Abstract
Rats were trained to discriminate fenfluramine (1.0 mg/kg) from saline in a two-lever drug discrimination task. The dose-response curve for this discrimination was orderly with an ED50 of about one-half of the training dose (0.52 mg/kg). In substitution tests, indirect (p-chloroamphetamine) and direct (quipazine, MK-212, lisuride) serotonin (5-HT) agonists substituted for fenfluramine. Since none of these compounds have been reported to be hallucinogenic and the potent hallucinogen LSD did not substitute completely, it was suggested that the discriminative stimulus properties of fenfluramine are not related to its ability to produce hallucinations in humans. The fenfluramine cue, like the quipazine cue, was antagonized by the 5-HT antagonists cyproheptadine and methiothepin. Unlike quipazine, fenfluramine was also partially antagonized by the 5-HT uptake inhibitor, fluoxetine, and the 5-HT synthesis inhibitor, p-chlorophenylalanine. Thus, the fenfluramine cue differs from that of quipazine in that it is mediated via indirect actions on 5-HT receptors. Since the indirect dopamine (DA) agonist d-amphetamine failed to substitute and the DA antagonist haloperidol failed to block the fenfluramine cue, a mediating role for DA was not indicated. Another indirect DA agonist, cocaine, substituted partially for fenfluramine, a result which paralleled that seen with fluoxetine. Both of these partial substututions were reduced by cyproheptadine; therefore, it was concluded that these effects may be due to the common ability of cocaine, fluoxetine, and fenfluramine to inhibit 5-HT uptake.
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References
Bueno OFA, Carlini EA, Finkelfarb E, Suzuki JS (1976) 114-1, ethanol, and amphetamine as discriminative stimuli-generalization tests with other drugs. Psychopharmacologia 46:235–243
Clineschmidt BV, McGuffin JC (1978) Pharmacological differentiation of the central 5-hydroxytryptamine-like actions of MK-212 (6-chloro-2-[1-piperazinyl]-pyrazine), p-methoxyamphetamine and fenfluramine in an in vivo model system. Eur J Pharmacol 50:369–375
D'Mello GD, Stolerman IP (1978) Methodological issues in drug-discrimination research. In: Colpaert FC, Rosecrans JA (eds) Stimulus properties of drugs: ten years of progress Elsevier/North-Holland Biomedical, Amsterdam, pp 243–252
Fillion GMB, Rousselle JC, Fillion MP, Beaudoin DM, Goiny MR, Deniau JV, Jacob JJ (1978) High-affinity binding of [3H]5-hydroxytryptamine to brain synaptosomal membranes: comparison with [3H] lysergic acid diethylamide binding. Mol Pharmacol 14:50–59
Fuller RW, Perry KW, Molloy BB (1974) Effect of an uptake inhibitor on serotonin metabolism in the rat brain: studies with 3-(trifluromethylphenoxy)-N-methyl-phenylpropylamine (Lilly 110140). Life Sci 15:1161–1171
Fuxe D, Fredholm LO, Hamburger 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 (Suppl) 51:35–45
Garattini S, Buczko W, Jori A, Samanin R (1975) On the mechanism of action of fenfluramine. Postgrad Med J (Suppl) 51:27–34
Glowinski L (1970) Effects of amphetamine on various aspects of catecholamine metabolism in the central nervous system of the rat. In: Costa E, Garattini S (eds) Amphetamines and related compounds. Raven, New York, pp 301–316
Gotesman KG, Gunne LM (1972) Subjective effects of two anorexigenic agents, fenfluramine and AN448, in amphetamine-dependent subjects. Br J Addict 67:39–44
Goudie AJ (1977) Discriminative stimulus properties of fenfluramine in an operant task; an analysis of its cue function. Psychopharmacology 53:97–102
Griffith JD, Nutt JG, Jasinski DR (1975) A comparison of fenfluramine and amphetamine in man. Clin Pharmacol Ther 18:563–570
Hamon M, Nelson DL, Herbert A, Glowinski J (1980) Multiple receptors for serotonin in the rat brain. In: Pepeu G, Kuhar MJ, Enna SJ (eds) Receptors for neurotransmitters and peptide hormones. Raven, New York, pp 223–233
Harvey JA (1978) Neurotoxic action of halogenated amphetamines. NY Acad Sci 305:289–302
Hernandez LL, Holohean AM, Appel JB (1978) Effects of opiates on the discriminative stimulus properties of dopamine agonists. Pharmacol Biochem Behav 9:459–463
