Effects of 4-(3-indolyl-alkyl) piperidine derivatives on brain 5-hydroxytryptamine turnover and on cardiac and brain noradrenaline or 5-hydroxytryptamine depletion induced by 6-hydroxydopamine, H 7512 and 4-chloroamphetamine

Fur, G. Le; Mitrani, N.; Uzan, A.

doi:10.1016/0006-2952(77)90325-2

Cited by 14 publications

(1 citation statement)

References 22 publications

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“…In vitro LM 5008 is as potent as imipramine and chlorimipramine in inhibiting [3H]-5-HT uptake into synaptosomes . However, in vivo LM 5008 was far more potent than the tricyclic uptake blockers (Le Fur, Mitrani & Uzan, 1977). Our behavioural studies confirm the in vivo data of Le Fur et al (1977).…”

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confidence: 90%

Behavioural hyperactivity in rats treated with selective monoamine oxidase inhibitors and LM 5008, a selective 5‐hydroxytryptamine uptake blocker

Ashkenazi

Finberg

Youdim

1983

British J Pharmacology

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1 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. 2 A similar behavioural response was elicited by the administration of LM 5008 to rats pretreated with 5-hydroxytryptophan. 3 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. 4 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. 5 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. 6 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. Introduction When rats are treated with an irreversible monoamine oxidase (MAO) inhibitor and Ltryptophan they display a stereotyped hyperactivity syndrome (Hess & Doepfner, 1961;Horita & Carino, 1970;Grahame-Smith, 1971;Modigh & Svensson, 1972). This syndrome is believed to be mediated by 5-hydroxytryptamine (5-HT), since inhibition of 5-HT synthesis by prior treatment with p-chlorophenylalanine (PCPA) prevents its production (Horita & Carino, 1970;Grahame-Smith, 1971; Modigh and Svenssen, 1972). Hyperactivity is not closely correlated with the cerebral content of 5-HT (Hess & Doepfner, 1961) but is related to the rate of 5-HT accumulation. Grahame-Smith (1971) has suggested that when the nerve terminal is unable to store the excess of 5-HT, which accumulates as a result of precursor loading combined with decreased metabolic degradation, the amine 'spills over' into the synaptic cleft and causes the hyperactivity syndrome. If this is so, then the inhibition of 5-HT reuptake in association with increased neuronal 5-HT synthesis would also provide extraneuronal excess of 5-HT and should result in hyperactivity. Potentiation of behavioural response to Ltryptophan by the 5-HT uptake inhibitors, chlorimipramine and fluoxetine, in rats pretreated with MAO inhibitors has been reported by Fuller, Perry & Molloy (1974). Holman, Seagraves, Elliot & Barchas (1976) have shown that the combined treatment with the non-selective MAO inhibitor tranylcypromine (Tcp) and either Lilly 110140 or 5-hydroxytryptoline (which selectively inhibit 5-HT uptake) resulted in a behavioural hyperactivity similar to that seen after Tcp and L-tryptophan administration. Green & Youdim (1975) and Squires & Lassen (1975) attempted to define the role of MAO-A and MAO-B in eliciting behavioural excitat...

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Section: -1/ O 400-]supporting

confidence: 90%

Behavioural hyperactivity in rats treated with selective monoamine oxidase inhibitors and LM 5008, a selective 5‐hydroxytryptamine uptake blocker

Ashkenazi

Finberg

Youdim

1983

British J Pharmacology

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Further studies on the mechanism of serotonin-dependent anorexia in rats

et al. 1980

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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.

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The role of different types of adrenergic receptors in phentylenetetrazol-induced seizures and the effect of di-n-propylacetate in the rat

1983

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Selective depletion of forebrain noradrenaline has been shown to potentiate various types of experimentally induced seizures. This study was aimed at exploring the role of different types of adrenergic receptors in pentylenetetrazol (PTZ)-induced seizures in rats and the anticonvulsive effect of di-n-propylacetate (DPA). Piperoxane (10 and 20 mg/kg, IP) significantly potentiated PTZ-induced tonic seizures and mortality. Similar effects were observed after 6-hydroxydopamine (6-OHDA)-induced depletion of forebrain noradrenaline, whereas no effects were found in animals with depletion of spinal noradrenaline. Neither phenoxybenzamine (20 mg/kg, IP) nor prazosin (1 and 10 mg/kg, IP) nor propranolol (2 and 5 mg/kg, IP) modified tonic seizures and mortality caused by PTZ. Combined treatment with propranolol (5 mg/kg, IP) and prazosin (10 mg/kg, IP) had no effect either. Various agents used to increase central serotonin transmission (d-fenfluramine, 5 mg/kg, IP; quipazine, 10 mg/kg, IP; m-chlorophenylpiperazine, 3 mg/kg, IP) did not alter the effect of piperoxane on PTZ-induced seizures. None of the conditions used to diminish central adrenergic function significantly affected the inhibitory effect of DPA on tonic seizures and mortality caused by PTZ. Combined treatment with subthreshold doses of clonidine (0.1 mg/kg, IP) and DPA (75 mg/kg, IP) significantly reduced tonic seizures and mortality caused by PTZ. The data suggest that alpha 2 type adrenoceptors are involved in the control of PTZ-induced seizures in rats. The peculiarity of the role of these receptors in the effect of PTZ is discussed.

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Effects of 4-(3-indolyl-alkyl) piperidine derivatives on brain 5-hydroxytryptamine turnover and on cardiac and brain noradrenaline or 5-hydroxytryptamine depletion induced by 6-hydroxydopamine, H 7512 and 4-chloroamphetamine

Cited by 14 publications

References 22 publications

Behavioural hyperactivity in rats treated with selective monoamine oxidase inhibitors and LM 5008, a selective 5‐hydroxytryptamine uptake blocker

Behavioural hyperactivity in rats treated with selective monoamine oxidase inhibitors and LM 5008, a selective 5‐hydroxytryptamine uptake blocker

Further studies on the mechanism of serotonin-dependent anorexia in rats

The role of different types of adrenergic receptors in phentylenetetrazol-induced seizures and the effect of di-n-propylacetate in the rat

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