Abstract
Previous work has suggested that repeated treatment with substituted amphetamines including PCA, MDMA andd-fenfluramine produces a persistent neurodegeneration which is relatively selective for the fine serotoninergic terminals arising from the dorsal raphe nucleus. The aim of the present study was to investigate whether the acute releasing effect ofd-fenfluramine might also be sensitive to lesions produced by PCA, MDMA andd-fenfluramine itself. Basal and 5-HT release evoked byd-fenfluramine or 100 mM KCl was measured by microdialysis in frontal or parietal cortex of rats 2 weeks after they had been treated with a neurodegenerative regime of PCA, MDMA,d-fenfluramine, or vehicle. In frontal cortex of vehicle controls,d-fenfluramine (10 mg/kg IP) and KCl (100 mM via microdialysis probe) evoked an increase in 5-HT of 1740% and 779% of basal, respectively. PCA pretreatment reducedd-fenfluramine-evoked 5-HT release by 90.9% while potassium-evoked release was reduced by only 66.8%. Similar results were obtained in parietal cortex. MDMA (20 mg/kg×8) andd-fenfluramine (12.5 mg/kg×8) pretreatment reducedd-fenfluramine-evoked release of 5-HT in frontal cortex by 45.2% and 72.0%, respectively. Overall, the present data are consistent with the hypothesis that the acute release of 5-HT evoked byd-fenfluramine occurs via those terminals destroyed by pretreatment with PCA, MDMA andd-fenfluramine, while KCl evokes release from both PCA-sensitive and PCA-insensitive terminals. The significance of these results for the interpretation of neuroendocrine data fromd-fenfluramine challenge tests is discussed.
Similar content being viewed by others
References
Anderson IM, Ware CJ, Da Roza Davis JM, Cowen PJ (1992) Decreased 5-HT-mediated prolactin release in major depression. Br J Psychiatry 160:372–378
Battaglia G, Sharkey J, Kuhar MJ, De Souza EB (1991) Neuroanatomic specificity and time course of alterations in rat brain serotonergic pathways induced by MDMA (3,4-methylenedioxy-methamphetamine): assessment using quantitative autoradiography. Synapse 8:249–260
Baumgarten G, Garattini S, Lorens S, Wurtman R (1992) Dexfenfluramine and neurotoxicity. Lancet 339:359
Blue ME, Yagaloff KA, Mamounas LA, Hartig PR, Molliver ME (1988) Correspondence between 5-HT2 receptors and serotonergic axons in rat neocortex. Brain Res 453:315–328
Cowen PJ (1992) Neuroendocrine measures of 5-HT receptor subtype function in depression. In: Bradley PB, Handley SL, Cooper SJ, Key BJ, Barnes NM, Coote JH (eds) Serotonin, CNS receptors and brain function (Advances in the Biosciences, 85). Pergamon Press, Oxford, pp 287–296
Fuller RW, Baker JC, Perry KW, Molloy BB (1975) Comparison of 4-chlor- 4-bromo- and 4-fluoroamphetamine in rats: drug levels in brain and effects on brain serotonin metabolism. Neuropharmacology 75:739–746
Goodall EM, Cowen PJ, Franklin M, Silverstone T (1993) Ritanserin attenuates anorectic, endocrine and thermic responses tod-fenfluramine in human volunteers. Psychopharmacology 112:461–466
Haring JH, Meyerson L, Hoffman TL (1992) Effects of parachloroamphetamine upon the serotonergic innervation of the rat hippocampus. Brain Res 577:253–260
Johnson MP, Conarty PF, Nichols DE (1991) [3H] Monoamine releasing and uptake inhibition properties of 3,4-methylenedioxymethamphetamine andp-chloroamphetamine analogues. Eur J Pharmacol 200:9–16
Kleven MS, Seiden LS (1989)d- l- anddl-Fenfluramine cause long-lasting depletions of serotonin in rat brain. Brain Res 505:351–353
Köhler C, Chan-Palay V, Haglund L, Steinbusch H (1980) Immunohistochemical localization of serotonin nerve terminals in the lateral entorhinal cortex of the rat: demonstration of two separate patterns of innervation from the midbrain raphe. Anat Embryol 160:121–129
Kosofsky BE, Molliver ME (1987) The serotonergic innervation of cerebral cortex: different classes of axon terminals arise from dorsal and median raphe nuclei. Synapse 1:153–168
Kreiss DS, Wieland S, Lucki I (1993) The presence of a serotonin uptake inhibitor alters pharmacological manipulations of serotonin release. Neuroscience 52:295–301
Laferrere B, Wurtman RJ (1989) Effect ofd-fenfluramine on serotonin release in brains of anaesthetized rats. Brain Res 504:258–263
