Serotonin function in anxiety

II. Effects of the serotonin agonist MCPP in panic disorder patients and healthy subjects

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.

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References

  1. Advis JP, Simpkins G, Meites J (1979) Serotonergic control of prolactin release in male rats. Life Sci 24:359–366

    Google Scholar 

  2. Aloi JA, Insel TR, Mueller EA, Murphy DL (1984) Neuroendocrine and behavioral effects of m-chlorophenylpiperazine administration in rhesus monkeys. Life Sci 34:1325–1331

    Google Scholar 

  3. Birge CA, Jacobs LS, Hammer CT, Daughaday WH (1970) Catecholamine inhibition of prolactin secretion by isolated rat adenohypophyses. Endocrinology 86:120–130

    Google 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 234:106–112

    Google 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 235:436–441

    Google Scholar 

  6. Caccia S, Ballabio M, Samanin R (1981) (-)-m-chlorophenylpiperazine, a central 5-hydroxytryptamine agonist, is a metabolite of trazodone. J Pharm Pharmacol 33:477–478

    Google 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 34:605–606

    Google 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 63:297–313

    Google 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 18:303–305

    Google 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 43:1059–1065

    Google 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 41:751–763

    Google Scholar 

  12. Charney DS, Heninger GR, Jatlow PI (1985) Increased anxiogenic effects of caffeine in panic disorders. Arch Gen Psychiatry 42:233–243

    Google Scholar 

  13. Clemens JA, Roush ME, Fuller RW (1978) Evidence that serotonin neurons stimulate secretion of prolactin releasing factor. Life Sci 22:2209–2213

    Google Scholar 

  14. Dorsa DM, Conners MH (1979) Canine growth hormone responsiveness during pentobarbital anesthesia: a method for evaluating serotonergic stimulatory action. Endocrinology 104:101–106

    Google 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 105:365–368

    Google Scholar 

  16. Fischette CT, Biegon A, McEwen BS (1984) Sex steroid modulation of the serotonin behavioral syndrome. Life Sci 35:1997–1206

    Google Scholar 

  17. Fuller RW (1981) Serotonergic stimulation of pituitary-adrenocortical function in rats. Neuroendocrinology 32:118–127

    Google Scholar 

  18. Fuller RW, Snoddy HD (1980) Effect of serotonin-releasing drugs on serum corticosterone concentration in rats. Neuroendocrinology 31:96–100

    Google Scholar 

  19. Fuller RW, Snoddy HD, Mason NR, Owen JE (1981) Disposition and pharmacological effects of m-chlorophenylpiperazine in rats. Neuropharmacology 20:155–162

    Google Scholar 

  20. Garthwaite TL, Hagen TC (1979) Evidence that serotonin stimulates a prolactin-releasing factor in the rat. Neuroendocrinology 29:215–230

    Google Scholar 

  21. Geller I, Blum K (1970) The effects of 5-HTP on para-chlorophenylalanine (p-CPA) attenuation of “conflict” behavior. Eur J Pharmacol 9:319–324

    Google 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 152:555–566

    Google 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 280:176–179

    Google Scholar 

  24. Glaser T, Traber J (1983) Buspirone: Action on serotonin receptors in calf hippocampus. Eur J Pharmacol 88S:137–138

    Google 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 329:211–215

    Google Scholar 

  26. Gloger S, Grunhaus L, Birmacher B (1981) Treatment of spontaneous panic attacks with chlorimipramine. Am J Psychiatry 138:1215–1217

    Google Scholar 

  27. Graeff FG, Silveira Filho NG (1978) Behavioral inhibition induced by electrical stimulation of the median raphe nucleus of the rat. Physiol Behav 21:477–484

    Google Scholar 

  28. Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62

    CAS  PubMed  Google Scholar 

  29. Hamilton M (1969) Diagnosis and ratings of anxiety. Br J Psychiatry 3:76–79

    Google 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):398–402

    Google 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 269–277

    Google 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)

  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 3:239–244

    Google Scholar 

  34. Kahn RS, Westenberg HGM (1985) L-5-Hydroxytryptophan in the treatment of anxiety disorders}. J Affect Dis 8:197–200

    Google Scholar 

  35. Kamberi IA, Mical RS, Porter JC (1971) Effect of melatonin and serotonin on the release of FSH and prolactin. Endocrinology 88:1288–1293

