Abstract
Serotonin (5-HT) releasing agents such as d-fenfluramine are known to cause long-term depletion of forebrain 5-HT in animals, but the mechanism of this effect is unknown. In the present study, we examined the relationship between drug-induced 5-HT release and long-term 5-HT depletion in rat brain. The 5-HT-releasing actions of d-fenfluramine and a non-amphetamine 5-HT drug, 1-(m-chlorophenyl)piperazine (mCPP), were compared using in vivo microdialysis in the nucleus accumbens. The ability of d-fenfluramine and mCPP to interact with 5-HT transporters was tested using in vitro assays for [3H]5-HT uptake and radioligand binding. Local infusion of d-fenfluramine or mCPP (1–100 μM) increased extracellular 5-HT, with elevations in dopamine occurring at high doses. Intravenous injection of either drug (1–10 μmol/kg) produced dose-related increases in 5-HT without affecting dopamine. d-Fenfluramine and mCPP exhibited similar potency in their ability to stimulate 5-HT efflux in vivo and interact with 5-HT transporters in vitro. When rats received high-dose d-fenfluramine or mCPP (10 or 30 μmol/kg, i.p., every 2 h, 4 doses), only d-fenfluramine-treated rats displayed long-term 5-HT depletions. Thus, mCPP is a 5-HT releaser that does not appear to cause 5-HT depletion. Our data support the notion that 5-HT release per se may not be sufficient to produce the long-term 5-HT deficits associated with d-fenfluramine and other amphetamines.
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References
Appel NM, Mitchell WM, Contrera JF, De Souza EB . (1990): Effects of high dose fenfluramine treatment on monoamine uptake sites in rat brain: Assessment using quantitative autoradiography. Synapse 6: 33–44
Baumann MH, Rutter JJ, Auerbach SB . (1993): Intravenous administration of the serotonin agonist m-chlorophenylpiperazine (mCPP) increases extracellular serotonin in the diencephalon of awake rats. Neuropharmacology 32: 1381–1385
Baumann MH, Char GU, De Costa BR, Rice KC, Rothman RB . (1994): GBR12909 attenuates cocaine-induced activation of mesolimbic dopamine neurons in the rat. J Pharmacol Exp Ther 271: 1216–1222
Baumann MH, Mash DC, Staley JK . (1995): The serotonin agonist m-chlorophenylpiperazine (mCPP) binds to serotonin transporter sites in human brain. Neuroreport 6: 2150–2152
Baumann MH, Ayestas MA, Rothman RB . (1998): Functional consequences of central serotonin depletion produced by repeated fenfluramine administration in rats. J Neurosci 18: 9069–9077
Bengel D, Issacs KR, Heils A, Lesch KP, Murphy DL . (1998): The appetite suppressant d-fenfluramine induces apoptosis in human serotonergic cells. Neuroreport 9: 2989–2993
Berger UV, Gu XF, Azmitia EC . (1992): The substituted amphetamines 3,4-methylenedioxymethamphetamine, methamphetamine, p-chloroamphetamine and fenfluramine induce 5-hydroxytryptamine release via a common mechanism blocked by fluoxetine and cocaine. Eur J Pharmacol 215: 153–160
Boja JW, Mitchell WM, Patel A, Kopajtic T, Carroll FI, Lewin AH, Abraham P, Kuhar MJ . (1992): High-affinity binding of [125I]RTI-55 to dopamine and serotonin transporters in rat brain. Synapse 12: 27–36
Caccia S, Anelli M, Ferrarese A, Fracasso C, Garattini S . (1992): Single- and multiple-dose kinetics of d-fenfluramine in rats given anorectic and toxic doses. Xenobiotica 22: 217–225
Cadet JL, Brannock C . (1998): Free radicals and the pathobiology of brain dopamine systems. Neurochem Int 32: 117–131
Carboni E, Di Chiara G . (1989): Serotonin release estimated by transcortical dialysis in freely-moving rats. Neuroscience 32: 637–645
Clausing P, Newport GD, Bowyer JF . (1998): Fenfluramine and norfenfluramine levels in brain microdialysate, brain tissue, and plasma of rats administered doses of d-fenfluramine known to deplete 5-hydroxytryptamine levels in brain. J Pharmacol Exp Ther 284: 618–624
Clineschmidt BV, Zacchei AG, Totaro JA, Pflueger AB, McGuffin JC, Wishousky TI . (1978): Fenfluramine and brain serotonin. Ann N Y Acad Sci 308: 222–241
Commins DL, Axt KJ, Vosmer G, Seiden LS . (1987): 5,6-Dihydroxytryptamine, a serotonin neurotoxin, is formed endogenously in rat brain. Brain Res 403: 7–14
Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Schaff HV . (1997): Valvular heart disease associated with fenfluramine-phentermine. New Eng J Med 337: 581–588
