Abstract
To investigate the role of 5-HT in human anxiety, the 5-HT releaser and uptake blockerd-fenfluramine (FEN) was administered to healthy volunteers under two models of experimental anxiety. The first was a simulated public speaking (SPS) test consisting of talking in front of a video camera, anxiety being evaluated mainly by self-rating scales. The second was a conditioned fear test, in which the changes in skin electrical conductance caused by a tone associated once with an aversive white noise were measured. The doses of 15 and 30 mg FEN, PO, decreased anxiety induced by SPS in a dose-dependent way, as indicated by the anxiety factor of Norris Visual Analogue Mood Scale. In the conditioned fear test, however, the amplitude and level of skin conductance responses to the conditioned aversive stimulus were not significantly changed by FEN. The differential effects of FEN in these human experimental models of anxiety, together with similar results reported in rats, support the view that 5-HT exerts a dual action on brain mechanisms regulating anxiety, facilitating conditioned while inhibiting unconditioned fear. The presumed reduction in unconditioned fear caused by FEN may have implications for the treatment of panic disorder.
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References
Aghajanian GK (1992) Central 5-HT receptor subtypes: physiological responses and signal transduction mechanisms. In: Marsden CA, Heal DJ (eds) Central serotonin receptors and psychotropic drugs. Blackwell, Oxford, pp 39–55
Bel N, Artigas F (1992) Fluvoxamine preferentially increases extracellular 5-hydroxytryptamine in the raphe nuclei: an in vivo microdialysis study. Eur J Pharmacol 229:101–103
Bel N, Artigas F (1993) Chronic treatment with fluvoxamine increases extracellular serotonin in frontal cortex but not in raphe nuclei. Synapse 15:240–245
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
Biaggio AMB, Natalício L, Spielberger CD (1976) The development and validation of an experimental Portuguese form of the state-trait anxiety inventory. In: Spielberger CD, Diaz-Guerrero R (eds) Cross-cultural research on anxiety. Hemisphere/Wiley, Washington DC, p 29
Blier P, de Montigny C, Chaput Y (1987) Modification of the serotonin system by the antidepressant treatments: implications for the therapeutic response in major depression. J Clin Psychopharmacol 7:24S-35S
Bond A, Lader M (1974) The use of analogue scales in rating subjective feelings. Br J Med Psychol 47:211–218
Bonnano G, Fassio A, Severi P. Ruelle A, Raiteri M (1994) Fenfluramine releases serotonin from human brain nerve endings by a dual mechanism. J Neurochem 63:1163–1166
Celeumans DLS, Hoppenbrouwers MLJA, Gelders YG, Reynjens AHM (1982) The influence of ritanserin, a serotonin antagonist in anxiety disorders: a double-blind placebo-controlled study versus lorazepam. Pharmacopsychiatry 18:303–305
Deakin JWF, Graeff FG (1991) 5-HT and mechanisms of defence. J Psychopharmacol 5:305–315
Deakin JFW, Graeff FG, Guimarães FS (1992) 5-HT receptor subtypes and the modulation of aversion. In: Marsden CA, Heal DJ (eds) Central serotonin receptors and psychotropic drugs. Blackwell, Oxford, pp 147–174
Deakin JFW, Guimarães FS, Graeff GF (1994) Testing 5HT theories of anxiety in normal volunteers. In: Palomo T, Archer T (eds) Strategies for studying brain disorders, vol. 1. Farrand Press, London, pp 211–238
Den Boer JA, Westenberg HGM (1990) Serotonin function in panic disorder: a double blind placebo controlled study with fluvoxamine and ritanserin. Psychopharmacology 102:85–94
Fuller RW, Snoddy HD, Robertson DW (1988) Mechanisms of effects ofd-fenfluramine on brain serotonin metabolism in rats: uptake inhibition versus release. Pharmacol Biochem Behav 30:715–721
Graeff FG (1990) Brain defense systems and anxiety. In: Roth M, Burrows GD, Noyes R (eds) Handbook of anxiety vol 3: the neurobiology of anxiety. Elsevier, Amsterdam, pp 307–354
Graeff FG (1993) Role of 5-HT in defensive behavior and anxiety. Rev Neurosci 4:181–211
Graeff FG, Zuardi AW, Giglio JS, Lima Filho EC, Kamiol IG (1985) Effect of methergoline on human anxiety. Psychopharmacology 86:334–336
Graeff FG, Viana MB, Tomaz CAB (1993a) The elevated T-maze, a new experimental model of anxiety and memory: effect of diazepam. Braz J Med Biol Res 26:67–70
Graeff FG, Silveira MCL, Nogueira RL, Audi EA, de Oliveira RMW (1993b) Role of the amygdala and periaqueductal gray in anxiety and panic. Behav Brain Res 58:123–131
