Skip to main content
SpringerLink
Log in

Studies on the role of serotonin in different regions of the rat central nervous system of pentylenetetrazol-induced seizures and the effect of di-n-propylacetate

  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Summary

5,7-Dihydroxytryptamine (5,7-DHT) injections which caused selective depletion of serotonin in the forebrain enhanced the seizures caused by pentylenetetrazol (PTZ 90 mg/kg s.c.) in rats. No effect was observed in rats with 5,7-DHT-induced depletion of spinal serotonin or treated with metergoline (1 mg/kg i.p.) or methysergide (10 mg/kg i.p.).

The various procedures aimed at decreasing serotonin transmission did not significantly modify the effect of di-n-propylacetate (DPA) on tonic seizures and mortality caused by PTZ but significantly reduced the DPA-induced increase in the latency to the first convulsion. More animals with clonic seizures were seen in the DPA-treated group which had been subjected to selective depletion of spinal serotonin or treated with methysergide than in DPA-treated controls.

Combined treatment with d-fenfluramine (1.25 mg/kg i.p.) and DPA (75 mg/kg i.p.), doses which by themselves had no significant effect, reduced tonic seizures and mortality caused by PTZ.

The results show that a diffuse deficit in forebrain serotonin enhances PTZ-induced seizures. Serotonin does not play an important role in the effect of DPA against PTZ-induced tonic seizures but may contribute to the effect of DPA on clonic convulsions. Agents increasing serotonin transmission may enhance the anticonvulsant activity of DPA.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Aghajanian GK, Wang RY (1978) Physiology and pharmacology of central serotonergic neurons. In: Lipton MA, DiMascio A, Killam KF (eds) Psychopharmacology: A generation of progress. Raven, New York, pp 171–183

    Google Scholar 

  • Anlezark G, Horton RW, Meldrum BS, Sawaya CB (1976) Anticonvulsant action of ethanolamine-o-sulphate and di-n-propylacetate and the metabolism of γ-aminobutyric acid (GABA) in mice with audiogenic seizures. Biochem Pharmacol 25:413–417

    Google Scholar 

  • Assaf SY, Crunelli V, Kelly JS (1981) Action of 5-hydroxytryptamine on granule cells in the rat hippocampal slice. J Physiol (Paris) 77: 377–380

    Google Scholar 

  • Azmitia EC (1978) The serotonin-producing neurons of the midbrain median and dorsal raphe nuclei. In: Iversen LL, Iversen SD, Snyder SH (eds) Handbook of psychopharmacology, Chemical pathways in the brain, vol 9. Plenum, New York, pp 233–304

    Google Scholar 

  • Baldino F Jr, Geller HM (1981) Sodium valproate enhancement of γ-aminobutyric acid (GABA) inhibition: Electrophysiological evidence for anticonvulsant activity. J Pharmacol Exp Ther 217: 445–450

    Google Scholar 

  • Baumgarten HG, Lachenmayer L (1972) 5,7-Dihydroxytryptamine: Improvement in chemical lesioning of indoleamine neurons in the mammalian brain. Z Zellforsch Mikroskop Anat 135:399–414

    Google Scholar 

  • Bourgoin S, Artaud F, Bockaert J, Héry F, Glowinski J, Hamon M (1978) Paradoxical decrease of brain 5-HT turnover by metergoline, a central 5-HT receptor blocker. Naunyn-Schmiedeberg's Arch Pharmacol 302:313–321

    Google Scholar 

  • Browning RA, Hoffmann WE, Simonton RL (1978) Changes in seizure susceptibility after intracerebral treatment with 5,7-dihydroxytryptamine: Role of serotonergic neurons. Ann NY Acad Sci 305: 437–456

    Google Scholar 

  • De La Torre JC, Kanawaga HM, Mullan S (1970) Seizure susceptibility after manipulation of brain serotonin. Arch Int Pharmacodyn Ther 188:298–304

