Abstract
To assess the role of serotonin function in the development of panic anxiety, the behavioral and biochemical responses to the serotonin receptor agonist, m-chlorophenylpiperazine (MCPP) was examined in healthy subjects and agoraphobic and panic disorder patients. MCPP had anxiogenic effects in both the healthy subjects and patients. Panic attacks meeting DSM-III criteria occurred following MCPP in 12 of 23 patients and 6 of 19 healthy subjects (NS) and other ratings of anxiety also did not distinguish the two groups. MCPP resulted in significant but similar increases in cortisol, prolactin, and growth hormone in the healthy subjects and patients. The results of this investigation suggest that serotonin neuronal dysfunction may not be of etiologic significance in most panic disorder patients. However, the observed anxiogenic properties of MCPP suggest that additional studies of the role of serotonin systems in the pathophysiology of human anxiety disorders are indicated.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Advis JP, Simpkins G, Meites J (1979) Serotonergic control of prolactin release in male rats. Life Sci 24:359–366
Aloi JA, Insel TR, Mueller EA, Murphy DL (1984) Neuroendocrine and behavioral effects of m-chlorophenylpiperazine administration in rhesus monkeys. Life Sci 34:1325–1331
Birge CA, Jacobs LS, Hammer CT, Daughaday WH (1970) Catecholamine inhibition of prolactin secretion by isolated rat adenohypophyses. Endocrinology 86:120–130
Brady LS, Barrett JE (1985a) Effects of serotonin receptor antagonists on punished responding maintained by stimulus-shock termination or food presentation in squirrel monkeys. J Pharmacol Exp Ther 234:106–112
Brady LS, Barrett JE (1985b) Effects of serotonin receptor agonists and antagonists on schedule-controlled behavior of squirrel monkeys. J Pharmacol Exp Ther 235:436–441
Caccia S, Ballabio M, Samanin R (1981) (-)-m-chlorophenylpiperazine, a central 5-hydroxytryptamine agonist, is a metabolite of trazodone. J Pharm Pharmacol 33:477–478
Caccia S, Fong MH, Garattini Zanini MG (1982) Plasma concentrations of trazodone and 1-(3-chlorophenyl)piperazine in man after a single oral dose of trazodone. J Pharm Pharmacol 34:605–606
Carlsson M, Svensson K, Eriksson E, Carlsson A (1985) Rat brain serotonin: Biochemical and functional evidence for a sex difference. J Neural Transm 63:297–313
Ceulemans DLS, Hoppenbrouwers HJA, Gelders YG, Reyntjens AJM (1985) The influence of ritanserin, a serotonin antagonist, in anxiety disorders: A double-blind placebo-controlled study versus lorazepam. Pharmacopsychiatry 18:303–305
Charney DS, Heninger GR (1986) Serotonin function in panic disorders: The effect of intravenous tryptophan in healthy subjects and panic disorder patients before and during alprazolam treatment. Arch Gen Psychiatry 43:1059–1065
Charney DS, Heninger GR, Breier A (1984) Noradrenergic function in panic anxiety: Effects of yohimbine in healthy subjects and patients with agoraphobia and panic disorder. Arch Gen Psychiatry 41:751–763
Charney DS, Heninger GR, Jatlow PI (1985) Increased anxiogenic effects of caffeine in panic disorders. Arch Gen Psychiatry 42:233–243
Clemens JA, Roush ME, Fuller RW (1978) Evidence that serotonin neurons stimulate secretion of prolactin releasing factor. Life Sci 22:2209–2213
Dorsa DM, Conners MH (1979) Canine growth hormone responsiveness during pentobarbital anesthesia: a method for evaluating serotonergic stimulatory action. Endocrinology 104:101–106
Engel JA, Hjorth S, Svensson K, Carlsson A, Liljequist S (1984) Anticonflict effect of the putative serotonin receptor agonist 8-hydroxy-2-(DI-n-propylamino)tetralin(8-OH-DPAT). Eur J Pharmacol 105:365–368
Fischette CT, Biegon A, McEwen BS (1984) Sex steroid modulation of the serotonin behavioral syndrome. Life Sci 35:1997–1206
Fuller RW (1981) Serotonergic stimulation of pituitary-adrenocortical function in rats. Neuroendocrinology 32:118–127
Fuller RW, Snoddy HD (1980) Effect of serotonin-releasing drugs on serum corticosterone concentration in rats. Neuroendocrinology 31:96–100
Fuller RW, Snoddy HD, Mason NR, Owen JE (1981) Disposition and pharmacological effects of m-chlorophenylpiperazine in rats. Neuropharmacology 20:155–162