Mamounas LA, Molliver ME (1988) Evidence for dual serotonergic projections to neocortex: axons from the dorsal and median raphe nuclei are differentially vulnerable to the neurotoxinp-chloroamphetamine (PCA). Exp Neurol 102:23–36
Mamounas LA, Mullen CA, O'Hearn E, Molliver ME (1991) Dual serotoninergic projections to forebrain in the rat: morphologically distinct 5-HT axon terminals exhibit differential vulnerability to neurotoxic amphetamine derivatives. J Comp Neurol 314:558–586
McQuade R, Cowen PJ, Sharp T (1994) Effect of the 5-HT neurotoxinp-chloroamphetamine on rat hippocampal 5-HT release evoked by electrical stimulation of the dorsal and median raphe nuclei. Br J Pharmacol 111 [Suppl]:157P
Molliver DC, Molliver ME (1990) Anatomic evidence for a neurotoxic effect of (±)-fenfluramine upon serotonergic projections in the rat. Brain Res 511:165–168
Molliver ME, Berger UV, Mamounas LA, Molliver DC, O'Hearn E, Wilson MA (1990) Neurotoxicity of MDMA and related compounds: anatomic studies. Ann NY Acad Sci 600:640–664
O'Hearn E, Battaglia G, De Souza EB, Kuhar MJ, Molliver ME (1988) Methylenedioxyamphetamine (MDA) and methylene-dioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity. J Neurosci 8:2788–2803
Power AC, Cowen PJ (1992) Neuroendocrine challenge tests: assessment of 5-HT function in anxiety and depression. Molec Aspects Med 13:205–220
Ricaurte GA, Molliver ME, Martello MB, Katz JL, Wilson MA, Martello AL (1991) Dexfenfluramine neurotoxicity in brains of non-human primates. Lancet 338:1487–1488
Ricaurte GA, Martello AL, Katz JL, Martello MB (1992) Lasting effects of (±)-3,4-methylenedioxymethamphetamine (MDMA) on central serotonergic synapses in nonhuman primates: neurochemical observations. J Pharmacol Exp Ther 261:616–622
Sanders-Bush E, Martin LL (1982) Storage and release of serotonin. In: Osborne NN (ed) Biology of serotonergic transmission. Wiley, Chichester, pp 95–118
Sanders-Bush E, Bushing JA, Sulser F (1975) Long-term effects ofp-chloroamphetamine and related drugs on central serotonergic mechanisms. J Pharmacol Exp Ther 192:33–41
Sarkissian CF, Wurtman RJ, Morse AN, Gleason R (1990) Effects of fluoxetine ord-fenfluramine on serotonin release from, and levels in, rat frontal cortex. Brain Res 529:294–301
Series HG, Sharp T, Grahame-Smith DG (1993) Evidence thatd-fenfluramine releases 5-HT selectively from terminals of dorsal raphe neurons. Br J Pharmacol 109:92P
Sharp T, Foster GA (1989) In vivo measurement using microdialysis of the release and metabolism of 5-hydroxytryptamine in raphe neurones grafted to the rat hippocampus. J Neurochem 53:303–306
Sharp T, Zetterström T (1992) In vivo measurement of monoamine neurotransmitter release and metabolism using brain microdialysis. In: Stamford JA (ed) Monitoring neuronal activity: a practical approach. OUP, London, pp. 147–179
Sharp T, Zetterström T, Christmanson L, Ungerstedt U (1986)p-Chloroamphetamine releases both serotonin and dopamine into rat brain dialysates in vivo. Neurosci Lett 72:320–324
Shoulson I, Chase TN (1975) Fenfluramine in man: hypophagia associated with diminished serotonin turnover. Clin Pharmacol Ther 17:616–621
Stone DM, Stahl DC, Hanson GR, Gibb JW (1986) The effects of 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) on monoaminergic systems in the rat brain. Eur J Pharmacol 128:41–48
Törk I (1990) Anatomy of the serotonergic system. Ann NY Acad Sci 600:9–35
Wilson MA, Molliver ME (1991) The organization of serotonergic projections to cerebral cortex in primates: regional distribution of axon terminals. Neuroscience 44:537–553
Wilson MA, Ricaurte GA, Molliver ME (1989) Distinct morphologic classes of serotonergic axons in primates exhibit differential vulnerability to the psychotropic drug 3,4-methylenedioxymethamphetamine. Neuroscience 28:121–137
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Series, H.G., Cowen, P.J. & Sharp, T. p-Chloroamphetamine (PCA), 3,4-methylenedioxymethamphetamine (MDMA) andd-fenfluramine pretreatment attenuatesd-fenfluramine-evoked release of 5-HT in vivo. Psychopharmacology 116, 508–514 (1994). https://doi.org/10.1007/BF02247485
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF02247485