    Google Scholar 

  • Diaz PM (1974) Interaction of pentylenetetrazol and trimethadione on the metabolism of serotonin in brain and its relation to the anticonvulsant action of trimethadione. Neuropharmacology 13: 615–621

    Google Scholar 

  • Fuxe K, Farnebo LO, Hamberger B, Ogren SO (1975) On the in vivo and in vitro actions of fenfluramine and its derivatives on central monoamine neurons, especially 5-hydroxytryptamine neurons, and their relation to the anorectic activity of fenfluramine. Postgrad Med J 51 Suppl 1:35–45

    Google Scholar 

  • Garattini S, Samanin R (1978) Drugs affecting serotonin: A survey. In: Essman WB (ed) serotonin in health and disease: Physiological regulation and pharmacological action, vol II. Spectrum Publications, New York, pp 247–293

    Google Scholar 

  • Garattini S, Buczko W, Jori A, Samanin R (1975) On the mechanism of action of fenfluramine. Postgrad Med J 51 suppl 1:27–35

    Google Scholar 

  • Green AR, Hall JE, Rees AR (1981) A behavioural and biochemical study in rats of 5-hydroxytryptamine receptor agonists and antagonists, with observations on structure-activity requirements for the agonists. Br J Pharmacol 73:703–719

    Google Scholar 

  • Haigler HJ, Aghajanian GK (1977) Serotonin receptors in the brain. Fed Proc 36:2159–2164

    Google Scholar 

  • Hammond EJ, Wilder BJ, Bruni J (1981) Central actions of valproic acid in man and in experimental models of epilepsy. Life Sci 29:2561–2574

    Google Scholar 

  • Horton RW, Anlezark GM, Sawaya MCB, Meldrum BS (1977) Monoamine and GABA metabolism and the anticonvulsant action of di-n-propylacetate and ethanolamine-o-sulphate. Eur J Pharmacol 41:387–397

    Google Scholar 

  • Hwang EC, Van Woert MH (1979) Effect of valproic acid on serotonin metabolism. neuropharmacology 18:391–397

    Google Scholar 

  • Iadarola MJ, Gale K (1979) Dissociation between drug-induced increases in nerve terminal and non-nerve terminal pools of GABA in vivo. Eur J Pharmacol 59:125–129

    Google Scholar 

  • Iadarola MJ, Raines A, Gale K (1979) Differential effects on n-dipropylacetate and amino-oxyacetic acid on γ-aminobutyric acid levels in discrete areas of rat brain. J Neurochem 33:1119–1123

    Google Scholar 

  • Johnston GAR (1978) Neuropharmacology of amino acid inhibitory transmitters. Ann Rev Pharmacol Toxicol 18:269–289

    Google Scholar 

  • Keller R, Oke A, Mefford I, Adams RN (1976) Liquid chromatographic analysis of catecholamines routine assay for regional brain mapping. Life Sci 19:995–1004

    Google Scholar 

  • Kerwin RW, Olpe H-R (1980) The effect of sodium valporate on single unit activity in the rat brain. Br J Pharmacol 70:76P

    Google Scholar 

  • Kerwin RW, Olpe H-R, Schmutz M (1980) The effect of sodium-n-dipropyl acetate on γ-aminobutyric acid-dependent inhibition in the rat cortex and substantia nigra in relation to its anticonvulsant activity. Br J Pharmacol 71:545–551

    Google Scholar 

  • Kilian M, Frey H-H (1973) Central monoamines and convulsive thresholds in mice and rats. Neuropharmacology 12:681–692

    Google Scholar 

  • Koe BK, Weissman A (1966) p-Chlorophenylalamine: A specific depletor of brain serotonin. J Pharmacol Exp Ther 154:499–516

    Google Scholar 

  • König JFR, Klippel RA (1963) The rat brain. A stereotaxic atlas of the forebrain and lower parts of the brain stem. Williams and Wilkins Co, Baltimore

