Abstract
Rationale
Despite increased education regarding its dangers, cigarette smoking remains a significant public health concern due to serious associated health consequences such as cancer and respiratory and cardiovascular diseases. Most smokers fail in their attempts to quit smoking, and current pharmacological interventions have relatively low levels of efficacy and are associated with significant adverse events. We have previously reported that combinations of metyrapone and oxazepam, administered at doses that were ineffective when delivered singly, resulted in dose-related decreases in cocaine self-administration in rats while not affecting food-maintained responding during the same sessions.
Objectives
The current study was designed to test the effects of the administration of a metyrapone:oxazepam combination on nicotine self-administration in rats.
Methods
Several dose combinations of metyrapone (12.5, 25 or 50 mg/kg) and oxazepam (5 or 10 mg/kg) were tested in rats trained to intravenously (IV) self-administer nicotine (0.03 mg/kg/infusion) during 1-h self-administration sessions using both fixed-ratio and progressive-ratio (PR) schedules of reinforcement.
Results
The administration of low doses of metyrapone and oxazepam in combination significantly decreased IV nicotine self-administration in rats. At the lowest doses of 12.5 mg/kg of metyrapone and 5 mg/kg of oxazepam, the drugs alone did not decrease IV nicotine self-administration, but the combination was effective. Varenicline was also tested using the fixed-ratio schedule, and reductions in nicotine intake were similar to those seen with the moderate dose of the combination.
Conclusions
The results of this study suggest a potential utility of the combination of metyrapone and oxazepam for smoking cessation in humans.
Similar content being viewed by others
References
Albertsen K, Borg V, Oldenburg B (2006) A systematic review of the impact of work environment on smoking cessation, relapse and amount smoked. Prev Med 43:291–305. doi:10.1016/j.ypmed.2006.05.001
Aubin HJ, Bobak A, Britton JR, Oncken C, Billing CB Jr, Gong J, Williams KE, Reeves KR (2008) Varenicline versus transdermal nicotine patch for smoking cessation: results from a randomised open-label trial. Thorax 63:717–724. doi:10.1136/thx.2007.090647
Caggiula AR, Donny EC, Epstein LH, Sved AF, Knopf S, Rose C, McAllister CG, Antelman SM, Perkins KA (1998) The role of corticosteroids in nicotine’s physiological and behavioral effects. Psychoneuroendocrinology 23:143–159. doi:10.1016/S0306-4530(97)00078-4
Cahill K, Stead L, Lancaster T (2009) A preliminary benefit–risk assessment of varenicline in smoking cessation. Drug Saf 32:119–135. doi:10.2165/00002018-200932020-00005
Chen H, Fu Y, Sharp BM (2008) Chronic nicotine self-administration augments hypothalamic–pituitary–adrenal responses to mild acute stress. Neuropsychopharmacology 33:721–730. doi:10.1038/sj.npp. 1301466
Chouinard G (2004) Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound. J Clin Psychiatry 65(Suppl 5):7–12
Doll R, Peto R, Boreham J, Sutherland I (2004) Mortality in relation to smoking: 50 years’ observations on male British doctors. BMJ 328:1519. doi:10.1136/bmj.38142.554479
Engelhardt D, Dorr G, Jaspers C, Knorr D (1985) Ketoconazole blocks cortisol secretion in man by inhibition of adrenal 11 beta-hydroxylase. Klin Wochenschr 63:607–612
George O, Ghozland S, Azar MR, Cottone P, Zorrilla EP, Parsons LH, O’Dell LE, Richardson HN, Koob GF (2007) CRF-CRF1 system activation mediates withdrawal-induced increases in nicotine self-administration in nicotine-dependent rats. Proc Natl Acad Sci USA 104:17198–17203. doi:10.1073/pnas.070758510
George O, Lloyd A, Carroll FI, Damaj MI, Koob GF (2011) Varenicline blocks nicotine intake in rats with extended access to nicotine self-administration. Psychopharmacology (Berl) 213:715–722. doi:10.1007/s00213-010-2024-34
