Advertisement

Psychopharmacology

, Volume 215, Issue 3, pp 429–439 | Cite as

Physiological doses of progesterone potentiate the effects of triazolam in healthy, premenopausal women

  • Shanna BabalonisEmail author
  • Joshua A. Lile
  • Catherine A. Martin
  • Thomas H. Kelly
Original Investigation

Abstract

Rationale

Gender plays a critical role in the effects of drugs and drug abuse liability. Biological factors, including ovarian hormones, may contribute to gender differences in drug abuse. Preclinical and some clinical research suggests that progesterone and its metabolites have activity at the GABAA receptor and may enhance the effect of GABAergic compounds (e.g., benzodiazepines). Because women are exposed to varying levels of progesterone from puberty until menopause, and appear more sensitive to the negative consequences of benzodiazepine use, it is important to understand the impact of progesterone on GABAergic drug effects.

Objectives

The purpose of this experiment was to characterize the behavioral effects of progesterone, alone and in combination with the short-acting benzodiazepine, triazolam, to determine if progesterone potentiates the behavioral effects of triazolam.

Methods

Oral micronized progesterone (0, 100, and 200 mg) and oral triazolam (0.00, 0.12, and 0.25 mg/70 kg) were administered to healthy, premenopausal women (n = 11) under conditions of low circulating sex hormones. The subjective, performance and physiological effects of progesterone, alone and in combination with triazolam, were assessed.

Results

Triazolam alone produced prototypical sedative-like effects. Progesterone alone also engendered some sedative effects, although the time course of the effects was more limited than that of triazolam. Progesterone increased and extended the duration of triazolam effects and delayed the onset of triazolam peak effects, most notably at the 0.12 mg/70 kg dose.

Conclusions

Progesterone potentiates the behavioral effects of benzodiazepines and may contribute to benzodiazepine use and abuse among women.

Keywords

Progesterone Prometrium Neurosteroid Benzodiazepine Triazolam Subjective effects Performance effects Women’s health 

Notes

Acknowledgments

The authors wish to thank Stephanie LaBedz, Stephanie Douglas, Dustin Lee, Laura Mudd, Caroline Kimathi, Cleeve Emurian, Glenn Robbins, Phoebe Brown, and Beth Eaves for expert technical assistance. We also thank Steven Sitzlar of the University of Kentucky Investigational Drug Service.

This research and the preparation of this manuscript were supported by grants from the National Institute on Drug Abuse (R36 DA024127, T32 DA007304) and the Center for Biomedical Research Excellence (P20 RR015592). The authors do not have any financial relationship with these funding sources and have no conflict of interest to report.

