Skip to main content
SpringerLink
Log in

Behavioral, biochemical, and blood pressure responses to alprazolam in healthy subjects: Interactions with Yohimbine

  • Original Investigations
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

The effect of single doses of alprazolam (1.5 mg) and yohimbine (30 mg) and alprazolam and yohimbine given together on plasma free 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), cortisol, blood pressure, and subjective behavioral ratings was studied in eight healthy subjects. In comparison to placebo, alprazolam significantly reduced plasma MHPG and cortisol, systolic and diastolic blood pressure, and increased subjective ratings of drowsiness and mellow. Yohimbine and the alprazolam-yohimbine combination significantly increased plasma free MHPG. Concomitant yohimbine administration antagonized the effects of alprazolam on blood pressure and attenuated alprazolam-induced changes in cortisol and subjective ratings. The ability of alprazolam to decrease plasma MHPG and blood pressure contrasts with previously reported effects of diazepam. The implications of the findings of the present investigation to the postulated role of brain noradrenergic function in the etiology of panic anxiety and the therapeutic mechanism of action of antipanic treatment are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Beary MD, Lacey JH, Bhat AV (1983) The neuroendocrine impact of 3-hydroxy-diazepam in women. Psychopharmacology 79:295–297

    Google Scholar 

  • Bousquet P, Schwartz J (1983) Commentary, Alpha-Adrenergic Drugs: Pharmacological tools for the study of the central vasomotor control. Biochemical Pharmacol 32:1459–1465

    Google Scholar 

  • Braestrup C, Nielsen M (1983) Benzodiazepine receptors. In: Iverson L, Iverson SD, Snyder SM (eds) Handbook of psychopharmacology, New York, Plenum Publishing Corp, pp 285–384

    Google Scholar 

  • Bruni G, DalPra P, Dotti MT, Segre G (1980) Plasma ACTH and cortisol in benzodiazepine treated rats. Pharmacol Res Commun 12:163–175

    Google Scholar 

  • Butler PWP, Bessor GM, Steinberg H (1968) Changes in plasma cortisol induced by dexamphetamine and chlordiazepoxide given alone and in combination in men. J Endocrinol 40:391–392

    Google Scholar 

  • Charney DS, Redmond DE Jr (1983) Neurobiological mechanisms in human anxiety: evidence for noradrenergic hyperactivity. Neuropharmacology 22:1531–1536

    Google Scholar 

  • Charney DS, Heninger GR (1985a) Noradrenergic function and the mechanism of action of antianxiety treatment: I. The effect of long term alprazolam treatment. Arch Gen Psychiatry 42:458–467

    Google Scholar 

  • Charney DS, Heninger GR (1985b) Noradrenergic function and the mechanism of action of antianxiety treatment: II. The effect of long term imipramine treatment. Arch Gen Psychiatry 42:473–481

    Google Scholar 

  • Charney DS, Heninger GR, Sternberg DE, Roth RH (1981) Plasma MHPG in depression: effects of acute and chronic desipramine treatment. Psychiatr Res 5:217–229

    Google Scholar 

  • Charney DS, Heninger GR, Redmond DE Jr (1983a) Yohimbine induced anxiety and increased noradrenergic function in humans: effects of diazepam and clonidine. Life Sci 33:19–29

    Google Scholar 

  • Charney DS, Heninger GR, Sternberg DE (1983) Alpha-2 adrenergic receptor sensitivity and the mechanism of action of antidepressant therapy: the effect of long-term amitriptyline treatment. Br J Psychiatry 142:265–275

    Google Scholar 

  • 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 

  • Chou DT, Wang SC (1977) Unit activity of amygdala and hippocampal neurons: Effects of morphine and benzodiazepines. Brain Res 126:427–440

    Google Scholar 

  • Chouinard G, Annable L, Fontaine R, Solyom L (1982) Alprazolam in the treatment of generalized anxiety and panic disorders: A double-blind, placebo-controlled study. Psychopharmacology 77:229–233

