Components of the visual system also show pronounced labelling with [3H]indalpine. The finding that limbic structures are strongly labelled by this drug may be related to the antidepressant activity of indalpine. The anatomical distribution of binding sites demonstrated is consistent with the specific labelling of 5-HT neurons by [3H]indalpine and confirms previous studies carried out with another 5-HT uptake inhibitor, [3H]imipramine.

Topics: Animals; Autoradiography; Binding Sites; Brain; Hippocampus; Hypothalamus; Limbic System; Locus Coeruleus; Male; Piperidines; Raphe Nuclei; Rats; Rats, Inbred Strains; Serotonin; Substantia Nigra; Superior Colliculi

Topics: Brain; Depressive Disorder; Dexamethasone; Glycols; Humans; Hypothalamo-Hypophyseal System; Maprotiline; Methoxyhydroxyphenylglycol; Norepinephrine; Piperidines; Pituitary-Adrenal System; Random Allocation

Topics: Aged; Agranulocytosis; Antidepressive Agents; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Piperidines

In order to document the role of monoamines in the reduction of paradoxical sleep by antidepressant drugs, we examined the effect of indalpine , a selective inhibitor of serotonin uptake. Indalpine dose dependently decreased paradoxical sleep and delayed its first appearance. Pretreatment with parachlorophenylalanine markedly decreased the effect of indalpine . In contrast, pretreatment with alpha-methylparatyrosine potentiated the indalpine -induced depression of paradoxical sleep. The results of the study indicate that the increase of extracellular concentration of 5-HT has an inhibitory effect on paradoxical sleep, and this effect is enlarged if catecholaminergic activity is reduced.

Topics: alpha-Methyltyrosine; Animals; Antidepressive Agents; Brain; Catecholamines; Dose-Response Relationship, Drug; Drug Interactions; Fenclonine; Male; Methyltyrosines; Piperidines; Rats; Rats, Inbred Strains; Serotonin; Serotonin Antagonists; Sleep, REM

Several antidepressant treatments enhance serotonergic neurotransmission. The present electrophysiological studies were undertaken to assess the effect of mianserin and indalpine, two antidepressant drugs with different pharmacological profiles, on serotonergic neurotransmission. In a first series of experiments, the responsiveness of hippocampal pyramidal neurons to microiontophoretic applications of serotonin (5-HT), norepinephrine (NE) and gamma-aminobutyric acid (GABA) was assessed following mianserin, imipramine (5 mg/kg/day IP) or saline administration for 14 days. At 48 h after the last dose of mianserin, responsiveness to 5-HT was increased whereas that to NE and GABA was not modified. The degree of sensitization to 5-HT was the same as that produced by imipramine. Acute IV administration of mianserin (up to 10 mg/kg) did not decrease the firing rate of dorsal raphe 5-HT neurons. In a second series of experiments, long-term administration of indalpine (5 mg/kg/day IP for 14 days) did not modify the responsiveness of hippocampal pyramidal neurons to microiontophoretically applied 5-HT, NE and GABA whereas imipramine treatment (5 mg/kg/day IP) increased selectively their sensitivity to 5-HT when compared to indalpine-treated rats. In keeping with its potent reuptake-blocking property, acute IV indalpine produced a marked decrease in the firing rate of dorsal raphe 5-HT neurons (ED50 0.33 mg/kg). The firing rate of dorsal raphe 5-HT neurons was assessed following 2-, 7- and 14-day treatments with indalpine (5 mg/day IP). After 2 days, the firing rate of 5-HT neurons was greatly reduced, after 7 days it had recovered partially and after 14 days it had returned to normal.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Action Potentials; Animals; Antidepressive Agents; Dibenzazepines; gamma-Aminobutyric Acid; Hippocampus; Imipramine; Lysergic Acid Diethylamide; Male; Mianserin; Neurons; Norepinephrine; Piperidines; Pyramidal Tracts; Raphe Nuclei; Rats; Rats, Inbred Strains; Serotonin; Serotonin Antagonists

Topics: Adult; Cognition Disorders; Confusion; Dibenzocycloheptenes; Drug Therapy, Combination; Female; Humans; Middle Aged; Piperidines

Topics: Affective Disorders, Psychotic; Aged; Delusions; Humans; Male; Middle Aged; Piperidines