Goeders NE (2002) Stress and cocaine addiction. J Pharmacol Exp Ther 301:785–789. doi:10.1124/jpet.301.3.785
Goeders NE (2004) Stress, motivation, and drug addiction. Current directions in psychological science 13:33–35. http://www.jstor.org/stable/20182902
Goeders NE (2007) Hypothalamic–pituitary–adrenocortical axis and addiction. In: al’Absi M (ed) Stress and addiction. Elsevier Neuroscience, London, pp 21–40
Goeders NE, Guerin GF (1996) Effects of surgical and pharmacological adrenalectomy on the initiation and maintenance of intravenous cocaine self-administration in rats. Brain Res 722:145–152. doi:10.1016/0006-8993(96)00206-5
Goeders NE, Guerin GF (2008) Effects of the combination of metyrapone and oxazepam on cocaine and food self-administration in rats. Pharmacol Biochem Behav 91:181–189. doi:10.1016/j.pbb.2008.07.005
Goeders NE, McNulty MA, Mirkis S, McAllister KH (1989) Chlordiazepoxide alters intravenous cocaine self-administration in rats. Pharmacol Biochem Behav 33:859–866. doi:10.1016/0091-3057(89)90483-8
Goeders NE, McNulty MA, Guerin GF (1993) Effects of alprazolam on intravenous cocaine self-administration in rats. Pharmacol Biochem Behav 44:471–474. doi:10.1016/0091-3057(93)90493-D
Goeders NE, Peltier RL, Guerin GF (1998) Ketoconazole reduces low dose cocaine self-administration in rats. Drug Alcohol Depend 53:67–77. doi:10.1016/S0376-8716(98)00108-2
Gonzales D, Rennard SI, Nides M, Oncken C, Azoulay S, Billing CB, Watsky EJ, Gong J, Williams KE, Reeves KR (2006) Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial. JAMA 296:47–55. doi:10.1001/jama.296.1.47
Grottoli S, Maccagno B, Ramunni J, Di Vito L, Giordano R, Gianotti L, DeStefanis S, Camanni F, Ghigo E, Arvat E (2002) Alprazolam, a benzodiazepine, does not modify the ACTH and cortisol response to hCRH and AVP, but blunts the cortisol response to ACTH in humans. J Endocrinol Invest 25:420–425
Haleem DJ, Kennett G, Curzon G (1988) Adaptation of female rats to stress: shift to male pattern by inhibition of corticosterone synthesis. Brain Res 458:339–347. doi:10.1016/0006-8993(88)90476-3
Harrison-Woolrych M (2009) Varenicline and suicide. Safety data from New Zealand BMJ 339:b5654. doi:10.1136/bmj.b5654
Haynes RC Jr (1990) Adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogs; inhibitors of the synthesis and actions of adrenocortical hormones. In: Gilman AG, Rall TW, Nies AS, Taylor P (eds) The pharmacological basis of therapeutics. Pergamon, New York, pp 1431–1462
Heishman SJ (1999) Behavioral and cognitive effects of smoking: relationship to nicotine addiction. Nicotine Tob Res 1(Suppl 2):S143–S147. doi:10.1080/14622299050011971, discussion S165–146
Hubner CB, Koob GF (1990) The ventral pallidum plays a role in mediating cocaine and heroin self-administration in the rat. Brain Res 508:20–29. doi:10.1016/0006-8993(90)91112-T
Hyytia P, Schulteis G, Koob GF (1996) Intravenous heroin and ethanol self-administration by alcohol-preferring AA and alcohol-avoiding ANA rats. Psychopharmacology (Berl) 125:248–254. doi:10.1007/BF02247335
Jonkman S, Risbrough VB, Geyer MA, Markou A (2008) Spontaneous nicotine withdrawal potentiates the effects of stress in rats. Neuropsychopharmacology 33:2131–2138. doi:10.1038/sj.npp. 1301607
Jorenby DE, Hays JT, Rigotti NA, Azoulay S, Watsky EJ, Williams KE, Billing CB, Gong J, Reeves KR (2006) Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs. placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA 296:56–63. doi:10.1001/jama.296.1.56
Kassel JD, Stroud LR, Paronis CA (2003) Smoking, stress, and negative affect: correlation, causation, and context across stages of smoking. Psychol Bull 129:270–304. doi:10.1037/0033-2909.129.2.270
Keating GM, Lyseng-Williamson KA (2010) Varenicline: a pharmacoeconomic review of its use as an aid to smoking cessation. PharmacoEconomics 28:231–254. doi:10.2165/11204380-000000000-00000
