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. 1986 May;88(1):269–275. doi: 10.1111/j.1476-5381.1986.tb09495.x

Effect of long term amineptine treatment on pre- and postsynaptic mechanisms in rat brain.

A Ceci, S Garattini, M Gobbi, T Mennini
PMCID: PMC1917102  PMID: 3708219

Abstract

The effect of amineptine and its two metabolites on monoamine uptake, release and receptor binding was studied in vitro. Amineptine and its two metabolites did not displace labelled ligands for known neurotransmitters and drug receptor sites. Amineptine and its two metabolites did not influence [3H]-5-hydroxytryptamine ([3H]-5-HT) uptake or release by rat brain synaptosomes. Amineptine inhibited [3H]-dopamine and [3H]-noradrenaline ([3H]-NA) accumulation, with IC50 values of 1.4 and 10 microM, respectively. The effect was retained, though with lower efficacy, by the two metabolites. Amineptine released [3H]-dopamine from preloaded synaptosomes. Metabolite 1 had no effect on catecholamine release, and metabolite 2 was about half as active as the parent compound on [3H]-dopamine release. The releasing effect of amineptine on [3H]-dopamine was potentiated by reserpine pretreatment, suggesting that the drug acts on the cytoplasmic neurotransmitter pool. Chronic treatment with amineptine (20 mg kg-1, twice daily for 15 days followed by a 3 days drug withdrawal period) resulted in a decrease of [3H]-spiperone binding sites in striatum, and of [3H]-dihyroalprenolol and [3H]-clonidine in cortex. Chronic treatment with amineptine reduced basal [3H]-dopamine accumulation in striatal synaptosomes, without affecting [3H]-NA or [3H]-5-HT accumulation. The adaptive changes in the pre- and postsynaptic dopamine mechanisms observed after long term treatment with amineptine are consistent with the drug acting as an indirect dopamine agonist. The down regulation of beta- and alpha 2-noradrenoceptors observed after long term amineptine treatment may play a role in the antidepressant activity of the drug.