    Google Scholar 

  • Kovacs DA, Zoll JG (1974) Seizure inhibition by median raphe nucleus stimulation in rat. Brain Res 70:165–169

    Google Scholar 

  • Kupferberg HJ (1980) Antiepileptic drugs. Sodium valproate. In: Glaser GH, Penry JK, Woodbury DM (eds) Antiepileptic drugs: Mechanisms of action. Raven, New York, pp 643–654

    Google Scholar 

  • Lazarova MB, Roussinov KS (1978) On certain effects of dopaminergic agents in pentylenetetrazol convulsions. Acta Physiol Pharmacol Bulg 4:50–55

    Google Scholar 

  • Lazarova MB, Roussinov KS (1981) Effect of m-chlorophenylpiperazine on convulsive-seizure reactions. CR Acad Bulgare Sci 34:139–140

    Google Scholar 

  • Lazarova M, Przewlocka B, Mogilnicka E, Stala L (1979) The effect of l-Dopa and l-5-hydroxytryptophan on the pentetrazole seizures in rats after lesions of the median raphe nucleus and substantia nigra. Pol J Pharmacol Pharm 31:547–554

    Google Scholar 

  • Lazarova MB, Roussinov KS, Yanev SG, Petkov VD (1980a) Influence of chronic treatment with 5-hydroxytryptophan on the pentylenetetrazol convulsive-seizure reactions. CR Acad Bulgare Sci 33: 1147–1149

    Google Scholar 

  • Lazarova M, Roussinov K, Kleinrok Z, Rajtar G (1980b) On some relationships between GABA-ergic and 5-HT-ergic mechanisms in pentylenetetrazol convulsive-seizure reactions. Agressologie 21: 253–257

    Google Scholar 

  • Löscher W (1979) 3-Mercaptopropionic acid: Convulsant properties, effects on enzymes of the γ-aminobutyrate system in mouse brain and antagonism by certain anticonvulsant drugs, aminooxyacetic acid and gabaculine. Biochem Pharmacol 28:1397–1407

    Google Scholar 

  • Löscher W (1981) Effect of inhibitors of GABA aminotransferase on the metabolism of GABA in brain tissue and synaptosomal fractions. J Neurochem 36:1521–1527

    Google Scholar 

  • Löscher W, Böhme G, Schäfer H, Kochen W (1981) Effect of metabolites of valproic acid on the metabolism of GABA in brain and brain nerve endings. Neuropharmacology 20:1187–1192

    Google Scholar 

  • Luscombe G, Jenner P, Marsden CD (1981) Pharmacological analysis of the myoclonus induced by 5-hydroxytryptophan in the guinea pig suggests the presence of multiple 5-hydroxytryptamine receptors in the brain. Neuropharmacology 20:819–831

    Google Scholar 

  • Mason ST, Corcoran ME (1979) Catecholamines and convulsions. Brain Res 170:497–507

    Google Scholar 

  • Myslinski NR, Thut PD (1977) The effect of 5,6-dihydroxytryptamine on post-decapitation convulsions. Life Sci 21:1475–1482

    Google Scholar 

  • Pellegrino LJ, Pellegrino AS, Cushman AJ (1979) A stereotaxic atlas of the rat brain. Plenum, New York

    Google Scholar 

  • Ponzio F, Jonsson G (1979) A rapid and simple method for the determination of picogram of serotonin in brain tissue using liquid chromatography with electrochemical detection. J Neurochem 32:129–132

    Google Scholar 

  • Rall TW, Schleifer LS (1980) Drugs effective in the therapy of the epilepsies. In: Goodman Gilman A, Goodman LS, Gilman A (eds) The pharmacological basis of therapeutics, 6th ed. Macmillan, New York, pp 448–474