Keim KL, Sigg EB (1977) Plasma corticosterone and brain catecholamines in stress: effect of psychotropic drugs. Pharmacol Biochem Behav 6:79–85. doi:10.1016/0091-3057(77)90162-9
Koob GF, Goeders NE (1989) Neuroanatomical substrates of drug self-administration. Oxford University Press, London
Koob G, Kreek MJ (2007) Stress, dysregulation of drug reward pathways, and the transition to drug dependence. Am J Psychiatry 164:1149–1159. doi:10.1176/appi.ajp.2007.05030503
Le Foll B, Goldberg SR (2006) Nicotine as a typical drug of abuse in experimental animals and humans. Psychopharmacology (Berl) 184:367–381. doi:10.1007/s00213-005-0155-8
Lilja J, Larsson S, Skinhoj KT, Hamilton D (2001) Evaluation of programs for the treatment of benzodiazepine dependency. Subst Use Misuse 36:1213–1231. doi:10.1081/JA-100106224
Lowery EG, Thiele TE (2010) Pre-clinical evidence that corticotropin-releasing factor (CRF) receptor antagonists are promising targets for pharmacological treatment of alcoholism. CNS Neurol Disord Drug Targets 9:77–86
Majewska MD (2002) HPA axis and stimulant dependence: an enigmatic relationship. Psychoneuroendocrinology 27:5–12. doi:10.1016/S0306-4530(01)00033-6
Marcinkiewcz CA, Prado MM, Isaac SK, Marshall A, Rylkova D, Bruijnzeel AW (2009) Corticotropin-releasing factor within the central nucleus of the amygdala and the nucleus accumbens shell mediates the negative affective state of nicotine withdrawal in rats. Neuropsychopharmacology 34:1743–1752. doi:10.1038/npp.2008.231
McNeil JJ, Piccenna L, Ioannides-Demos LL (2010) Smoking cessation—recent advances. Cardiovasc Drugs Ther 24:359–367. doi:10.1007/s10557-010-6246-8
Meador-Woodruff JH, Greden JF (1988) Effects of psychotropic medications on hypothalamic–pituitary–adrenal regulation. Endocrinol Metab Clin North Am 17:225–234
Mendelson JH, Sholar MB, Goletiani N, Siegel AJ, Mello NK (2005) Effects of low- and high-nicotine cigarette smoking on mood states and the HPA axis in men. Neuropsychopharmacology 30:1751–1763. doi:10.1038/sj.npp.1300753
Mendelson JH, Goletiani N, Sholar MB, Siegel AJ, Mello NK (2008) Effects of smoking successive low- and high-nicotine cigarettes on hypothalamic–pituitary–adrenal axis hormones and mood in men. Neuropsychopharmacology 33:749–760. doi:10.1038/sj.npp.1301455
Moore TJ, Furberg CD (2009) Varenicline and suicide. Risk of psychiatric side effects with varenicline. BMJ 339:b4964. doi:10.1136/bmj.b4964
Moore D, Aveyard P, Connock M, Wang D, Fry-Smith A, Barton P (2009) Effectiveness and safety of nicotine replacement therapy assisted reduction to stop smoking: systematic review and meta-analysis. BMJ 338:b1024. doi:10.1136/bmj.b1024
O’Brien CP (2005) Benzodiazepine use, abuse, and dependence. J Clin Psychiatry 66(Suppl 2):28–33
O’Connor EC, Parker D, Rollema H, Mead AN (2010) The alpha4beta2 nicotinic acetylcholine-receptor partial agonist varenicline inhibits both nicotine self-administration following repeated dosing and reinstatement of nicotine seeking in rats. Psychopharmacology (Berl) 208:365–376. doi:10.1007/s00213-009-1739-
O’Dell LE, Khroyan TV (2009) Rodent models of nicotine reward: what do they tell us about tobacco abuse in humans? Pharmacol Biochem Behav 91:481–488. doi:10.1016/j.pbb.2008.12.011
Paterson NE (2009) Behavioural and pharmacological mechanisms of bupropion’s anti-smoking effects: recent preclinical and clinical insights. Eur J Pharmacol 603:1–11. doi:10.1016/j.ejphar.2008.12.009
Pecina S, Schulkin J, Berridge KC (2006) Nucleus accumbens corticotropin-releasing factor increases cue-triggered motivation for sucrose reward: paradoxical positive incentive effects in stress? BMC Biol 4:8. doi:10.1186/1741-7007-4-8
Peto R, Darby S, Deo H, Silcocks P, Whitley E, Doll R (2000) Smoking, smoking cessation, and lung cancer in the UK since 1950: combination of national statistics with two case–control studies. BMJ 321:323–329. doi:10.1136/bmj.321.7257.323