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Selected References

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  1. Bennett J. P., Jr, Snyder S. H. Serotonin and lysergic acid diethylamide binding in rat brain membranes: relationship to postsynaptic serotonin receptors. Mol Pharmacol. 1976 May;12(3):373–389. [PubMed] [Google Scholar]
  2. Borsini F., Bendotti C., Velkov V., Rech R., Samanin R. Immobility test: effects of 5-hydroxytryptaminergic drugs and role of catecholamines in the activity of some antidepressants. J Pharm Pharmacol. 1981 Jan;33(1):33–37. doi: 10.1111/j.2042-7158.1981.tb13697.x. [DOI] [PubMed] [Google Scholar]
  3. Bylund D. B., Snyder S. H. Beta adrenergic receptor binding in membrane preparations from mammalian brain. Mol Pharmacol. 1976 Jul;12(4):568–580. [PubMed] [Google Scholar]
  4. Charney D. S., Menkes D. B., Heninger G. R. Receptor sensitivity and the mechanism of action of antidepressant treatment. Implications for the etiology and therapy of depression. Arch Gen Psychiatry. 1981 Oct;38(10):1160–1180. doi: 10.1001/archpsyc.1981.01780350094011. [DOI] [PubMed] [Google Scholar]
  5. Creese I., Prosser T., Synder S. H. Dopamine receptor binding: specificity, localization and regulation by ions and guanyl nucleotides. Life Sci. 1978 Aug 7;23(5):495–499. doi: 10.1016/0024-3205(78)90160-1. [DOI] [PubMed] [Google Scholar]
  6. Creese I., Sibley D. R. Receptor adaptations to centrally acting drugs. Annu Rev Pharmacol Toxicol. 1981;21:357–391. doi: 10.1146/annurev.pa.21.040181.002041. [DOI] [PubMed] [Google Scholar]
  7. Creese I., Snyder S. H. Dopamine receptor binding of 3H-ADTN (2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene) regulated by guanyl nucleotides. Eur J Pharmacol. 1978 Aug 15;50(4):459–461. doi: 10.1016/0014-2999(78)90156-5. [DOI] [PubMed] [Google Scholar]
  8. Dankova J., Boucher R., Poirier L. J. Effects of 1694 and other dopaminergic agents on circling behavior. Eur J Pharmacol. 1977 Mar 21;42(2):113–121. doi: 10.1016/0014-2999(77)90350-8. [DOI] [PubMed] [Google Scholar]
  9. Ehlert F. J., Roeske W. R., Yamamura H. I. Multiple benzodiazepine receptors and their regulation by gamma-aminobutyric acid. Life Sci. 1981 Jul 20;29(3):235–248. doi: 10.1016/0024-3205(81)90239-3. [DOI] [PubMed] [Google Scholar]
  10. GRAY E. G., WHITTAKER V. P. The isolation of nerve endings from brain: an electron-microscopic study of cell fragments derived by homogenization and centrifugation. J Anat. 1962 Jan;96:79–88. [PMC free article] [PubMed] [Google Scholar]
  11. Greenberg D. A., Prichard D. C., Snyder S. H. Alpha-noradrenergic receptor binding in mammalian brain: differential labeling of agonist and antagonist states. Life Sci. 1976 Jul 1;19(1):69–76. doi: 10.1016/0024-3205(76)90375-1. [DOI] [PubMed] [Google Scholar]
  12. Greengrass P., Bremner R. Binding characteristics of 3H-prazosin to rat brain alpha-adrenergic receptors. Eur J Pharmacol. 1979 May 1;55(3):323–326. doi: 10.1016/0014-2999(79)90202-4. [DOI] [PubMed] [Google Scholar]
  13. Herschel M., Baldessarini R. J. Evidence for two types of binding of 3H-gaba and 3H-muscimol in rat cerebral cortex and cerebellum. Life Sci. 1979 May 14;24(20):1849–1854. doi: 10.1016/0024-3205(79)90235-2. [DOI] [PubMed] [Google Scholar]
  14. Leysen J. E., Niemegeers C. J., Van Nueten J. M., Laduron P. M. [3H]Ketanserin (R 41 468), a selective 3H-ligand for serotonin2 receptor binding sites. Binding properties, brain distribution, and functional role. Mol Pharmacol. 1982 Mar;21(2):301–314. [PubMed] [Google Scholar]
  15. Mennini T., Pataccini R., Samanin R. Effects of narcotic analgesics on the uptake and release of 5-hydroxytryptamine in rat synaptosomal preparations. Br J Pharmacol. 1978 Sep;64(1):75–82. doi: 10.1111/j.1476-5381.1978.tb08643.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Nelson D. L., Herbet A., Bourgoin S., Glowinski J., Hamon M. Characteristics of central 5-HT receptors and their adaptive changes following intracerebral 5,7-dihydroxytryptamine administration in the rat. Mol Pharmacol. 1978 Nov;14(6):983–995. [PubMed] [Google Scholar]
  17. Raisman R., Briley M. S., Langer S. Z. Specific tricyclic antidepressant binding sites in rat brain characterised by high-affinity 3H-imipramine binding. Eur J Pharmacol. 1980 Feb;61(4):373–380. doi: 10.1016/0014-2999(80)90076-x. [DOI] [PubMed] [Google Scholar]
  18. Raisman R., Sette M., Pimoule C., Briley M., Langer S. Z. High-affinity [3H]desipramine binding in the peripheral and central nervous system: a specific site associated with the neuronal uptake of noradrenaline. Eur J Pharmacol. 1982 Mar 12;78(3):345–351. doi: 10.1016/0014-2999(82)90036-x. [DOI] [PubMed] [Google Scholar]
  19. Raiteri M., Angelini F., Levi G. A simple apparatus for studying the release of neurotransmitters from synaptosomes. Eur J Pharmacol. 1974 Mar;25(3):411–414. doi: 10.1016/0014-2999(74)90272-6. [DOI] [PubMed] [Google Scholar]
  20. Samanin R., Jori A., Bernasconi S., Morpugo E., Garattini S. Biochemical and pharmacological studies on amineptine (S 1694) and (+)-amphetamine in the rat. J Pharm Pharmacol. 1977 Sep;29(9):555–558. doi: 10.1111/j.2042-7158.1977.tb11395.x. [DOI] [PubMed] [Google Scholar]
  21. Sbarra C., Castelli M. G., Noseda A., Fanelli R. Pharmacokinetics of amineptine in man. Eur J Drug Metab Pharmacokinet. 1981;6(2):123–126. doi: 10.1007/BF03189478. [DOI] [PubMed] [Google Scholar]
  22. Sbarra C., Negrini P., Fanelli R. Quantitative analysis of amineptine (S-1694) in biological samples by gas chromatography--mass fragmentography. J Chromatogr. 1979 Jan 1;162(1):31–38. doi: 10.1016/s0378-4347(00)82060-5. [DOI] [PubMed] [Google Scholar]
  23. Tran V. T., Chang R. S., Snyder S. H. Histamine H1 receptors identified in mammalian brain membranes with [3H]mepyramine. Proc Natl Acad Sci U S A. 1978 Dec;75(12):6290–6294. doi: 10.1073/pnas.75.12.6290. [DOI] [PMC free article] [PubMed] [Google Scholar]

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