The administration of 4-[2-(3-indolyl)ethyl]piperidine (LM 5008), a selective 5-hydroxytryptamine (5-HT) uptake blocker to rats pretreated with tranylcypromine (Tcp) resulted in a behavioural syndrome of locomotor hyperactivity which is indistinguishable from that following combined treatment with Tcp and L-tryptophan. A similar behavioural response was elicited by the administration of LM 5008 to rats pretreated with 5-hydroxytryptophan. The response to LM 5008 after monoamine oxidase (MAO) inhibition was abolished by pretreatment with p-chlorophenylalanine, indicating the involvement of 5-HT in producing the hyperactivity syndrome. The administration of imipramine and chlorimipramine in combination with Tcp also resulted in hyperactivity, but these drugs were much less potent than LM 5008 in producing the syndrome. In contrast to L-tryptophan, which can produce hyperactivity only after the inhibition of both type A and type B MAO, LM 5008 can elicit the syndrome after selective inhibition of MAO type A only but not after inhibition of MAO type B. The behavioural results indicate that when MAO type A is inhibited, LM 5008 treatment elicits hyperactivity by preventing the availability of 5-HT to be metabolized by MAO-B component.

Topics: 5-Hydroxytryptophan; Animals; Behavior, Animal; Clorgyline; Drug Combinations; Male; Monoamine Oxidase Inhibitors; Motor Activity; Piperidines; Rats; Rats, Inbred Strains; Selegiline; Tranylcypromine

LM 5008 (4-[2-(3-indolyl)ethyl]piperidine) (10, 20 and 50 mg kg-1) had no significant effect on pressor responses to noradrenaline or tyramine in rats anaesthetized with urethane. Desmethylimipramine (1 mg kg-1) blocked the response to tyramine but chlorimipramine (5 mg kg-1) had no significant effect on responses to noradrenaline or tyramine. In the rabbit, anaesthetized with chloralose, LM 5008 (5 mg kg-1) had no effect on pressor responses to noradrenaline, tyramine or angiotensin II, while desmethylimipramine (0.25 mg kg-1) inhibited responses to tyramine and potentiated those to noradrenaline. LM 5008 (10 mg kg-1) had no effect on resting blood pressure of conscious normotensive or DOCA-saline hypertensive rats. Tranylcypromine (5 mg kg-1) produced a fall in blood pressure in conscious normotensive and in DOCA hypertensive rats. Treatment with a combination of LM 5008 (10 mg kg-1) and tranylcypromine (5 mg kg-1) resulted in the appearance of a behavioural hyperactivity syndrome, but blood pressure was not different from that of animals treated with tranylcypromine alone. These results further demonstrate the selectivity of LM 5008 for 5-hydroxytryptamine as opposed to catecholamine uptake.

Topics: Angiotensin II; Animals; Blood Pressure; Clomipramine; Desipramine; Drug Interactions; Female; Male; Norepinephrine; Piperidines; Rabbits; Rats; Rats, Inbred Strains; Serotonin Antagonists; Species Specificity; Sympathomimetics; Tyramine

The recoveries were compared of acetylsalicylic acid (ASA) and indalpine (1) after buccal absorption in three trained human volunteers. Recovery of the poorly lipid soluble ASA was less than 1% at pH 5 or 8, while that of the lipid soluble I was 19% and 13% at pH 5 and 8 respectively. This difference in recovery may represent a difference in their storage within the buccal mucosa dependent on their different lipid solubilities.

Topics: Absorption; Aspirin; Cheek; Chemistry, Pharmaceutical; Humans; Hydrogen-Ion Concentration; Kinetics; Mouth Mucosa; Piperidines

The proserotoninergic hypothesis of depression has been for a long time founded on biochemical parameters (brain from suicide patients, CSF and plasma from depressed patients) or more recently on measurement of platelets 5-HT uptake or imipramine binding. New specific proserotoninergic agents confirm this hypothesis since indalpine, a specific 5-HT uptake inhibitor, has a neurochemical and pharmacological profile characteristics of proserotoninergic agents and is effectively antidepressant in human. 5-HT uptake inhibition seems an important property because when we compared two isomers one, a 5-HT uptake inhibitor and at the same time 5-HT releaser, and the other only releaser, we observed that the first has experimental properties similar to indalpine whereas the second has not the classical spectrum of a proserotoninergic agent.

