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Psychopharmacology

, Volume 108, Issue 3, pp 313–319 | Cite as

Dose-response relationship for oral idazoxan effects in healthy human subjects: comparison with oral yohimbine

  • John H. Krystal
  • Christopher J. McDougle
  • Scott W. Woods
  • Lawrence H. Price
  • George R. Heninger
  • Dennis S. Charney
Original Investigations

Abstract

The effects of oral administration of the α2 adrenergic receptor antagonists idazoxan (20 mg, 40 mg, 80 mg) and yohimbine (20 mg) were compared using a placebo-controlled within-subjects design. Healthy subjects completed 5 test days during which medication effects on mood and anxiety states, physiologic indices, plasma cortisol levels, and plasma levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) were assessed. Idazoxan dose-dependently increased plasma MHPG, plasma cortisol, systolic and diastolic blood pressure, and Panic Attack Symptom Scale scores in healthy subjects. Overall, yohimbine and idazoxan produced a similar pattern of behavioral and neuroendocrine responses. Since idazoxan possesses relatively greater receptor specificity compared to yohimbine, it may be a more useful α2 antagonist in humans.

Key words

Idazoxan Yohimbine α-Adrenergic receptor Norepinephrine Anxiety Cortisol Blood pressure MHPG 

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References

  1. al-Damluji S (1988) Adrenergic mechanisms in the control of corticotrophin secretion. J Endocrinol 119:5–14Google Scholar
  2. al-Damluji S, Bouloux, White A, Besser M (1990) The role of alpha-2 adrenoceptors in the control of ACTH secretion; interaction with the opioid system. Neuroendocrinology 51:76–81Google Scholar
  3. American Psychiatric Association (1987) Diagnostic and statistical manual of mental disorders, 3rd edn, revised. American Psychiatric Association, Washington, DCGoogle Scholar
  4. Beckett PJ, Finch L (1982) The α1- and α2-adrenoceptor involvement in the central cardiovascular action of clonidine in the conscious renal hypertensive cat. Eur J Pharmacol 82:155–160Google Scholar
  5. Bricca G, Dontenwill M; Molines A, Feldman J, Belcourt A, Bousquet P (1989) The imidazoline preferring receptor: binding studies in bovine, rat, and human brainstem. Eur J Pharmacol 162:1–9Google Scholar
  6. Brown MJ, Struthers AD, Burrin JM, Di Silvio L, Brown DC (1985) The physiological and pharmacological role of presynaptic α- and β-adrenergic receptors in man. Br J Clin Pharmacol 20:649–658Google Scholar
  7. Cedarbaum JM, Aghajanian GK (1976) Noradrenergic neurons of the locus coeruleus: inhibition by epinephrine and activation by the alpha-antagonist piperoxane. Brain Res 112:413–419Google Scholar
  8. Chapleo CB, Myers PL, Butler RCM, Doxey JC, Roach AG, Smith CFC (1983) α-Adrenoceptor reagents. 1. Synthesis of some 1,4 benzodioxans as selective presynaptic α2-adrenoceptor antagonists and potential antidepressants. J Med Chem 26:823–831Google Scholar
  9. Charney DS, Heninger GR, Sternberg DE (1982) Assessment of α2 autoreceptor function in humans: effects of oral yohimbine. Life Sci 30:2033–2041Google Scholar
  10. Charney DS, Heninger GR, Brier 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
  11. Charney DS, Woods SW, Price LH, Goodman WK, Glazer WM, Heninger GR (1990) Noradrenergic dysregulation in panic disorder. In: Ballenger JC (ed) Neurobiology of panic disorder. Wiley-Liss, New York, pp 91–105Google Scholar
  12. Dekirmenjian H, Maas JW (1974) MHPG in plasma. Clin Chem Acta 52:203–208Google Scholar
  13. Doxey JC, Roach AG, Smith CFC (1983) Studies on RX 781094: a selective, potent and specific antagonist of α2 adrenoceptors. Br J Pharmacol 78:489–505Google Scholar