Cozzi NV, Frescas S, Marona-Lewicka D, Huang X, Nichols DE . (1998): Indan analogs of fenfluramine and norfenfluramine have reduced neurotoxic potential. Pharmacol Biochem Behav 59: 709–715
Eriksson E, Engberg G, Bing O, Nissbrandt H . (1999): Effects of mCPP on the extracellular concentrations of serotonin and dopamine in rat brain. Neuropsychopharmacology 20: 287–296
Fuller RW, Snoddy HD, Mason NR, Owen JE . (1981): Disposition and pharmacological effects of m-chlorophenylpiperazine in rats. Neuropharmacology 20: 155–162
Fuller RW, Snoddy HD, Robertson DW . (1988): Mechanisms of effects of d-fenfluramine on brain serotonin metabolism in rats: uptake inhibition versus release. Pharmacol Biochem Behav 30: 715–721
Fuxe K, Hamberger B, Farnebo L-O, Ogren S-O . (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
Garattini S, Jori A, Buczko W, Samanin R . (1975): The mechanism of action of fenfluramine. Postgrad Med J 51(Suppl 1):27–34
Garattini S, Mennini T, Samanin R . (1989): Reduction of food intake by manipulation of central serotonin. Br J Psychiatry 155(Suppl 8):41–51
Gundlah C, Martin KF, Heal DJ, Auerbach SB . (1997): In vivo criteria to differentiate monoamine reuptake inhibitors from releasing agents: Sibutramine is a reuptake inhibitor. J Pharmacol Exp Ther 283: 581–591
Jiang XR, Wrona MZ, Dryhurst G . (1999): Tryptamine-4,5-dione, a putative endotoxic metabolite of the superoxide-mediated oxidation of serotonin, is a mitochondrial toxin: Possible implications in neurodegenerative brain disorders. Chem Res Toxicol 12: 429–436
Johnson MP, Nichols DE . (1990): Comparative serotonin neurotoxicity of the stereoisomers of fenfluramine and norfenfluramine. Pharmacol Biochem Behav 36: 105–109
Johnson MP, Huang X, Oberlender R, Nash JF, Nichols DE . (1990): Behavioral, biochemical, and neurotoxicological actions of the α-ethyl homologue of p-chloroamphetamine. Eur J Pharmacol 191: 1–10
Johnson MP, Conarty PF, Nichols DE . (1991): [3H]Monoamine releasing and uptake inhibition properties of 3,4-methylenedioxymethamphetamine and p-chloroamphetamine analogues. Eur J Pharmacol 200: 9–16
Kahn RS, Wetzler S . (1991): m-Chlorophenylpiperazine as a probe of serotonin function. Biol Psychiatry 30: 1139–1166
Kleven MS, Seiden LS . (1989): D-, L-, and DL-Fenfluramine cause long-lasting depletions of serotonin in rat brain. Brain Res 501: 351–353
Levi G, Raiteri M . (1993): Carrier-mediated release of neurotransmitters. Trends Neurosci 16: 415–419
McCann U, Hatzidimitriou G, Ridenour A, Fischer C, Yuan J, Katz J, Ricaurte G . (1994): Dexfenfluramine and serotonin neurotoxicity: Further preclinical evidence that clinical caution is indicated. J Pharmacol Exp Ther 269: 792–798
McCann UD, Seiden LS, Rubin LJ, Ricaurte GA . (1997): Brain serotonin neurotoxicity and primary pulmonary hypertension from fenfluramine and dexfenfluramine. J Am Med Assoc 278: 666–672
McTavish D, Heel RC . (1992): Dexfenfluramine: A review of its pharmacological properties and therapeutic potential in obesity. Drugs 43: 713–733
Nichols DE, Brewster WK, Johnson MP, Oberlender R, Riggs RM . (1990): Non-neurotoxic tetralin and indan analogues of 3,4-(methylenedioxy)amphetamine. J Med Chem 33: 703–710
Nichols DE . (1994): Medicinal chemistry and structure-activity relationships. In Cho AK, Segal DS (eds), Amphetamine and its Analogs: Psychopharmacology, Toxicology, and Abuse. New York, Academic Press, pp 1–41
Owens MJ, Morgan WN, Plott SJ, Nemeroff CB . (1997): Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites. J Pharmacol Exp Ther 283: 1305–1322
Pettibone DJ, Williams M . (1984): Serotonin-releasing effects of substituted piperazines in vitro. Biochem Pharmacol 9: 1531–1537
Porter RHP, Benwell KR, Lamb H, Malcolm CS, Allen NH, Revell DF, Adams DR, Sheardown MJ . (1998): Functional characterization of agonists at recombinant human 5-HT2A, 5-HT2B and 5-HT2C receptors in CHO-K1 cells. Br J Pharmacol 128: 13–20
Rothman RB, Lewis B, Dersch CM, Xu H, Radesca L, de Costa BR, Rice KC, Kilburn RB, Akunne HC, Pert A . (1993): Identification of a GBR12935 homolog, LR1111, which is over 4000-fold selective for the dopamine transporter, relative to serotonin and norepinephrine transporters. Synapse 14: 34–39
Rothman RB, Cadet JL, Akunne HC, Silverthorn ML, Baumann MH, Carroll FI, Rice KC, de Costa BR, Partilla JS, Wang JB . (1994): Studies of the biogenic amine transporters. IV. demonstration of a multiplicity of binding sites in rat caudate membranes for the cocaine analog [125I]RTI-55. J Pharmacol Exp Ther 270: 296–309