References

  1. Andreen L, Spigset O, Andersson A, Nyberg S, Backstrom T (2006) Pharmacokinetics of progesterone and its metabolites allopregnanolone and pregnanolone after oral administration of low-dose progesterone. Maturitas 54(3):238–244PubMedCrossRefGoogle Scholar
  2. Anthony JC, Warner LA, Kessler RC (1994) Comparative epidemiology of dependence on tobacco, alcohol, controlled substances and inhalants: basic findings from the National Comorbidity Survey. Exp Clin Psychopharmacol 2(3):244–268CrossRefGoogle Scholar
  3. Babalonis S, Emurian CS, Martin CA, Lile JA, Kelly TH (2008) Modulation of the discriminative stimulus effects of triazolam across the menstrual cycle phase in healthy pre-menopausal women. Drug Alcohol Depend 94(1-3):276–280PubMedCrossRefGoogle Scholar
  4. Bertz RJ, Reynolds IJ, Kroboth PD (1995) Effect of neuroactive steroids on [3h]flumazenil binding to the GABAA receptor complex in vitro. Neuropharmacology 34(9):1169–1175PubMedCrossRefGoogle Scholar
  5. Chakmakjian ZH, Zachariah NY (1987) Bioavailability of progesterone with different modes of administration. J Reprod Med 32(6):443–448PubMedGoogle Scholar
  6. de Wit H, Schmitt L, Purdy R, Hauger R (2001) Effects of acute progesterone administration in healthy postmenopausal women and normally-cycling women. Psychoneuroendocrinology 26(7):697–710PubMedCrossRefGoogle Scholar
  7. Evans SM, Foltin RW (2006) Exogenous progesterone attenuates the subjective effects of smoked cocaine in women, but not in men. Neuropsychopharmacology 31(3):659–674PubMedCrossRefGoogle Scholar
  8. Foltin RW, Fischman MW (1991) Assessment of abuse liability of stimulant drugs in humans: a methodological survey. Drug Alcohol Depend 28:3–48PubMedCrossRefGoogle Scholar
  9. Foltin RW, Fischman MW, Pippen PA, Kelly TH (1993) Behavioral effects of cocaine alone and in combination with ethanol or marijuana in humans. Drug Alcohol Depend 32:93–106PubMedCrossRefGoogle Scholar
  10. Geiselmann B, Linden M (1991) Prescription and intake patterns in long-term and ultra-long-term benzodiazepine treatment in primary care practice. Pharmacopsychiatry 24(2):55–61PubMedCrossRefGoogle Scholar
  11. Grant KA, Azarov A, Shively CA, Purdy RH (1997) Discriminative stimulus effects of ethanol and 3 alpha-hydroxy-5 alpha-pregnan-20-one in relation to menstrual cycle phase in cynomolgus monkeys (Macaca fascicularis). Psychopharmacology (Berl) 130(1):59–68CrossRefGoogle Scholar
  12. Grant KA, Helms CM, Rogers LS, Purdy RH (2008) Neuroactive steroid stereospecificity of ethanol-like discriminative stimulus effects in monkeys. J Pharmacol Exp Ther 326(1):354–361PubMedCrossRefGoogle Scholar
  13. Green KL, Azarov AV, Szeliga KT, Purdy RH, Grant KA (1999) The influence of menstrual cycle phase on sensitivity to ethanol-like discriminative stimulus effects of GABAA-positive modulators. Pharmacol Biochem Behav 64(2):379–383PubMedCrossRefGoogle Scholar
  14. Greenblatt DJ, Gan L, Harmatz JS, Shader RI (2005) Pharmocokinetics and pharmacodynamics of single-dose triazolam: electroencephalography compared with the digit–symbol substitution test. Br J Clin Pharmacol 60(3):244–248PubMedCrossRefGoogle Scholar
  15. Grobin AC, Morrow AL (2000) 3alpha-hydroxy-5alpha-pregnan-20-one exposure reduces GABA(a) receptor alpha4 subunit mRNA levels. Eur J Pharmacol 409(2):R1–R2PubMedCrossRefGoogle Scholar
  16. Higgins ST, Rush CR, Bickel WK, Hughes JR, Lynn M, Capeless MA (1993) Acute behavioral and cardiac effects of cocaine and alcohol combinations in humans. Psychopharmacology (Berl) 111(3):285–294CrossRefGoogle Scholar
  17. Holdstock L, de Wit H (2000) Effects of ethanol at four phases of the menstrual cycle. Psychopharmacology (Berl) 150(4):374–382CrossRefGoogle Scholar