    Google Scholar 

  • Rose D (1979) Facilitation of bicuculline-and picrotoxin-induced seizures by sodium valproate in rats. Arch Int Pharmacodyn Ther 239:78–85

    Google Scholar 

  • Roussinov KS, Lazarova MB, Yanev SG (1975) On some correlations between adrenergic and serotonergic mechanisms of convulsiveseizure reactivity. Pol J Pharmacol Pharm 27 suppl: 231–235

    Google Scholar 

  • Samanin R, Bernasconi S, Garattini S (1975) The effect of nomifensine on depletion of brain serotonin and catecholamines induced respectively by fenfluramine and 6-hydroxydopamine in rats. Eur J Pharmacol 34:377–380

    Google Scholar 

  • Sastry BSR, Phillis JW (1977) Metergoline as a selective 5-hydroxytryptamine antagonist in the cerebral cortex. Can J Physiol Pharmacol 55:130–133

    Google Scholar 

  • Schmutz M, Olpe H-R, Koella WP (1979) Central actions of valproate sodium. J Pharm Pharmacol 31:413–414

    Google Scholar 

  • Segal M (1975) Physiological and pharmacological evidence for a serotonergic projection to the hippocampus. Brain Res 94:115–131

    Google Scholar 

  • Simler S, Ciesielski L, Maitre M, Randrianarisoa H, Mandel P (1973) Effect of sodium n-dipropylacetate on audiogenic seizures and brain γ-aminobutyric acid level. Biochem Pharmacol 22:1701–1708

    Google Scholar 

  • Simler S, Ciesielski L, Klein M, Mandel P (1982) Anticonvulsant and antiaggressive properties of di-n-propyl acetate after repeated treatment. Neuropharmacology 21:133–140

    Google Scholar 

  • Simon D, Penry JK (1975) Sodium di-n-propylacetate (DPA) in the treatment of epilepsy. Epilepsia 16:549–573

    Google Scholar 

  • Stone WE (1977) Effects of alterations in the metabolism of γ-aminobutyric on anticonvulsant potencies. Epilepsia 18:507–515

    Google Scholar 

  • Stone WE, Javid MJ (1979) Quantitative evaluation of the actions of anticonvulsants against different chemical convulsants. Arch Int Pharmacodyn Ther 240:66–78

    Google Scholar 

  • Turner AJ, Whittle SR (1980) Sodium valproate, GABA and epilepsy. Trends Pharmacol Sci 1:257–260

    Google Scholar 

  • Van Woert MH, Hwang EC (1981) Role of brain serotonin in myoclonus. In: Morselli PL, Lloyd KG, Löscher W, Meldrum B, Reynolds EH (eds) Neurotransmitters, seizures, and epilepsy. Raven, New York, pp 239–249

    Google Scholar 

  • Wood JD, Kurylo E, Tsui S-K (1981) Interactions of di-n-propylacetate, gabaculine, and aminooxyacetic acid: Anticonvulsant activity and the γ-aminobutyrate system. J Neurochem 37:1440–1447

    Google Scholar 

Download references

Author information

Author notes

  1. M. Lazarova (Visiting Scientist from Institute of Physiology)

    Present address: Bulgarian Academy of Sciences, Sofia, Bulgaria

Authors and Affiliations

  1. Istituto di Ricerche Farmacologiche ‘Mario Negri’, Via Eritrea, 62, I-20157, Milano, Italia

    M. Lazarova (Visiting Scientist from Institute of Physiology), C. Bendotti & R. Samanin

Authors
  1. M. Lazarova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C. Bendotti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. Samanin
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lazarova, M., Bendotti, C. & Samanin, R. Studies on the role of serotonin in different regions of the rat central nervous system of pentylenetetrazol-induced seizures and the effect of di-n-propylacetate. Naunyn-Schmiedeberg's Arch. Pharmacol. 322, 147–152 (1983). https://doi.org/10.1007/BF00512388

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00512388

Key words

Search

Navigation