Rothman RB, Ayestas MA, Dersch CM, Baumann MH . (1999): Aminorex, fenfluramine and chlorphentermine are serotonin transporter substrates: Implications for primary pulmonary hypertension. Circulation 100: 869–875
Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen J, Roth BL . (2000): Evidence for possible involvement of 5-HT2B receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation 102: 2836–2841
Rudnick G . (1997): Mechanisms of biogenic amine transporters. In Reith MEA (ed), Neurotransmitter Transporters: Structure, Function, and Regulation. Totowa NJ, Humana Press, pp 73–100
Sabol KE, Richards JB, Seiden LS . (1992): Fluoxetine attenuates the d,l-fenfluramine-induced increase in extracellular serotonin as measured by in vivo microdialysis. Brain Res 585: 421–424
Sanders-Bush E, Bushing JA, Sulser F . (1975): Long-term effects of p-chloroamphetamine and related drugs on the central serotonergic mechanisms. J Pharmacol Exp Ther 192: 33–41
Schmidt CJ, Abbate GM, Black CK, Taylor VL . (1990): Selective 5-hydroxytryptamine2 receptor antagonists protect against the neurotoxicity of methylenedioxy methamphetamine in rats. J Pharmacol Exp Ther 255: 478–483
Schmidt CJ, Taylor VL, Abbate GM, Neiduzak TR . (1991): 5-HT2 antagonists stereoselectively prevent the neurotoxicity of 3,4-methylenedioxymethamphetamine by blocking the acute stimulation of dopamine synthesis: reversal by L-Dopa. J Pharmacol Exp Ther 256: 230–235
Schoeffter P, Hoyer D . (1989): Interaction of arylpiperazines with 5-HT1A, 5-HT1B, 5-HT1C, and 5-HT1D receptors: Do discriminatory 5-HT1B receptor ligands exist? Naunyn-Schmiedeberg's Arch Pharmacol 339: 675–683
Schuldiner S, Steiner-Mordoch S, Yelin R, Wall SC, Rudnick G . (1993): Amphetamine derivatives interact with both plasma membrane and secretory vesicle biogenic amine transporters. Mol Pharmacol 44: 1227–1231
Schwartz D, Hernandez L, Hoebel BG . (1989): Fenfluramine administered systemically or locally increases extracellular serotonin in the lateral hypothalamus as measured by microdialysis. Brain Res 482: 261–270
Seiden LS, Sabol KE . (1996): Methamphetamine and methylenendioxy-methamphetamine neurotoxicity: Possible mechanisms of cell destruction. NIDA Res Monogr 163: 251–276
Series HG, Cowen PJ, Sharp T . (1994): p-Chloroamphetamine (PCA), 3,4-methylenedioxymethamphetamine (MDMA) and d-fenfluramine pretreatment attenuates d-fenfluramine-evoked release of 5-HT in vivo. Psychopharmacology 116: 508–514
Steranka LR, Sanders-Bush E . (1979): Long-term effects of fenfluramine on central serotonergic mechanisms. Neuropharmacology 18: 895–995
Ulrichsen J, Partilla JS, Dax EM . (1992): Long-term administration of m-chlorophenylpiperazine (mCPP) to rats induces changes in serotonin receptor binding, dopamine levels and locomotor activity without altering prolactin and corticosterone secretion. Psychopharmacology 107: 229–235
Wolf WA, Kuhn DM . (1991): 5-HT transporter is an additional site of action for the 5-HT agonists RU24969 and TFMPP. Neurochem Int 19: 39–44
Wrona MZ, Dryhurst G . (1998): Oxidation of serotonin by superoxide radical: Implications to neurodegenerative brain disorders. Chem Res Toxicol 11: 639–650
Yang Z, Wrona M, Dryhurst G . (1997): 5-Hydroxy-3-ethylamino-2-oxindole is not formed in rat brain following a neurotoxic dose of methamphetamine: Evidence that methamphetamine does not induce the hydroxy radical-mediated oxidation of serotonin. J Neurochem 68: 1929–1941
Zaczek R, Battaglia G, Culp S, Appel NM, Contrera JF, De Souza EB . (1990): Effects of repeated fenfluramine administration on indices of monoamine function in rat brain: Pharmacokinetic, dose response, regional specificity and time course data. J Pharmacol Exp Ther 253: 104–112
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Baumann, M., Ayestas, M., Dersch, C. et al. 1-(m-Chlorophenyl)piperazine (mCPP) Dissociates In Vivo Serotonin Release from Long-Term Serotonin Depletion in Rat Brain. Neuropsychopharmacol 24, 492–501 (2001). https://doi.org/10.1016/S0893-133X(00)00221-9
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DOI: https://doi.org/10.1016/S0893-133X(00)00221-9
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