    Google Scholar 

  • Corrodi H, Fuxe K, Hokfelt T (1967) The effect of some psychoactive drugs on central monoamine neurons. Eur J Pharmacol 1:363–368

    Google Scholar 

  • Corrodi H, Fuxe K, Lidbrink P, Olson L (1971) Minor tranquillizers, stress and central catecholamine neurons. Brain Res 29:1–16

    Google Scholar 

  • Dekirmenjian H, Maas JW (1974) MHPG in plasma. Clinica Chim Acta 52:203–208

    Google Scholar 

  • Elias AN, Valenta LJ, Szekeres AV, Grossman MK (1982) Regulatory role of gamma-aminobutyric acid in pituitary hormone secretion. Psychoneuroendocrinology 7:15–30

    Google Scholar 

  • Fabre LF, McLendon DM (1979) A double blind study comparing the efficacy and safety of alprazolam with diazepam and placebo in anxious out-patients. Curr Ther Res 25:519–526

    Google Scholar 

  • Feighner JB, Aden GC, Fabre LF, Rickels K, Smith WT (1983) Comparison of alprazolam, imipramine and placebo in the treatment of depression. JAMA 249:3057–3064

    Google Scholar 

  • Fuxe K, Agnati LF, Bolme P, Hokfelt T, Lidbrink P, Ljungdahl A, Perez de la Mora M, Ogren S (1975) The possible involvement of GABA mechanisms in the action of benzodiazepines on central catecholamine neurons. In: Costa E, Greengard P (eds) Mechanism of action of benzodiazepines. New york, Raven Press, pp 45–61

    Google Scholar 

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

    Google Scholar 

  • Grandison L, Cavagnini F, Schmid R, Invitti C, Guidotti A (1982) Gamma-aminobutyric acid and benzodiazepine binding sites in human anterior pituitary tissue. J Clin Endocrinol Metab 54:597–601

    Google Scholar 

  • Grant SJ, Huang YH, Redmond DE Jr (1980) Benzodiazepines attenuate single unit activity in the locus coeruleus. Life Sci 27:2231–2236

    Google Scholar 

  • Grant SJ, Mayor R, Redmond DE Jr (1984) Effects of alprazolam, a novel triozolobenzodiazepine, on locus coeruleus unit activity. Neurosci Abstr 10:952

    Google Scholar 

  • Greenblatt DJ, Shader RJ, Abernethy DR (1983) Current Status of Benzodiazepines. New Engl J Med 309:354–358

    Google Scholar 

  • Holmberg G, Gershon S (1961) Autonomic and psychiatric effects of yohimbine hydrochloride. Psychopharmacologia 2:93–106

    Google Scholar 

  • Insel TR, Ninan PT, Aloi J, Jimerson DC, Skolnick P, Paul SM (1984) A benzodiazepine receptor mediated model of anxiety. Arch Gen Psychiatry 41:741–750

    Google Scholar 

  • Johnstone EC, Ferrier IN (1980) Neuroendocrine markers of CNS drug effects. BR J Clin Pharmacol 10:5–21

    Google Scholar 

  • Klein DF, Zitrin CM, Woerner M (1978) Antidepressants, anxiety, panic and phobia. In: Lipton MA, DiMascio A, Killam KF (eds) Psychopharmacology: A generation of progress. New York, Raven Press, pp 1401–1410

    Google Scholar 

  • Kuhar MJ (1981) Autoradiographic localization of drug and neurotransmitter receptors in the brain. Trends Neurosci 4:(3):60–64

    Google Scholar 

  • Linnoila M, Karoum F, Calil HM, Kopin IJ, Potter WZ (1982) Alteration of norepinephrine metabolism with desipramine and zimelidine in depressed patients. Arch Gen Psychiatry 39:1025–1028

    Google Scholar 

  • Maas JW, Hattox SE, Roth RH (1976) The determination of a brain arteriovenous difference for 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG). Brain Res 118:167–174

