Effects of the combination of metyrapone and oxazepam on intravenous nicotine self-administration in rats
- 223 Downloads
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.
The current study was designed to test the effects of the administration of a metyrapone:oxazepam combination on nicotine self-administration in rats.
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.
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.
The results of this study suggest a potential utility of the combination of metyrapone and oxazepam for smoking cessation in humans.
KeywordsNicotine Self-administration Metyrapone Oxazepam Reinforcement Varenicline HPA axis Benzodiazepine Corticotropin-releasing factor Rat
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.
- 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 PubMedCrossRefGoogle Scholar
- Goeders NE (2004) Stress, motivation, and drug addiction. Current directions in psychological science 13:33–35. http://www.jstor.org/stable/20182902
- 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 PubMedCrossRefGoogle Scholar
- 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 25:420–425PubMedGoogle Scholar
- 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 1431–1462Google Scholar
- 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 PubMedCrossRefGoogle Scholar
- Koob GF, Goeders NE (1989) Neuroanatomical substrates of drug self-administration. Oxford University Press, LondonGoogle Scholar
- 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 PubMedCrossRefGoogle Scholar
- 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- CrossRefGoogle Scholar
- 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 PubMedCrossRefGoogle Scholar
- 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 PubMedCrossRefGoogle Scholar