    Google 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 13:213–223

    Google Scholar 

  37. Lamberts SWJ, MacLeod RM (1978) The interaction of serotonergic and dopaminergic systems on prolactin secretion in the rat. Endocrinology 103:287–295

    Google 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 313:189–194

    Google Scholar 

  39. Lewis DA, McChesney C (1985) Tritiated imipramine binding to platelets is decreased in patients with agoraphobia. Psychiatr Res 16:1–9

    Google 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 5:1–7

    Google Scholar 

  41. Meites J, Sonntag WE (1981) Hypothalamic hypophysiotropic hormones and neurotransmitter regulation: current views. Annu Rev Pharmacol Toxicol 21:295–322

    Google 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 18:715–724

    Google Scholar 

  43. Mueller EA, Murphy DL, Sunderland T (1985) Neuroendocrine effects of m-Chlorophenylpiperazine, a serotonin agonist, in humans. J Clin Endocrinol Metab 61:1179–1183

    Google Scholar 

  44. Munaro NI (1978) The effect of ovarian steroids on hypothalamic 5-hydroxy-tryptamine neuronal activity. Neuroendocrinology 26:270–276

    Google Scholar 

  45. Nakamura M, Fukushima H (1977) Effect of benzodiazepines on central serotonergic neuron systems. Psychopharmacology 53:121–126

    Google 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 26:953–959

    Google Scholar 

  47. Pazos A, Palacios JM (1985) Quantitative autoradiographic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors. Brain Res 346:205–230

    Google 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 346:231–249

    Google Scholar 

  49. Peroutka SJ (1985) Selective labeling of 5-HT 1A and 5-HT1B binding sites in bovine brain. Brain Res 344:167–171

    Google 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 232:77–87

    Google 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 308:159–163

    Google Scholar 

  52. Schoenfeld RI (1976) Lysteric acid diethylamide-and mescaline-induced attenuation of the effect of punishment in the rat. Science 192:801–803

    Google 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 231:480–487

    Google 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 99–143

    Google 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):526–532

    Google Scholar 

  56. Sprouse JS, Aghajanian (1987) Electrophysiological responses of serotonergic dorsal raphe neurons to 5-HT1A and 5-HT1B agonists. Synapse (in press)

  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 299–326

    Google Scholar 

  58. Stein L, Belluzzi JD, Wise CD (1977) Benzodiazepines: Behavioral and neurochemical mechanisms. Am J Psychiatry 134(6):665–669

    Google Scholar 

  59. Steinbusch HWM (1981) Distribution of serotonin-immunoreactivity in the central nervous system of the rat-cell bodies and terminals. Neuroscience 6:557–618

    Google 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):2287–2294

    Google 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 12:741–744

    Google Scholar 

  62. Tye NC, Iversen SD, Green AR (1979) The effects of benzodiazepines and serotonergic manipulations on punished responding. Neuropharmacology 18:689–695

    Google 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]:8–23

    Google 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 557–576

  65. Van de Kar LD, Bethea CL (1982) Pharmacological evidence that serotonergic stimulation of prolactin secretion is mediated via the dorsal raphe nucleus. Neuroendocrinology 35:225–230

    Google 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 235:233–243

    Google 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 41:380–384

    Google 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 43:947

    Google Scholar 

  69. Weiner RI, Ganong WF (1978) Monoamines and histamine in regulation of anterior pituitary secretion. Physiol Rev 58:905–976

    Google Scholar 

  70. Wise CD, Berger BD, Stein L (1972) Benzodiazepines: Anxiety-reducing activity by reduction of serotonin turnover in the brain. Science 177:180–183

    Google Scholar 

  71. Zitrin GM, Klein DF, Woerner MG, Ross DC (1983) Treatment of phobias: Comparison of imipramine and placebo. Arch Gen Psychiatry 40:125–138

    Google Scholar 

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Correspondence to D. S. Charney.

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Charney, D.S., Woods, S.W., Goodman, W.K. et al. Serotonin function in anxiety. Psychopharmacology 92, 14–24 (1987). https://doi.org/10.1007/BF00215473

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Key words

  • Serotonin
  • MCPP
  • Cortisol
  • Prolactin
  • Growth hormone
  • Anxiety