Ho BT, Huang JT (1975) Role of dopamine in d-amphetamine-induced discriminative responding. Pharmacol Biochem Behav 3:1085–1092
Koe BK, Weissman A (1966) p-Chlorophenylalanine: a specific depletor of brain serotonin. J Pharmacol Exp Ther 154:499–516
Kuhn DM, White FJ, Appel JB (1978) The discriminative stimulus properties of LSD: mechanisms of action. Neuropharmacology 17:257–263
Lovell RA, Freedman DX (1976) Stereospecific receptor sites for d-lysergic acid diethylamide in rat brain: effects of neurotransmitters, amine antagonists and other psychotropic drugs. Mol Pharmacol 12:621–630
McKenna ML, Ho BT (1980) The role of dopamine in the discriminative stimulus properties of cocaine. Neuropharmacology 19:297–303
Peroutka SJ, Snyder SH (1979) Multiple serotonin receptors: differential binding of [3H]-5-hydroxytryptamine, [3H] lysergic acid diethylamide and [3H] spiroperidol. Mol Pharmacol 16:687–699
Pickens R, Harris WC (1968) Self-administration of d-amphetamine by rats. Psychopharmacologia 12:158–163
Pieri L, Keller HH, Burkard W, DaPrada M (1978a) Effects of lisuride and LSD on cerebral monoamine systems and hallucinosis. Nature 272:278–280
Pieri M, Schaffner L, Pieri L, DaPrada M, Haefely W (1978b) Turning in MFB-lesioned rats and antagonism of neuroleptic-induced catalepsy after lisuride and LSD. Life Sci 22:1615–1622
Rogawski MA, Aghajanian GK (1979) Response of central monoaminergic neurons to lisuride: comparison with LSD. Life Sci 24:1289–1298
Sanders-Bush E, Gallagher DA, Sulser F (1974) On the mechanism of brain 5-hydroxytryptamine depletion by p-chloramphetamine and related drugs and the specificity of their action. Adv Biochem Psychopharmacol 10:185–194
Schechter MD (1977) Amphetamine discrimination as a test for anti-Parkinsonism drugs. Eur J Pharmacol 44:51–56
Schechter MD, Cook DG (1975) Dopamine mediation of the interoceptive cue produced by d-amphetamine in rats. Psychopharmacologia 42:185–193
Schechter MD, Rosecrans JA (1973) d-Amphetamine as a discriminative cue: drugs with similar stimulus properties. Eur J Pharmacol 21:212–216
Silbergeld EK, Hruska R (1979) Lisuride and LSD: dopaminergic and serotonergic interactions in the “serotonin syndrome”. Psychopharmacology 65:233–237
Silverstone T, Fincham J, Campbell B (1975) The anorectic activity of fenfluramine. Postgrad Med J (Suppl) 51:171–174
Somerville BW, Herrmann WM (1978) Migraine prophylaxis with lisuride hydrogen maleate — a double blind study of lisuride versus placebo. Headache 18:75–79
Taylor DL, Ho BT (1978) Comparison of inhibition of monoamine uptake by cocaine, methylphenidate and amphetamine. Res Commun Chem Pathol Pharmacol 21:67–75
Walters JR, Baring MD, Lakoski JM (1979) Effects of ergolines on dopaminergic and serotonergic single unit activity. In: Fuxe K, Calne DB (eds) Dopaminergic ergot derivatives and motor function. Pergamon, New York, pp 207–221
Weissman A, Koe BK, Tenen SS (1966) Antiamphetamine effects following inhibition of tyrosine hydroxylase. J Pharmacol Exp Ther 151:339–352
White FJ, Appel JB, Kuhn DM (1979) Discriminative stimulus properties of quipazine: direct serotonergic mediation. Neuropharmacology 18:143–151
White FJ, Kuhn DM, Appel JB (1977) Discriminative stimulus properties of quipazine. Neuropharmacology 16:827–832
Winer BJ (1971) Statistical principles in experimental design. McGraw-Hill, New York London
Winter JC (1980) Effects of the phenethylamine derivatives, BL 3912, fenfluramine, and SCH-12679, in rats trained with LSD as a discriminative stimulus. Psychopharmacology 68:159–162
Woods JH, Tessel RE (1974) Fenfluramine: amphetamine congener that fails to maintain drug-taking behavior in the rhesus monkey. Science 185:1067–1069
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White, F.J., Appel, J.B. A neuropharmacological analysis of the discriminative stimulus properties of fenfluramine. Psychopharmacology 73, 110–115 (1981). https://doi.org/10.1007/BF00429199
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DOI: https://doi.org/10.1007/BF00429199