  14. Doxey JC, Lane AC, Roach AG, Virdee NK (1984) Comparison of the α-adrenoceptor antagonist profiles of idazoxan (RX 781094), yohimbine, rauwolscine, and corynanthine. Naunyn-Schmiedeberg's Arch Pharmacol 325:136–144Google Scholar
  15. Dwoskin LP, Neal BS, Sparber SB (1988) Evidence for anti-serotonergic properties of yohimbine. Pharmacol Biochem Behav 31:321–326Google Scholar
  16. Elliott HL, Jones CR, Vincent J, Lawrie CB, Reid JL (1984) The alpha adrenoceptor antagonist properties of idazoxan in normal subjects. Clin Pharmacol Ther 36:190–196Google Scholar
  17. Elsworth JD, Redmond DE, Jr, Roth RH (1982) Plasma and cerebrospinal fluid 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) as indices of brain norepinephrine metabolism in primates. Brain Res 235:115–124Google Scholar
  18. Ernsberger P, Meeley MP, Mann JJ, Reis DJ (1987) Clonidine binds to imidazole binding sites as well as α2-adrenoceptors in the ventrolateral medulla. Eur J Pharmacol 134:1–13Google Scholar
  19. Ernsberger P, Giuliano R, Willette RN, Reis DJ (1990) Role of imidazole receptors in the vasodepressor response to clonidine analogs in the rostral ventrolateral medulla. J Pharmacol Exp Ther 253:408–418Google Scholar
  20. Goldberg MR, Robinson D (1983) Yohimbine: a pharmacological probe for study of the α2-adrenoreceptor. Pharmacol Rev 35:143–180Google Scholar
  21. Grunhaus L, Tiongco D, Zelnik T, Flegel P, Hollingsworth PJ, Smith CB (1989) Intravenous yohimbine: selective enhancer of norepinephrine and cortisol secretion and systolic blood pressure in humans. Clin Neuropharmacol 12:106–114Google Scholar
  22. Gurguis GNM, Uhde TW (1990) Plasma 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and growth hormone responses to yohimbine in panic disorder patients and normal controls. Psychoneuroendocrinology 15:217–224Google Scholar
  23. Herrick-Davis K, Titeler M, Leonhardt S, Struble R, Price D (1988) Serotonin 5-HT1D in human prefrontal cortex and caudate: interaction with a GTP binding protein. J Neurochem 51:1906–1912Google Scholar
  24. Hieble JP, Sulpizio, Nichols AJ, Willette RN, Ruffolo RR, Jr (1988) Pharmacologic characterization of SK&F 104078, a novel alpha-2 adrenoceptor antagonist which discriminates between pre- and postjunctional alpha-2 adrenoceptors. J Pharmacol Exp Ther 247:645–652Google Scholar
  25. Holmberg G, Gershon S (1961) Autonomic and psychic effects of yohimbine hydrochloride. Psychopharmacologia 2:93–106Google Scholar
  26. Ingram CG (1962) Some pharmacologic actions of yohimbine and chlorpromazine in man. Clin Pharmacol Ther 3:345–352Google Scholar
  27. Krystal JH, Southwick S, Charney DS (1990) Yohimbine effects in PTSD patients. 1990 CME Syllabus and Proceedings Summary, 143rd Annual Meeting, American Psychiatric Association. Abstract #54CGoogle Scholar
  28. Lacomblez L, Bensimon G, Isnard F, Diquet B, Lecrubrier Y, Puech AJ (1989) Effect of yohimbine on blood pressure in patients with depression and orthostatic hypotension induced by clomip-ramine. Clin Pharmacol Ther 45:241–251Google Scholar
  29. Langer SZ, Cavero I, Massinham R (1980) Recent developments in noradrenergic neurotransmission and its relevance to the mechanism of action of certain antihypertensive agents. Hypertension 2:372–382Google Scholar
  30. Lehmann J, Koenig-Berard E, Vitou P (1989) The imidazoline-preferring receptor. Life Sci 45:1609–1615Google Scholar
  31. Maas JW, Hattox SE, Roth RH (1976) The determination of a brain arteriovenous difference for 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG). Brain Res 118:167–174Google Scholar
  32. Onrot J, Goldberg MR, Biaggioni I, Wiley RG, Hollister AS, Robertson D (1987) Oral yohimbine in human autonomic failure. Neurology 37:215–220Google Scholar
  33. Osman OT, Rudorfer MV, Manji HK, Potter WZ (1989a) Idazoxan: a novel alpha-2 antagonist and antidepressant. In: 1989, New Research Program and Abstracts, American Psychiatric Association, 142nd Annual Meeting, (abstract: #NR52)Google Scholar