Garthwaite TL, Hagen TC (1979) Evidence that serotonin stimulates a prolactin-releasing factor in the rat. Neuroendocrinology 29:215–230
Geller I, Blum K (1970) The effects of 5-HTP on para-chlorophenylalanine (p-CPA) attenuation of “conflict” behavior. Eur J Pharmacol 9:319–324
Giambalvo CT, Snodgrass SR (1978) Biochemical and behavioral effects of serotonin neurotoxins on the nigrostriatal dopamine system: A comparison of injection sites. Brain Res 152:555–566
Gibbs DM, Vale W (1983) Effect of the serotonin reuptake inhibitor fluoxetine on corticotropin-releasing factor and vasopressin secretion into hypophysial portal blood. Brain Res 280:176–179
Glaser T, Traber J (1983) Buspirone: Action on serotonin receptors in calf hippocampus. Eur J Pharmacol 88S:137–138
Glaser T, Traber J (1985) Binding of the putative anxiolytic TVX Q 7821 to hippocampal 5-hydroxytryptamine (5-HT) recognition sites. Naunyn-Schmiedeberg's Arch Pharmacol 329:211–215
Gloger S, Grunhaus L, Birmacher B (1981) Treatment of spontaneous panic attacks with chlorimipramine. Am J Psychiatry 138:1215–1217
Graeff FG, Silveira Filho NG (1978) Behavioral inhibition induced by electrical stimulation of the median raphe nucleus of the rat. Physiol Behav 21:477–484
Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62
Hamilton M (1969) Diagnosis and ratings of anxiety. Br J Psychiatry 3:76–79
Heninger GR, Charney DS, Sternberg DE (1984) Serotonergic function in depression: Prolactin response to intravenous tryptophan in depressed patients and healthy subjects. Arch Gen Psychiatry 41(4):398–402
Howard JL, Pollard GT (1977) The Geller Conflict Test: A model of anxiety and a screening procedure for anxiolytics. In: Kanin I, Usdin E (eds) Animal models in psychiatry and neurology. Pergamon, New York, pp 269–277
Innis RB, Charney DS, Heninger GR (1987) Differential 3H-imipramine platelet binding in patients with panic disorder and depression. Psychiatr Res (in press)
Invernizzi R, cotecchia S, DeBlasi A, Mennini T, Pataccini R, Samanin R (1981) Effects of m-chlorophenylpiperazine on receptor binding and brain metabolism of monoamines in rats. Neurochem Int 3:239–244
Kahn RS, Westenberg HGM (1985) L-5-Hydroxytryptophan in the treatment of anxiety disorders}. J Affect Dis 8:197–200
Kamberi IA, Mical RS, Porter JC (1971) Effect of melatonin and serotonin on the release of FSH and prolactin. Endocrinology 88:1288–1293
Kordon C, Blake CA, Terkel J, Sawyer CH (1973) Participation of serotonin containing neurons in the suckling-induced rise in plasma prolactin levels in lactating rats. Neuroendocrinology 13:213–223
Lamberts SWJ, MacLeod RM (1978) The interaction of serotonergic and dopaminergic systems on prolactin secretion in the rat. Endocrinology 103:287–295
Langer SZ, Briley MS, Raisman R, Henry JF, Morsell PL (1980) Specific 3H-Imipramine binding in human platelets. Naunyn-Schmiedeberg's Arch Pharmacol 313:189–194
Lewis DA, McChesney C (1985) Tritiated imipramine binding to platelets is decreased in patients with agoraphobia. Psychiatr Res 16:1–9
Meites J, Simpkins J, Bruni J, Advis J (1977) Role of biogenic amines in control of anterior pituitary hormones. IRCS J Med Sci 5:1–7
Meites J, Sonntag WE (1981) Hypothalamic hypophysiotropic hormones and neurotransmitter regulation: current views. Annu Rev Pharmacol Toxicol 21:295–322
Mueller GP, Twohy CP, Chen HT, Advis JP, Meites J (1976) Effect of L-tryptophan and restraint stress on hypothalamine and brain serotonin turnover, and pituitary TSH and prolactin release in rats}. Life Sci 18:715–724
Mueller EA, Murphy DL, Sunderland T (1985) Neuroendocrine effects of m-Chlorophenylpiperazine, a serotonin agonist, in humans. J Clin Endocrinol Metab 61:1179–1183
Munaro NI (1978) The effect of ovarian steroids on hypothalamic 5-hydroxy-tryptamine neuronal activity. Neuroendocrinology 26:270–276
Nakamura M, Fukushima H (1977) Effect of benzodiazepines on central serotonergic neuron systems. Psychopharmacology 53:121–126
Paul SM, Rehavi M, Skolnick P, Goodwin FK (1980) Demonstration of specific “high affinity” binding sites for 3H-Imipramine on human platelets. Life Sci 26:953–959
Pazos A, Palacios JM (1985) Quantitative autoradiographic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors. Brain Res 346:205–230