  18. Howes JB, Ryan J, Fairbrother G, O'Neill K, Howes LG (1996) Benzodiazepine prescribing in a Sydney teaching hospital. Med J Aust 165(6):305–308PubMedGoogle Scholar
  19. Kandel DB, Warner LA, Kessler RC (1998) The epidemiology of substance use and dependence among women. In: Wetherington CL, Roman AB (eds) Drug addiction research and the health of women. Diane, Darby, pp 105–130Google Scholar
  20. Kroboth PD, Smith RB, Stoehr GP, Juhl RP (1985) Pharmacodynamic evaluation of the benzodiazepine–oral contraceptive interaction. Clin Pharmacol Ther 38(5):525–532PubMedCrossRefGoogle Scholar
  21. Lambert JJ, Cooper MA, Simmons RDJ, Weir CJ, Belelli D (2009) Neurosteroids: endogenous allosteric modulators of GABAA receptors. Psychoneuroendocrinology 34S:48–58CrossRefGoogle Scholar
  22. Lambert JJ, Belelli D, Hill-Venning C, Peters JA (1995) Neurosteroids and GABAA receptor function. Trends Pharmacol Sci 16(9):295–303PubMedCrossRefGoogle Scholar
  23. Lena C, Changeux JP, Mulle C (1993) Evidence for preterminal nicotinic receptors on GABAergic axons in the rat interpeduncular nucleus. J Neurosci 13(6):2680–2688PubMedGoogle Scholar
  24. Lejuez CW, Read JP, Kahler CW, Richards JB, Ramsey SE, Stuart GL, Strong DR, Brown RA (2002) Evaluation of a behavioral measure of risk taking: the balloon analogue risk task (BART). J Exp Psychol Appl 8(2):75–84PubMedCrossRefGoogle Scholar
  25. Martin WR, Sloan JW, Sapira JD, Jasinski DR (1971) Physiologic, subjective, and behavioral effects of amphetamine, methamphetamine, ephedrine, phenmetrazine, and methylphenidate in man. Clin Pharmacol Ther 12:245–258PubMedGoogle Scholar
  26. McAuley JW, Reynolds IJ, Kroboth FJ, Smith RB, Kroboth PD (1995) Orally administered progesterone enhances sensitivity to triazolam in postmenopausal women. J Clin Psychopharmacol 15(1):3–11PubMedCrossRefGoogle Scholar
  27. McLeod DR, Griffiths RR, Bigelow GE, Yingling JE (1982) An automated version of the digit symbol substitution test (DSST). Behav Res Meth Instrum 14:463–466CrossRefGoogle Scholar
  28. Nahoul K, Dehennin L, Jondet M, Roger M (1993) Profiles of plasma estrogens, progesterone and their metabolites after oral or vaginal administration of estradiol or progesterone. Maturitas 16(3):185–202PubMedCrossRefGoogle Scholar
  29. Nomura K, Nakao M, Sato M, Yano E (2006) Regular prescriptions for benzodiazepines: a cross-sectional study of outpatients at a university hospital. Intern Med 45(22):1279–1283PubMedCrossRefGoogle Scholar
  30. Oliveto AH, Bickel WK, Hughes JR, Higgins ST, Fenwick JW (1992) Triazolam as a discriminative stimulus in humans. Drug Alcohol Depend 30(2):133–142PubMedCrossRefGoogle Scholar
  31. Paul SM, Purdy RH (1992) Neuroactive steroids. FASEB 6(6):2311–2322Google Scholar
  32. Pluchino N, Luisi M, Lenzi E, Centofanti M, Begliuomini S, Freschi L, Ninni F, Genazzani AR (2006) Progesterone and progestins: effects on brain, allopregnanolone and beta-endorphin. J Steroid Biochem Mol Biol 102(1–5):205–213PubMedCrossRefGoogle Scholar
  33. Pisu MG, Serra M (2004) Neurosteroids and neuroactive drugs in mental disorders. Life Sci 74(26):3181–3197PubMedCrossRefGoogle Scholar
  34. Rhodes ME, Frye CA (2004) Progestins in the hippocampus of female rats have antiseizure effects in a pentylenetetrazole seizure model. Epilepsia 45(12):1531–1538PubMedCrossRefGoogle Scholar
  35. Rukstalis M, de Wit H (1999) Effects of triazolam at three phases of the menstrual cycle. J Clin Psychopharmacol 19(5):450–458PubMedCrossRefGoogle Scholar
  36. Rupprecht R (2003) Neuroactive steroids: mechanisms of action and neuropsychopharmacological properties. Psychoneuroendocrinology 28(2):139–168PubMedCrossRefGoogle Scholar
