, Volume 104, Issue 4, pp 479–484 | Cite as

Alprazolam attenuates metabolic stress-induced neuroendocrine and behavioral effects in humans

  • Alan Breier
  • Orlando R. Davis
  • Robert W. Buchanan
Original Investigations


The effects of benzodiazepine drugs and the role of their recognition site, the GABAA/benzodiazepine receptor, in acute glucoprivic stress are not known. In the present study, the effects of acute glucoprivation were examined in ten healthy human subjects. Glucoprivation was induced by infusion of the glucose analog, 2-deoxyglucose (2DG), at doses sufficient (50 mg/kg) to competitively inhibit glucose metabolism. In addition, the effects of the triazolobenzodiazepine alprazolam (1.5 mg) on the 2DG-induced stress response was assessed. 2DG produced significant elevations in plamsa cortisol (P=0.0001) and glucose (P=0.0003) levels. Alprazolam pretreatment attenuated the 2DG-related cortisol elevations (P=0.05) but did not effect 2DG-induced glucose increases. In addition, 2DG caused significant increases in hunger (P=0.01) and thirst (P=0.001), and alprazolam significantly blunted both of these responses. Lastly, 2DG had significant effects on heart rate, diastolic blood pressure and body temperature (P<0.05). Alprazolam did not effect these physiologic indices. The significance of these data for the mechanisms involved in acute glucoprivic stress are examined and the implications of the data for the pathophysiology of affective illness and eating disorders are discussed.