Pazos A, Cortes R, Palacios JM (1985) Quantitative Autoradiographic Mapping of serotonin receptors in the rat brain. II. Serotonin-2 receptors. Brain Res 346:231–249
Peroutka SJ (1985) Selective labeling of 5-HT 1A and 5-HT1B binding sites in bovine brain. Brain Res 344:167–171
Reisine T, Soubrie P, Artaud F (1982) Sensory stimuli differentially affect in vivo nigral and striatal [3H] serotonin release in the cat. Brain Res 232:77–87
Samanin R, Mennini T, Ferraris A (1979) m-Chlorophenylpiperazine: A central serotonin agonist causing powerful anorexia in rats. Naunyn-Schmiedeberg's Arch Pharmacol 308:159–163
Schoenfeld RI (1976) Lysteric acid diethylamide-and mescaline-induced attenuation of the effect of punishment in the rat. Science 192:801–803
Sills MA, Wolfe BB, Frazer A (1984) Determination of selective and nonselective compounds for the 5-HT1A and 5-HT1B receptor subtypes in rat frontal cortex. J Pharmacol Exp Ther 231:480–487
Simon P, Soubrie P (1979) Behavioral studies to differentiate anxiolytic and sedative activity of the tranquilizing drugs. In: Boissier JR (ed) Modern problems in pharmacopsychiatry, vol 14, Differential psychopharmacology of anxiolytics and sedatives. Karger, Basel, pp 99–143
Soubrie P, Blas C, Ferron A, Glowinski J (1983) Chlordiazepoxide reduces in vivo serotonin release in the basal ganglia of encephale isole but not anesthetized cats: Evidence for a dorsal raphe site of action. J Pharmacol Exp Ther 226(2):526–532
Sprouse JS, Aghajanian (1987) Electrophysiological responses of serotonergic dorsal raphe neurons to 5-HT1A and 5-HT1B agonists. Synapse (in press)
Stein L, Wise CD, Berger BD (1973) Anti-anxiety action of benzodiazepines: Decrease in activity of serotonin neurons in the punishment system. In: Costa E, Greengard P (eds) The benzodiazepines. Raven, New York, pp 299–326
Stein L, Belluzzi JD, Wise CD (1977) Benzodiazepines: Behavioral and neurochemical mechanisms. Am J Psychiatry 134(6):665–669
Steinbusch HWM (1981) Distribution of serotonin-immunoreactivity in the central nervous system of the rat-cell bodies and terminals. Neuroscience 6:557–618
Thiebot MH, Hamon M, Soubrie P (1982) Attenuation of induced-anxiety in rats by chlordiazepoxide: Role of raphe dorsalis benzodiazepine binding sites and serotoninergic neurons. Neuroscience 7(9):2287–2294
Traber J, Davies MA, Dompert WU, Glaser T, Schuurman T, Seidel P-R (1984) Brain serotonin receptors as a target for the putative anxiolytic TVX Q 7821. Brain Res Bull 12:741–744
Tye NC, Iversen SD, Green AR (1979) The effects of benzodiazepines and serotonergic manipulations on punished responding. Neuropharmacology 18:689–695
Uhde TW, Boulenger J-P, Post RM, Siever LJ, Vittone BJ, Jimerson DC, Roy-Byrne PP (1984) Fear and anxiety: Relationship to noradrenergic function. Psychopathology 17 [Suppl 3]:8–23
Uhde TW, Roy-Byrne PP, Vittone BJ, Boulenger JP, Post RM (1985) Phenomenology and neurobiology of panic disorder. In: Tuma AH, Maser JD (ed) Anxiety and anxiety disorders, pp 557–576
Van de Kar LD, Bethea CL (1982) Pharmacological evidence that serotonergic stimulation of prolactin secretion is mediated via the dorsal raphe nucleus. Neuroendocrinology 35:225–230
Van de Kar LD, Wilkinson CW, Skrobik Y, Brownfield MS, Ganong WF (1982) Evidence that serotonergic neurons in the dorsal raphe nucleus exert a stimulatory effect on the secretion of renin but not of corticosterone. Brain Res 235:233–243
Van de Kar LD, Karteszi M, Bethea CL, Ganong WF (1985) Serotonergic stimulation of prolactin and corticosterone secretion is mediated by different pathways from the mediobasal hypothalamus. Neuroendocrinology 41:380–384
Vander Maelen CP, Wilderman RC (1984) Iontophorelic and systemic administration of the nonbenzodiazepine anxiolytic drug buspirone causes inhibition of serotonergic dorsal raphe neurons in rats. Fed Proc 43:947
Weiner RI, Ganong WF (1978) Monoamines and histamine in regulation of anterior pituitary secretion. Physiol Rev 58:905–976
Wise CD, Berger BD, Stein L (1972) Benzodiazepines: Anxiety-reducing activity by reduction of serotonin turnover in the brain. Science 177:180–183
Zitrin GM, Klein DF, Woerner MG, Ross DC (1983) Treatment of phobias: Comparison of imipramine and placebo. Arch Gen Psychiatry 40:125–138