Graeff FG, Viana MB, Mora PO (1995) Opposed regulation by dorsal raphe nucleus 5-HT pathways of two types of fear in the elevated T maze. Pharmacol Biochem Behav 53:171–177
Guimarães FS, Zuardi AW, Graeff FG (1987) Effect of chlorimipramine and maprotiline on experimental anxiety in humans. J Psychopharmacol 1:184–192
Guimarães FS, Kohem CL, Fillmann HS, de Vecino MCA, de Paoli CL, Ribeiro AMS, Teixeira CC, Wannmacher L (1989) A simple simulated public speaking test for evaluation of anxiolytic drugs. Braz J Med Biol Res 22:1083–1089
Guimarães FS, Hellewell J, Hensman R, Wang M, Deakin JFW (1991) Characterisation of a psychophysiological model of classical fear conditioning in healthy volunteers: Influence of gender, instructions, personality and placebo. Psychopharmacology 104:231–236
Handley SL, McBlane JW (1993) 5HT drugs in animal models of anxiety. Psychopharmacology 112:13–20
Hensman R, Guimaräes FS, Wang M, Deakin JFW (1991) The effects of ritanserin on aversive classical conditioning in humans. Psychopharmacology 104:220–224
Hetem LAB (1995) Addition ofd-fenfluramine to benzodiazepines produced a marked improvement in refractory panic disorder — a case report. J Clin Psychopharmacol 16:77–78
Humble M, Aberg-Wistedt B, Bertilson L (1986) A pilot study of ritanserin (a selective serotonin-2 receptor antagonist) in panic disorder and agoraphobia. Clinical and biochemical effects. Abstracts of the 15th CINP Congress, p 165
Jensen HH, Hutchings B, Poulsen JC (1989) Conditioned emotional responding under diazepam; a psychological study of state depending learning. Psychopharmacology 98:392–397
Kahn RS, van Praag HM, Wetzler S, Asnis GM, Barr G (1988) Serotonin and anxiety revisited. Biol Psychiatry 23:189–208
McCann U, Hatzdimitriou G, Ridenour A, Fisher C, Yuan J, Katz J, Ricaurte G (1994) Dexfenfluramine and serotonin toxicity: further preclinical evidence that clinical caution is indicated. J Pharmacol Exp Ther 268:792–798
McNair DM, Frankenthaler LM, Czerlinsky T, White TW, Sasson S, Fischer S (1982) Simulated public speaking as a model of clinical anxiety. Psychopharmacology 77:7–10
McTavish D, Heel RC (1992) Dexfenfluramine: a review of its pharmacological properties and therapeutic potential in obesity. Drugs 43:713–733
Norris H (1971) The action of sedatives on brainstem oculomotor systems in man. Neuropharmacology 10:181–191
Nutt DJ (1991) Anxiety and its therapy: today and tomorrow. In: Briley M, File SE (eds) New concepts in anxiety. Macmillan Press, London, pp 1–2
Palma SM, Guimarães FS, Zuardi AW (1994) Anxiety induced by simulated public speaking and stroop color word test in healthy subjects: effects of different trait-anxiety levels. Braz J Med Biol Res 27:2895–2902
Puttkammer Von M, Gaertner HJ, Mahal A, May J, Binz U, Heimann H (1987) Zur anxiolytishen Wirkung eines Phenoxypropanolamin-Derivates im Vergleich zu Propranolol, Diazepam und Plazebo. Drug Res 37:721–725
Sheehan DV, Raj AB, Sheehan KH, Soto S (1990) Is buspirone effective in the treatment of panic disorder? J Clin Psychopharmacol 10:3–11
Solyom L (1994) Controlling panic attacks with fenfluramine. Am J Psychiatry 151:621–622
Spielberger CD, Gorsuch RI, Lushene RE (1970) Manual for the state-trait anxiety inventory. Consulting Psychologists Press, Palo, Alto, California, USA
Targum SD (1990) Differential responses to anxiogenic challenge studies in patients with major depressive disorder and panic disorder. Biol Psychiatry 28:2–34
Targum SD, Marshall LE (1989) Fenfluramine provocation of anxiety in patients with panic disorder. Psychiatry Res 28:295–306
Venables PH, Christie MJ (1980) Electrodermal activity. In: Martin I, Venables PH (eds) Techniques in psychophysiology. Wiley, Chichester pp 3–67
Viana MB, Tomaz C, Graeff FG (1994) The elevated T maze: a new animal model of anxiety and memory. Pharmacol Biochem Behav 49:549–554
Wise CD, Berger BD, Stein L (1972) Benzodiazepines: anxiety-reducing activity by reduction of serotonin turnover in the brain. Science 177:180–183
Zuardi AW, Karniol IG (1981) Estudo transcultural de uma escala de auto-avaliação para estados subjectivos. J Bras Psiq 131:403–406
Zuardi AW, Cosme RA, Graeff FG, Guimarães FS (1993) Effects of ipsapirone and cannabidiol on human experimental anxiety. J Psychopharmacol 7:62–88
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Hetem, L.A.B., de Souza, C.J., Zuardi, A.W. et al. Effect ofd-fenfluramine on human experimental anxiety. Psychopharmacology 127, 276–282 (1996). https://doi.org/10.1007/BF02246136
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DOI: https://doi.org/10.1007/BF02246136