Key words

Metabolic stress Glucoprivation Benzodiazepines Cortisol Behavioral response 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Balch OK (1976) Brain noradrenergic participation in glocoprivic feeding evaluated using catecholamine biosysthesis inhibitors. Masters thesis, University of Idaho, Dept. of Veterinary ScienceGoogle Scholar
  2. Berger BD, Wise CD, Stein L (1971) Norepinephrine: reversal of anorexia in rats with lateral hypothalamic damage. Science 172:281–284Google Scholar
  3. Booth DA (1967) Localization of adrenergic feeding system in the rat diencephalon. Science 158:515–557Google Scholar
  4. Breier A (1989) Experimental approaches to human stress research: Assessment of neurobiological mechanisms of stress in volunteers and psychiatric patients. Biol Psychiatry 26:438–462Google Scholar
  5. Breier A, Paul SM (1988) Anxiety and the benzodiazepine-GABA receptor complex. In: Roth M, Noyes R, Burrows GD (eds) Handbook of anxiety, vol 1. Biological, clinical and cultural perspectives. Elsevier, Cambridge pp 193–212Google Scholar
  6. Breier A, Paul SM (1990) GABAA/benzodiazepine receptor: implications for the molecular basis of anxiety. J Psychiatr Res 24:91–104Google Scholar
  7. Breier A, Charney DS, Heninger GR (1986) Intravenous diazepam fails to change growth hormone and cortisol secretion in humans. Psychiatry Res 18:293–299Google Scholar
  8. Breier A, Goldstein D, Rappaport M, Paul SM, Pickar D (1987) Metabolic stress effects in normal volunteers and schizophrenic patients. Proc American College of Neuropsychopharmacology, p 159Google Scholar
  9. Breier A, Wolkowitz OM, Rappaport M, Paul SM, Pickar D (1988) Metabolic stress effects in normal volunteers and schizophrenic patients. Psychopharmacol Bull 24:431–433Google Scholar
  10. Brodows RG, Pi-Sunyer FX, Campbell RG (1973) Neural control of counter-regulatory events during glucopenia in man. J Clin Invest 52:1841–1844Google Scholar
  11. Brodows RG, Pi-Sunyer FX, Campbell RG (1975) Sympathetic control of hepatic glycogenolysis during glucopenia in man. Metabolism 24:617–624Google Scholar
  12. Brown MR, Fisher LA (1985) Corticotropin-releasing factor: effects on the autonomic nervous system and visceral systems. Fed Proc 44:243–248Google Scholar
  13. Calogero AE, Kalogeras K, Tomai TP, Loriaux DL, Chrousos GP, Gold PW (1991) Inhibition of corticotropin releasing hormone secretion by GABA A and GABA B receptor action in vitro: clinical implications. In: Recent advances in adrenal regulation and function. Raven Press, New YorkGoogle Scholar
  14. Caraty A, Grino M, Locatelli A, Guillaume V, Boudouresque F, Conte-Devoix B, Oliver C (1990) Insulin-induced hypoglycemia stimulates corticotropin-releasing factor and arginine vasopressin secretion into hypophysial portal blood of conscious, unrestrained rams. J Clin Invest 85:1716–1721Google Scholar
  15. Carroll BJ (1985) Dexamethasone suppression test: a review of contemporary confusion. J Clin Psychol 46:13Google Scholar
  16. Charney DS, Breier A, Jatlow PI, Heninger GR (1986) Behavioral, biochemical and blood pressure responses to alprazolam in healthy subjects: interaction with yohimbine. Psychopharmacology 88:133–140Google Scholar
  17. Dorow R, Horowski R, Paschelke G, Amin M, Braestrup C (1983) Severe anxiety induced by FG-7142, a beta-carboline ligand for benzodiazepine receptors. Lancet i:98Google Scholar
  18. Fawcett J, Edwards JH, Kravitz HM (1987) Alprazolam: an anti-depressant? Alprazolam, desipramine, and an alprazolamdesipramine combination in the treatment of adult depressed outpatients. J Clin Psychopharmacol 7:295–310Google Scholar
  19. Feighner J, Aden GC, Fabre LF (1984) Comparison of alprazolam, imipramine and placebo in the treatment of depression. JAMA 249:3057–3064Google Scholar
  20. Gold PW, Rubinow DR (1987) Neuropeptide function in affective illness: Corticotropin-releasing hormone and somatostatin as model systems. In: Meltzer HY (ed) Psychopharmacology: the third generation of progress. Raven Press, New York, p 617Google Scholar
  21. Goldstein DS, Dionne R, Swett J, Gracely R, Brewer HB, Gregg R, Keiser HR (1982) Circulatory, plasma catecholomine, cortisol, lipid, and psychological responses to a real-life stress (third molar extractions): effects of diazepam sedation and of inclusion of epinephrine with the local anesthetic. Psychosom Med 44:259–272Google Scholar
  22. Gorman JM, Davis JM (1989) Antianxiety drugs. In: Kaplan HI, Sadock BJ (eds) Comprehensive textbook of psychiatry/V, vol 2, 5th edn. Williams & Wilkins, Baltimore, pp 1579–1590Google Scholar
  23. Grossman SP (1960) Eating or drinking elicited by direct adrenergic stimulation of the hypothalamus. Science 132:301–302Google Scholar
  24. Harlan WR, Laszlo J, Bogdonoff MD, Estes EH (1963) Alterations in free fatty acid metabolism in endocrine disorders. Part II: Sequential studies and the effect of 2-deoxy-d-glucose. J Clin Endocrinol Metab 23:41–49Google Scholar
  25. Havoudjian H, Paul SM, Skolnick P (1986) Rapid, stress-induced modification of the benzodiazepine receptor-coupled chloride ionophore. Brain Res 375:401Google Scholar
  26. Hudson JI, Hudson MS (1984) Endocrine dysfunction in anorexia nervosa and bulemia: comparison with abnormalities in other psychiatric disorders and disturbances due to metabolic factors. Psychiatr Dev 4:237Google Scholar