    Google Scholar 

  • Mason ST, Fibiger HC (1979) Anxiety: the locus coeruleus disconnection. Life Sci 25:2141–2147

    Google Scholar 

  • McCormick SR, Nielsen J, Jatlow PI (1984) Quantitation of alprazolam in serum or plasma by liquid chromatography. Clin Chem 30:652–655

    Google Scholar 

  • Moore RY, Bloom FE (1979) Central catecholamine neuron systems: Anatomy and physiology of the norepinephrine and epinephrine systems. Ann Rev Neurosci 2:113–168

    Google Scholar 

  • Niehoff DL, Kuhar MJ (1983) Benzodiazepine receptors: localization in rat amygdala. J Neurosci 3:2091–2097

    Google Scholar 

  • Nielsen M, Braestrup C (1977a) Desipramine and some other antidepressant drugs decrease the major norepinephrine metabolite 3,4-dihydroxyphenylglycol sulphate in the rat brain. Naunyn Schmiedebergs Arch Pharmacol 300:93–99

    Google Scholar 

  • Nielsen M, Braestrup C (1977b) Chronic treatment with desipramine caused a sustained decrease of 3,4-dihydroxyphenylglycol sulphate and total 3-methoxy-4-hydroxyphenylglycol in the rat brain. Naunyn Schmiedebergs Arch Pharmacol 300:87–92

    Google Scholar 

  • Novas ML, Medina JH, DeRobertis E (1983) Benzodiazepine receptors in the rat hippocampal formation: Action of catecholaminergic, serotoninergic and commissural denervation. Neuroscience 8:459–465

    Google Scholar 

  • Nyback HV, Walters JR, Aghajanian GK, Roth RH (1975) Tricyclic antidepressants: effects on the firing rate of brain noradrenergic neurons. Eur J Pharmacol 32:302–312

    Google Scholar 

  • Palacios JM, Kuhar MJ (1982) β-Adrenergic receptor localization in rat brain by light microscopic autoradiography. Neurochem Int 4:473–490

    Google Scholar 

  • Pecknold JC, McClure DJ, Appeltauer L, Allan T, Wrzesinski L (1982) Does tryptophan potentiate clomipramine in the treatment of agoraphobic and social phobic patients? Br J Psychiatry 140:484–490

    Google Scholar 

  • Potter WZ, Calil HM, Extein I, Zavadil AP 3rd, Goodwin FK (1981) Specific norepinephrine and serotonin uptake inhibitors in man: A crossover study with pharmacokinetic, biochemical, neuroendocrine and behavioral parameters. Acta Psychiatr Scand 63:152–165

    Google Scholar 

  • Rainbow TC, Biegon A (1983) Quantitative autoradiography of [3H] prazosin binding sites in rat forebrain. Neurosci Lett 40:221–226

    Google Scholar 

  • 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, New York, Spectrum Press, pp 153–203

    Google Scholar 

  • Rees L (1970) M.D. thesis. Univ London, UK

    Google Scholar 

  • Rickels K, Csanalosi I, Greisman P, Cohen D, Werblowsky J, Ross HA, Harris H (1983) A controlled clinical trial of alprazolam for the treatment of anxiety. Am J Psychiatry 140:82–84

    Google Scholar 

  • Robinson JH, Wang SC (1979) Unit activity of limbic system neurons: Effects of morphine, diazepam and neuroleptic agents. Brain Res 166:149–159

    Google Scholar 

  • Rosloff BN, Davis JM (1978) Decrease in brain NE turnover after chronic DMI treatment: No effect with iprindole. Psychopharmacology 56:335–341

    Google Scholar 

  • Sabato UC, Novas ML, Lowenstein P, Zieher LM, DeRobertis E (1981) Action of 6-hydroxydopamine on benzodiazepine receptors in rat cerebral cortex. Eur J Pharmacol 73:381–382