  37. Rush CR, Kelly TH, Fillmore MT, Hays LR (2003) Discriminative-stimulus effects of triazolam in light and moderate drinkers. Alcohol Clin Exp Res 27(4):638–646PubMedCrossRefGoogle Scholar
  38. Schumacher M, Coirini H, McEwen BS (1989) Regulation of high-affinity GABAA receptors in specific brain regions by ovarian hormones. Neuroendocrinology 50(3):315–320PubMedCrossRefGoogle Scholar
  39. Schumacher M, Robert F (2002) Progesterone: synthesis, metabolism, mechanisms of action, and effects in the nervous system. In: Pfaff DW (ed) Hormones, brain and behavior. Academic, San Diego, pp 683–745CrossRefGoogle Scholar
  40. Simon JA, Robinson DE, Andrews MC, Hildebrand JR, Rocci ML, Blake RE, Hodgen GD (1993) The absorption of oral micronized progesterone: the effect of food, dose proportionality, and comparison with intramuscular progesterone. Fertil Steril 60(1):26–33PubMedGoogle Scholar
  41. Simoni-Wastila L, Ross-Degnan D, Mah C, Gao X, Brown J, Cosler LE, Fanning T, Gallagher P, Salzman C, Soumerai SB (2004) A retrospective data analysis of the impact of the New York triplicate prescription program on benzodiazepine use in Medicaid patients with chronic psychiatric and neurologic disorders. Clin Ther 26(2):322–336PubMedCrossRefGoogle Scholar
  42. Simpson CA, Rush CR (2002) Acute performance-impairing and subject-rated effects of triazolam and temazepam, alone and in combination with ethanol, in humans. J Psychopharmacol 16(1):23–34PubMedCrossRefGoogle Scholar
  43. Smith SS, Gong QH, Hsu FC, Markowitz RS, French-Mullen JM, Li X (1998) GABAA receptor alpha4 subunit suppression prevents withdrawal properties of an endogenous steroid. Nature 392(6679):926–930PubMedCrossRefGoogle Scholar
  44. Soderpalm AH, Lindsey S, Purdy RH, Hauger R, de Wit H (2004) Administration of progesterone produces mild sedative-like effects in men and women. Psychoneuroendocrinology 29(3):339–354PubMedCrossRefGoogle Scholar
  45. Sofuoglu M, Babb DA, Hatsukami DK (2001) Progesterone treatment during the early follicular phase of the menstrual cycle: effects on smoking behavior in women. Pharmacol Biochem Behav 69(1–2):299–304PubMedCrossRefGoogle Scholar
  46. Sofuoglu M, Babb DA, Hatsukami DK (2002) Effects of progesterone treatment on smoked cocaine response in women. Pharmacol Biochem Behav 72(1–2):431–435PubMedCrossRefGoogle Scholar
  47. Stanczyk FZ (1999) Pharmacokinetics of progesterone administered by the oral and parenteral routes. J Reprod Med 44(2S):141–147PubMedGoogle Scholar
  48. Substance Abuse and Mental Health Services Administration (2009) Results from the 2008 National Survey on Drug Use and Health: national findings. Office of Applied Studies, NSDUH Series H-36, HHS Publication No. SMA 09-4434, Rockville, MDGoogle Scholar
  49. van der Waals FW, Mohrs J, Foets M (1993) Sex differences among recipients of benzodiazepines in Dutch general practice. Br Med J 307(6900):363–366CrossRefGoogle Scholar
  50. World Medical Association Declaration of Helsinki Ethical Principle for Medical Research Involving Human Subjects. Last revised October 2008. Available at http://www.wma.net/en/30publications/10policies/b3/index.html
  51. Wysowski DK, Baum C (1991) Outpatient use of prescription sedative-hypnotic drugs in the United States, 1970 through 1989. Arch Intern Med 151(9):1779–1783PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Shanna Babalonis
    • 1
    • 3
    Email author
  • Joshua A. Lile
    • 1
  • Catherine A. Martin
    • 2
  • Thomas H. Kelly
    • 1
    • 2
    • 3
  1. 1.Department of Behavioral Science, College of MedicineUniversity of Kentucky Medical CenterLexingtonUSA
  2. 2.Department of PsychiatryUniversity of Kentucky Medical CenterLexingtonUSA
  3. 3.Department of PsychologyUniversity of Kentucky College of Arts and SciencesLexingtonUSA

Personalised recommendations