  34. Osman OT, Rudorfer MV, Potter WZ (1989b) Idazoxan: a selective α2-antagonist and effective sustained antidepressant in two bipolar depressed patients. Arch Gen Psychiatry 46:958–959Google Scholar
  35. Osman OT, Rudorfer MV, Manji HK, Gorssman F, Potter WZ (1990) Idazoxan in treatment-resistant bipolar depression. In: 1990, New Research Program and Abstracts, American Psychiatric Association, 143rd Annual Meeting, (abstract: #NR432)Google Scholar
  36. Peroutka SJ, Switzer JA, Hamik A (1989) Identification of 5-hydroxytryptamine1D binding sites in human brain membranes. Synapse 3:61–66Google Scholar
  37. Pettibone DJ, Pfleuger AB, Totaro JA (1985) Comparison of the effects of recently developed α2-adrenergic antagonists with yohimbine and rauwolscine on monoamine synthesis in rat brain. Biochem Pharmacol 34:1093–1097Google Scholar
  38. Price LH, Charney DS, Rubin L, Heninger GR (1986) α2-adrenergic receptor function in depression: the cortisol response to yohimbine. Arch Gen Psychiatry 43:849–858Google Scholar
  39. Redmond DE, Jr (1979) New and old evidence for the involvement of a brain norepinephrine system in anxiety. In: Fann WE (ed) The phenomenology and treatment of anxiety. Plenum Press, New York, pp 153–203Google Scholar
  40. Reid K, Morales A, Harris C, Surridge DH, Condra M, Owen J (1987) Double-blind trial of yohimbine in treatment of psychogenic impotence. Lancet i:421–423Google Scholar
  41. Riley AJ, Goodman RE, Kellett JM, Orr R (1989) Double blind trial of yohimbine hydrochloride in the treatment of erection inadequacy. Sex Marital Ther 4:17–26Google Scholar
  42. Scatton B, Zivkivic B, Dedek J (1980) Antidopaminergic properties of yohimbine. J Pharmacol Exp Ther 215:494–499Google Scholar
  43. Scatton B, Dedek J, Zivkovic B (1983) Lack of involvement of α2-adrenoceptors in the regulation of striatal dopaminergic transmission. Eur J Pharmacol 86:427–433Google Scholar
  44. Seibyl JP, Krystal JH, Price LH, Charney DS (1989) Use of yohimbine to counteract nortriptyline-induced orthostatic hypotension. Letter. J Clin Psychopharmacol 9:67–68Google Scholar
  45. Starke K, Borowski E, Endo T (1975) Preferential blockade of presynaptic α-adrenoceptors by yohimbine. Eur J Pharmacol 34:385–388Google Scholar
  46. Struthers AD, Burrin JM, Brown MJ (1986) Exercise-induced increases in plasma catecholamines and growth hormone are augmented by selective α2 adrenoceptor blockade in man. Neuroendocrinology 44:22–28Google Scholar
  47. Sun M-K, Guyenet PG (1986) Effect of clonidine and γ-amino-butyric acid on the discharges of medullo-spinal sympathoexcitatory neurons in the rat. Brain Res 368:1–17Google Scholar
  48. van Oene JC, de Vries JB, Horn AS (1984) The effectiveness of yohimbine in blocking rat central dopamine autoreceptors in vivo. Naunyn-Schmiedeberg's Arch Pharmacol 327:304–311Google Scholar
  49. Waldmeier PC, Ortmann R, Bischoff S (1982) Modulation of dopaminergic transmission by alpha-noradrenergic agonists and antagonists: evidence for antidopaminergic properties of some alpha-antagonists. Experientia 38:1168–1176Google Scholar
  50. Winer BJ (1971) Statistical principles in experimental design. McGraw-Hill, New YorkGoogle Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • John H. Krystal
    • 1
    • 2
  • Christopher J. McDougle
    • 2
  • Scott W. Woods
    • 2
  • Lawrence H. Price
    • 2
  • George R. Heninger
    • 2
  • Dennis S. Charney
    • 1
    • 2
  1. 1.VA-yale Alcoholism Research CenterYale University School of Medicine, West Haven VA Medical CenterWest HavenUSA
  2. 2.Clinical Neuroscience Research UnitYale University School of Medicine, Connecticut Mental Health CenterNew HavenUSA

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