    Google Scholar 

  • Schubert J, Nyback H, Sedvall G (1970) Effect of antidepressant drugs on accumulation and disappearance of monoamines formed in vivo from labelled precursors in mouse brain. J Pharm Pharmacol 22:136–139

    Google Scholar 

  • Sethy VH, Hodges DH Jr (1982) Alprazolam in a biochemical model of depression. Biochem Pharmacol 31:3155–3157

    Google Scholar 

  • Sheehan DV (1982) Panic attacks and phobias. New England J Med 3:156–158

    Google Scholar 

  • Sheehan DV, Ballenger J, Jacobsen G (1980) Treatment of endogenous anxiety with phobic, hysterical and hypochondriacal symptoms. Arch Gen Psychiatry 37:51–59

    Google Scholar 

  • Sheehan DV, Coleman JH, Greenblatt DJ, Jones KJ, Levine PH, Orsulak PJ, Peterson M, Schildkraut JJ, Uzogara E, Watkins D (1984) Some biochemical correlates of panic attacks and their response to a new treatment. J Clin Psychopharmacol 4:66–75

    Google Scholar 

  • Smythe GA, Bradshaw JE, Vining RF (1983) Hypothalamic monoamine control of stress-induced adrenocorticotropin release in the rat. Endocrinology 113:1062–1071

    Google Scholar 

  • Svensson TH, Usdin T (1978) Feedback inhibition of brain noradrenaline neurons by tricyclic antidepressants: α2-receptor mediation. Science 202:1089–1091

    Google Scholar 

  • Tallman JF, Paul SM, Skolnick P, Gallagher DW (1980) Receptors for the age of anxiety. Science 207:274–281

    Google Scholar 

  • Taylor KM, Laverty R (1969) The effect of chlordiazepoxide, diazepam and nitrazepam on catecholamine metabolism in regions of the rat brain. Eur J Pharmacol 8:296–301

    Google Scholar 

  • Tung C, Onuora CO, Robertson D, Goldberg MR (1983) Hypertensive effect of yohimbine following selective injection into the nucleus tractus solitarii of normotensive rats. Brain Res 277:193–195

    Google Scholar 

  • Unnerstall JR, Kopajtic TA, Kuhar MJ (1984) Distribution of α2 agonist binding sites in the rat and human central nervous system: Analysis of some functional anatomic correlates of the pharmacologic effects of clonidine and related adrenergic agents. Brain Res 7:69–101

    Google Scholar 

  • Young WS III, Kuhar MJ (1979a) Autoradiographic localisation of benzodiazepine receptors in the brains of humans and animals. Nature 280:393–394

    Google Scholar 

  • Young WS III, Kuhar MJ (1979b) Radiohistochemical localization of benzodiazepine receptors in rat brain. J Pharmacol Exp Ther 212:337–346

    Google Scholar 

  • Young WS III, Niehoff D, Kuhar MJ, Beer B, Lippa AS (1980) Multiple benzodiazepine receptor localization by light microscopic radiohistochemistry. J Pharmacol Exp Ther 216:425–430

    Google Scholar 

  • 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 

Download references

Author information

Authors and Affiliations

  1. Clinical Neuroscience Research Unit, Ribicoff Research Facilities, Connecticut Mental Health Center, Departments of Psychiatry and Laboratory Medicine, Yale University School of Medicine, 34 Park Street, 06508, New Haven, CT, USA

    Dennis S. Charney, Alan Breier, Peter I. Jatlow & George R. Heninger

Authors
  1. Dennis S. Charney
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alan Breier
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peter I. Jatlow
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. George R. Heninger
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Charney, D.S., Breier, A., Jatlow, P.I. et al. Behavioral, biochemical, and blood pressure responses to alprazolam in healthy subjects: Interactions with Yohimbine. Psychopharmacologia 88, 133–140 (1986). https://doi.org/10.1007/BF00652229

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00652229

Key words

Search

Navigation