Pickworth WB, Fant RV (1998) Endocrine effects of nicotine administration, tobacco and other drug withdrawal in humans. Psychoneuroendocrinology 23:131–141. doi:10.1016/S0306-4530(97)00075-9
Pomerleau OF, Pomerleau CS (1991) Research on stress and smoking: progress and problems. Br J Addict 86:599–603. doi:10.1111/j.1360-0443.1991.tb01815.x
Ray R, Schnoll RA, Lerman C (2007) Pharmacogenetics and smoking cessation with nicotine replacement therapy. CNS Drugs 21:525–533
Rohleder N, Kirschbaum C (2006) The hypothalamic–pituitary–adrenal (HPA) axis in habitual smokers. Int J Psychophysiol 59:236–243. doi:10.1016/j.ijpsycho.2005.10.012
Rose JE, Behm FM, Salley AN, Bates JE, Coleman RE, Hawk TC, Turkington TG (2007) Regional brain activity correlates of nicotine dependence. Neuropsychopharmacology 32:2441–2452. doi:10.1038/sj.npp. 1301379
Silberman Y, Bajo M, Chappell AM, Christian DT, Cruz M, Diaz MR, Kash T, Lack AK, Messing RO, Siggins GR, Winder D, Roberto M, McCool BA, Weiner JL (2009) Neurobiological mechanisms contributing to alcohol–stress–anxiety interactions. Alcohol 43:509–519. doi:10.1016/j.alcohol.2009.01.002
Smagin GN, Goeders NE (2004) Effects of acute and chronic ketoconazole administration on hypothalamo–pituitary–adrenal axis activity and brain corticotropin-releasing hormone. Psychoneuroendocrinology 29:1223–1228. doi:10.1016/j.psyneuen.2004.02.004
Torpy DJ, Grice JE, Hockings GI, Walters MM, Crosbie GV, Jackson RV (1993) Alprazolam blocks the naloxone-stimulated hypothalamo–pituitary–adrenal axis in man. J Clin Endocrinol Metab 76:388–391. doi:10.1210/jc.76.2.388
Van Vugt DA, Piercy J, Farley AE, Reid RL, Rivest S (1997) Luteinizing hormone secretion and corticotropin-releasing factor gene expression in the paraventricular nucleus of rhesus monkeys following cortisol synthesis inhibition. Endocrinology 138:2249–2258. doi:10.1210/en.138.6.2249
West R (2009) The multiple facets of cigarette addiction and what they mean for encouraging and helping smokers to stop. COPD 6:277–283
Wilkes S (2008) The use of bupropion SR in cigarette smoking cessation. Int J Chron Obstruct Pulmon Dis 3:45–53. doi:10.2147/COPD.S1121
Wilson MA, Biscardi R, Smith MD, Wilson SP (1996) Effects of benzodiazepine agonist exposure on corticotropin-releasing factor content and hormonal stress responses: divergent responses in male and ovariectomized female rats. J Pharmacol Exp Ther 278:1073–1082
Yang XM, Gorman AL, Dunn AJ, Goeders NE (1992) Anxiogenic effects of acute and chronic cocaine administration: neurochemical and behavioral studies. Pharmacol Biochem Behav 41:643–650. doi:10.1016/0091-3057(92)90386-T
Acknowledgments
Part of this work was funded through a contract awarded to Behavioral Pharma, Inc. from Embera NeuroTherapeutics, Inc. and was conducted by Dr. Azar at Behavioral Pharma, Inc. in La Jolla, CA. Part of this research was also conducted at The Scripps Research Institute in La Jolla, CA and was supported, in part, by the Tobacco-Related Disease Research Program (TRDRP) from the State of California (grant 17RT-0095), the Pearson Center for Alcoholism and Addiction Research and the National Institute on Drug Abuse (DA023597). This is publication number 20890 from The Scripps Research Institute. All authors were involved in the design of the study and interpretation of the results, and the drafting and review of the manuscript, and all authors approved the final version. Dr. Goeders drafted the first version. Dr. Goeders is the Chief Scientific Officer and a founder of Embera NeuroTherapeutics. Drs. Goeders, Fox and Koob are consultants for Embera NeuroTherapeutics. Dr. Koob is a consultant for Behavioral Pharma.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Goeders, N.E., Cohen, A., Fox, B.S. et al. Effects of the combination of metyrapone and oxazepam on intravenous nicotine self-administration in rats. Psychopharmacology 223, 17–25 (2012). https://doi.org/10.1007/s00213-012-2682-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-012-2682-4