  27. Insel TR, Ninan PT, Aloi J, Jimerson DC, Skolnick P, Paul SM (1984) A benzodiazepine receptor-mediated model of anxiety: studies in non-human primates and clinical implications. Arch Gen Psychiatry 41:741Google Scholar
  28. Jezova D, Kvetnansky R, Kovacs K, Oprsalova Z, Vigas M, Makara GB (1987) Insulin-induced hypoglycemia activates the release of adrenocorticotropin predominantly via central and propranolol insensitive mechanisms. Endocrinology 120:409–415Google Scholar
  29. Kadish AH (1965) New methods for continuous monitoring for blood glucose by measurement of dissoloved oxygen. Clin Chem 11:869Google Scholar
  30. Kalogeras KT, Calogero AE, Kuribayiashi T, Khan I, Gallucci WT, Kling MA, Chrousos GP, Gold PW (1990) In vitro and in vivo effects of the triazolobenzodiazepine alprazolam on hypothalamic-pituitary-adrenal function: pharmacological and clinical implications. J Clin Endocrinol Metab 70:1462–1471Google Scholar
  31. Kathol RG, Noyes R, Lopez A (1988) Similarities in hypothalamicpituitary adrenal axis activity between patients with panic disorder and those experiencing external stress. Psychiatr Clin North Am 11:335–348Google Scholar
  32. Leff MJ, Roatch JF, Bunney WE (1970) Environmental factors preceding the onset of severe depression. Psychiatry 33:298–311Google Scholar
  33. Linton EA, Gillies GE, Lowry PJ (1983) Ovine corticotropin releasing factor and vasopressin antibody-quenching studies on hypothalamic extracts of normal and Brattleboro rats. Endocrinology 113:1878–1884Google Scholar
  34. Lloyd C (1980) Life events and depressive disorder reviewed. II. Events as precipitating factors. Arch Gen Psychiatry 37:541–548Google Scholar
  35. Muller EE, Cocchi D, Mantegazza P (1972) Brain adrenergic system in the feeding response induced by 2-deoxy-d-glucose. Am J Physiol 223:945–950Google Scholar
  36. Ninan PT, Insel TM, Cohen RM, Cook JM, Skolnick P, Paul SM (1982) Benzodiazepine receptor-mediated experimental “anxiety” in primates. Science 218:1332Google Scholar
  37. Ono N, Samson WK, McDonald JK, Lumpkin MD, Bedran de Castro JC, McCann SM (1985) Effects of intravenous and intraventricular injection of antisera directed against corticotropin-releasing factor on the secretion of anterior pituitary hormones. Proc Natl Acad Sci USA 82:7787–7790Google Scholar
  38. Owens MJ, Bissette G, Nemeroff CB (1989) Acute effects of alprazolam and adinazolam on the concentrations of corticotropin-releasing factor in the rat brain. Synapse 4:196–202Google Scholar
  39. Paykel ES, Myers JK, Dienelt MN, et al. (1969) Life events and depression: A controlled study. Arch Gen Psychiatry 21:753–760Google Scholar
  40. Pope HG, Hudson JI (1989) Eating disorders. In: Kaplan HI, Sadock BJ (eds) Comprehensive textbook of psychiatry/V, vol 2, 5th edn. Williams & Wilkins, Baltimore, pp 1854–1864Google Scholar
  41. Ritter RC, Epstein AN (1975) Control of meal size by central noradrenergic action. Proc Natl Acad Sci USA 72:3740–3743Google Scholar
  42. Ritter S, Pelzer NL, Ritter RC (1978) Absence of glucoprivic feeding after stress suggests impairment of noradrenergic neuron function. Brain Res 149:399–411Google Scholar
  43. Rivier C, Vale W (1983) Modulation of stress-induced ACTH release by corticotropin releasing factor, catecholamines and vasopressin. Nature 305:325–327Google Scholar
  44. Rivier C, Rivier J, Vale W (1982) Inhibition of adrenocorticotrophic hormone secretion in the rat by immunoneutralization of corticotropin releasing factor. Science 218:377–378Google Scholar
  45. Roy A, Breier A, Doran AR, Pickar D (1985) Life events in depression: relationship to subtypes. J Affect Dis 9:143–148Google Scholar
  46. Stokes PE, Sikes CR (1987) Hypothalamic-pituitary-adrenal axis in affective disorders. In: Meltzer HY (ed) Psychopharmacology: the third generation of progress. Raven Press, New York, p 589Google Scholar
  47. Stunkard AJ, Stellar E (1984) Eating and its disorders. Raven Press, New YorkGoogle Scholar
  48. Thompson CI, Zagon IA, McLaughlin PJ (1979) Hypophagia follows the initial hyperphagia produced by 2-deoxy-d-glucose in rats. Physiol Behav 23:187–190Google Scholar
  49. Welle SL, Thompson DA, Campbell RG, Lilavivathana U (1980) Increased hunger and thirst during gloprivation in humans. Physiol Behav 25:397–403Google Scholar
  50. Welle SL, Thommpson DA, Campbell RG (1982) B-adrenergic blockade inhibits thermogenesis and lipolysis during glucoprivation in humans. Am J Physiol 243:R379-R382Google Scholar
  51. Wolkowitz OM, Breier A, Doran AR, Kelsoe J, Lucas P, Paul SM, Pickar D (1988) Alprazolam augmentation of the antipsychotic effects of fluphenazine in schizophrenic patients: preliminary results. Arch Gen Psychiatry 45:664–671Google Scholar
  52. Woolf PD, Lee LA, Leebaw W, Thompson D, Lilavivathana U, Brodows R, Campbell R (1977) Intracellular glucopenia causes prolactin release in man. J Clin Endocrinol Metab 45:377–383Google Scholar
  53. Yamamoto H, Nagai K, Nakagawa H (1984) Bilateral lesions of the SCN abolish lipolytic and hyperphagic responses to 2DG. Biol Behav 32:1017–1020Google Scholar

Copyright information

© Springer-Verlag 1991

Authors and Affiliations

  • Alan Breier
    • 1
  • Orlando R. Davis
    • 1
  • Robert W. Buchanan
    • 1
  1. 1.Maryland Psychiatric Research Center, Department of PsychiatryUniversity of Maryland School of MedicineBaltimoreUSA

Personalised recommendations