Psychopharmacology

, Volume 92, Issue 1, pp 14–24 | Cite as

Serotonin function in anxiety

II. Effects of the serotonin agonist MCPP in panic disorder patients and healthy subjects
  • D. S. Charney
  • S. W. Woods
  • W. K. Goodman
  • G. R. Heninger
Original Investigations

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.

Key words

Serotonin MCPP Cortisol Prolactin Growth hormone Anxiety 

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References

  1. Advis JP, Simpkins G, Meites J (1979) Serotonergic control of prolactin release in male rats. Life Sci 24:359–366Google Scholar
  2. Aloi JA, Insel TR, Mueller EA, Murphy DL (1984) Neuroendocrine and behavioral effects of m-chlorophenylpiperazine administration in rhesus monkeys. Life Sci 34:1325–1331Google Scholar
  3. Birge CA, Jacobs LS, Hammer CT, Daughaday WH (1970) Catecholamine inhibition of prolactin secretion by isolated rat adenohypophyses. Endocrinology 86:120–130Google Scholar
  4. 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 234:106–112Google Scholar
  5. Brady LS, Barrett JE (1985b) Effects of serotonin receptor agonists and antagonists on schedule-controlled behavior of squirrel monkeys. J Pharmacol Exp Ther 235:436–441Google Scholar
  6. Caccia S, Ballabio M, Samanin R (1981) (-)-m-chlorophenylpiperazine, a central 5-hydroxytryptamine agonist, is a metabolite of trazodone. J Pharm Pharmacol 33:477–478Google Scholar
  7. 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 34:605–606Google Scholar
  8. Carlsson M, Svensson K, Eriksson E, Carlsson A (1985) Rat brain serotonin: Biochemical and functional evidence for a sex difference. J Neural Transm 63:297–313Google Scholar
  9. 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 18:303–305Google Scholar
  10. 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 43:1059–1065Google Scholar
  11. 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 41:751–763Google Scholar
  12. Charney DS, Heninger GR, Jatlow PI (1985) Increased anxiogenic effects of caffeine in panic disorders. Arch Gen Psychiatry 42:233–243Google Scholar
  13. Clemens JA, Roush ME, Fuller RW (1978) Evidence that serotonin neurons stimulate secretion of prolactin releasing factor. Life Sci 22:2209–2213Google Scholar
  14. Dorsa DM, Conners MH (1979) Canine growth hormone responsiveness during pentobarbital anesthesia: a method for evaluating serotonergic stimulatory action. Endocrinology 104:101–106Google Scholar
  15. 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 105:365–368Google Scholar
  16. Fischette CT, Biegon A, McEwen BS (1984) Sex steroid modulation of the serotonin behavioral syndrome. Life Sci 35:1997–1206Google Scholar
  17. Fuller RW (1981) Serotonergic stimulation of pituitary-adrenocortical function in rats. Neuroendocrinology 32:118–127Google Scholar
  18. Fuller RW, Snoddy HD (1980) Effect of serotonin-releasing drugs on serum corticosterone concentration in rats. Neuroendocrinology 31:96–100Google Scholar
  19. Fuller RW, Snoddy HD, Mason NR, Owen JE (1981) Disposition and pharmacological effects of m-chlorophenylpiperazine in rats. Neuropharmacology 20:155–162Google Scholar
  20. Garthwaite TL, Hagen TC (1979) Evidence that serotonin stimulates a prolactin-releasing factor in the rat. Neuroendocrinology 29:215–230Google Scholar
  21. Geller I, Blum K (1970) The effects of 5-HTP on para-chlorophenylalanine (p-CPA) attenuation of “conflict” behavior. Eur J Pharmacol 9:319–324Google Scholar
  22. Giambalvo CT, Snodgrass SR (1978) Biochemical and behavioral effects of serotonin neurotoxins on the nigrostriatal dopamine system: A comparison of injection sites. Brain Res 152:555–566Google Scholar
  23. 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 280:176–179Google Scholar
  24. Glaser T, Traber J (1983) Buspirone: Action on serotonin receptors in calf hippocampus. Eur J Pharmacol 88S:137–138Google Scholar
  25. 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 329:211–215Google Scholar
  26. Gloger S, Grunhaus L, Birmacher B (1981) Treatment of spontaneous panic attacks with chlorimipramine. Am J Psychiatry 138:1215–1217Google Scholar
  27. Graeff FG, Silveira Filho NG (1978) Behavioral inhibition induced by electrical stimulation of the median raphe nucleus of the rat. Physiol Behav 21:477–484Google Scholar
  28. Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62PubMedGoogle Scholar
  29. Hamilton M (1969) Diagnosis and ratings of anxiety. Br J Psychiatry 3:76–79Google Scholar
  30. 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):398–402Google Scholar
  31. 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 269–277Google Scholar
  32. Innis RB, Charney DS, Heninger GR (1987) Differential 3H-imipramine platelet binding in patients with panic disorder and depression. Psychiatr Res (in press)Google Scholar
  33. 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 3:239–244Google Scholar
  34. Kahn RS, Westenberg HGM (1985) L-5-Hydroxytryptophan in the treatment of anxiety disorders}. J Affect Dis 8:197–200Google Scholar
  35. Kamberi IA, Mical RS, Porter JC (1971) Effect of melatonin and serotonin on the release of FSH and prolactin. Endocrinology 88:1288–1293Google Scholar
  36. 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 13:213–223Google Scholar