Topics: Animals; Brain; Depressive Disorder; Dopamine; Humans; Norepinephrine; Piperidines; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Synaptic Transmission

Topics: Antidepressive Agents; Chromatography, High Pressure Liquid; Humans; Piperidines; Reference Values; Time Factors

Reserpine + nialamid administration to the rat induces a strong yellow fluorescence of the neuronal bodies of the raphe, due to serotonin (5-HT) accumulation. Under these conditions, administration of clomipramine (an antidepressant drug acting preferentially on 5-HT-mediated neurons) induces a decrease of intraneuronal fluorescence and its interneuronal diffusion. On this pattern we administered new antidepressant drugs which act on 5-HT neurons in a much more intensive way than clomipramine (fluvoxamine, clovoxamine, LM 5008, citalopram, Ro 11-2465). To varying degrees, we observed in the raphe, in addition to a decrease in intraneuronal fluorescence and interneuronal diffusion, the presence of a yellow fluorescence in capillary walls. It seems that under these antidepressants, 5-HT, which is outside neuronal bodies because of uptake blockade, is partly caught by the capillary walls. In these walls rich in monoamine oxydase, 5-HT would be catabolized, 5HIAA dispersed in the blood and thus, this 'capillary effect' could correspond to a loss of 5-HT in the raphe. Antidepressant drugs preferentially acting upon noradrenaline (NA) neurons do not, in this model, induce analogous phenomena in NA cell bodies of the locus coeruleus. So the 'capillary effect' differentiates antidepressant drugs acting specifically on 5-HT or NA neurons. It may be considered together with other parameters which also indicate asymmetries on the modes of action of antidepressant drugs, such as effects on monoamine turnover (increase for NA and decrease for 5-HT) and on receptor sensitivity (decrease for NA and increase for 5-HT).

Topics: Animals; Antidepressive Agents, Tricyclic; Benzofurans; Brain Stem; Citalopram; Clomipramine; Ethers; Fluvoxamine; Imipramine; Indoles; Locus Coeruleus; Male; Microscopy, Fluorescence; Norepinephrine; Oximes; Piperidines; Propylamines; Raphe Nuclei; Rats; Receptors, Serotonin; Serotonin

Topics: Alcohol Drinking; Alcoholism; Animals; Humans; Piperidines; Rats; Serotonin Antagonists

Topics: Analgesics; Animals; Binding, Competitive; Brain Chemistry; Drug Tolerance; Male; Meperidine; Mice; Morphine; Piperidines; Reaction Time; Receptors, Opioid; Serotonin Antagonists; Tryptamines

4-(3-Indolyl-2-ethyl) piperidine (LM 5008), 2-(1-piperazinyl) quinoline (quipazine), and metachlorophenylpiperazine (mCPP) were studied for their ability to affect serotonergic mechanisms in vitro. Their relative potency in inhibiting serotonin (5-HT) uptake in vivo and reducing food intake in rats was also examined. mCPP was very potent in displacing 3H-5-HT bound to brain membranes (IC50, 6.2 X 10(-7) M), followed by quipazine, which showed an IC50 of 3.8 X 10(-6) M. LM 5008 was the least effective with an IC50 of 3.6 X 10(-5) M. mCPP and quipazine were less potent than d-fenfluramine in releasing 14C-5-HT from brain synaptosomes, while LM 5008 caused no significant effects at a concentration of 10(-5) M. Conversely, both in vitro and in vivo studies on 5-HT uptake showed that LM 5008 was the most potent compound in inhibiting 5-HT uptake and mCPP the least potent. Since a 50% reduction of food intake was not reached even with a dose of LM 5008 27-times higher than the ED50 for inhibiting 5-HT uptake in vivo, it is suggested that even marked inhibition of 5-HT uptake at central synapses is not sufficient per se to trigger serotonin-dependent anorexia in the rat. Increased release and/or direct stimulation of post-synaptic receptors may be necessary to obtain this effect. This could be of interest for developing new agents which can cause anorexia by interacting with brain serotonin.

Topics: Animals; Anorexia; Brain; Feeding and Eating Disorders; Feeding Behavior; Female; Fenfluramine; Humans; Piperazines; Piperidines; Quipazine; Rats; Serotonin; Serotonin Antagonists; Synaptosomes; Time Factors

Topics: Animals; Anorexia; Appetite Depressants; Brain; Feeding Behavior; Fenfluramine; Piperazines; Piperidines; Quipazine; Rats; Receptors, Serotonin; Serotonin; Synaptosomes

Topics: Animals; Antidepressive Agents, Tricyclic; Brain; Dopamine; Female; Fluoxetine; In Vitro Techniques; Indoles; Male; Norepinephrine; Parasympatholytics; Piperidines; Rabbits; Rats; Receptors, Muscarinic; Saimiri; Serotonin; Synaptosomes

Topics: Animals; Biological Transport; Blood Platelets; Hydroxyindoleacetic Acid; Indoles; Kinetics; Male; Piperidines; Rats; Serotonin