  37. Lamberts SWJ, MacLeod RM (1978) The interaction of serotonergic and dopaminergic systems on prolactin secretion in the rat. Endocrinology 103:287–295Google Scholar
  38. Langer SZ, Briley MS, Raisman R, Henry JF, Morsell PL (1980) Specific 3H-Imipramine binding in human platelets. Naunyn-Schmiedeberg's Arch Pharmacol 313:189–194Google Scholar
  39. Lewis DA, McChesney C (1985) Tritiated imipramine binding to platelets is decreased in patients with agoraphobia. Psychiatr Res 16:1–9Google Scholar
  40. Meites J, Simpkins J, Bruni J, Advis J (1977) Role of biogenic amines in control of anterior pituitary hormones. IRCS J Med Sci 5:1–7Google Scholar
  41. Meites J, Sonntag WE (1981) Hypothalamic hypophysiotropic hormones and neurotransmitter regulation: current views. Annu Rev Pharmacol Toxicol 21:295–322Google Scholar
  42. 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 18:715–724Google Scholar
  43. Mueller EA, Murphy DL, Sunderland T (1985) Neuroendocrine effects of m-Chlorophenylpiperazine, a serotonin agonist, in humans. J Clin Endocrinol Metab 61:1179–1183Google Scholar
  44. Munaro NI (1978) The effect of ovarian steroids on hypothalamic 5-hydroxy-tryptamine neuronal activity. Neuroendocrinology 26:270–276Google Scholar
  45. Nakamura M, Fukushima H (1977) Effect of benzodiazepines on central serotonergic neuron systems. Psychopharmacology 53:121–126Google Scholar
  46. Paul SM, Rehavi M, Skolnick P, Goodwin FK (1980) Demonstration of specific “high affinity” binding sites for 3H-Imipramine on human platelets. Life Sci 26:953–959Google Scholar
  47. Pazos A, Palacios JM (1985) Quantitative autoradiographic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors. Brain Res 346:205–230Google Scholar
  48. Pazos A, Cortes R, Palacios JM (1985) Quantitative Autoradiographic Mapping of serotonin receptors in the rat brain. II. Serotonin-2 receptors. Brain Res 346:231–249Google Scholar
  49. Peroutka SJ (1985) Selective labeling of 5-HT 1A and 5-HT1B binding sites in bovine brain. Brain Res 344:167–171Google Scholar
  50. Reisine T, Soubrie P, Artaud F (1982) Sensory stimuli differentially affect in vivo nigral and striatal [3H] serotonin release in the cat. Brain Res 232:77–87Google Scholar
  51. Samanin R, Mennini T, Ferraris A (1979) m-Chlorophenylpiperazine: A central serotonin agonist causing powerful anorexia in rats. Naunyn-Schmiedeberg's Arch Pharmacol 308:159–163Google Scholar
  52. Schoenfeld RI (1976) Lysteric acid diethylamide-and mescaline-induced attenuation of the effect of punishment in the rat. Science 192:801–803Google Scholar
  53. 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 231:480–487Google Scholar
  54. 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 99–143Google Scholar
  55. 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):526–532Google Scholar
  56. Sprouse JS, Aghajanian (1987) Electrophysiological responses of serotonergic dorsal raphe neurons to 5-HT1A and 5-HT1B agonists. Synapse (in press)Google Scholar
  57. 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 299–326Google Scholar
  58. Stein L, Belluzzi JD, Wise CD (1977) Benzodiazepines: Behavioral and neurochemical mechanisms. Am J Psychiatry 134(6):665–669Google Scholar
  59. Steinbusch HWM (1981) Distribution of serotonin-immunoreactivity in the central nervous system of the rat-cell bodies and terminals. Neuroscience 6:557–618Google Scholar
  60. 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):2287–2294Google Scholar
  61. 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 12:741–744Google Scholar
  62. Tye NC, Iversen SD, Green AR (1979) The effects of benzodiazepines and serotonergic manipulations on punished responding. Neuropharmacology 18:689–695Google Scholar
  63. 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]:8–23Google Scholar
  64. 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 557–576Google Scholar
  65. Van de Kar LD, Bethea CL (1982) Pharmacological evidence that serotonergic stimulation of prolactin secretion is mediated via the dorsal raphe nucleus. Neuroendocrinology 35:225–230Google Scholar
  66. 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 235:233–243Google Scholar
  67. 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 41:380–384Google Scholar
  68. 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 43:947Google Scholar
  69. Weiner RI, Ganong WF (1978) Monoamines and histamine in regulation of anterior pituitary secretion. Physiol Rev 58:905–976Google Scholar
  70. Wise CD, Berger BD, Stein L (1972) Benzodiazepines: Anxiety-reducing activity by reduction of serotonin turnover in the brain. Science 177:180–183Google Scholar
  71. Zitrin GM, Klein DF, Woerner MG, Ross DC (1983) Treatment of phobias: Comparison of imipramine and placebo. Arch Gen Psychiatry 40:125–138Google Scholar

Copyright information

© Springer-Verlag 1987

Authors and Affiliations

  • D. S. Charney
    • 1
  • S. W. Woods
    • 1
  • W. K. Goodman
    • 1
  • G. R. Heninger
    • 1
  1. 1.Clinical Neuroscience Research Unit, Connecticut Mental Health Center, Ribicoff Research Facilities and Department of PsychiatryYale University School of MedicineNew HavenUSA

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