Effects of the combination of metyrapone and oxazepam on intravenous nicotine self-administration in rats

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.

Effects of varenicline on operant self-administration of alcohol and/or nicotine in a rat model of co-abuse

“…One is that the doses we used were in an ineffective range. However, this is unlikely as they were selected based on previous reports that doses of 1–2 mg/kg significantly reduce alcohol and nicotine SA [14–16, 22, 28, 29, 32], without having the non-specific motor inhibitory effects seen at higher doses (3 mg/kg) [21]. …”

The effects of varenicline on methamphetamine self-administration and drug-primed reinstatement in female rats

“…Varenicline is a partial α4β2 and full α7 nAChR agonist (Coe et al , 2005a; Coe et al , 2005b; Gonzales et al , 2006; Mihalak et al , 2006; Smith et al , 2007) currently approved by the United States Food and Drug Administration for treatment of nicotine dependence under the trade name Chantix ® . As detailed in Table 1, pretreatment with varenicline reduces nicotine self-administrationin pre-clinical models, (see Table 1; Chang et al , 2015; Costello et al , 2014; Funk et al , 2015; George et al , 2011; Goeders et al , 2012; Hall et al , 2015; Le Foll et al , 2012; Mello et al , 2014; O'Connor et al , 2010; Panlilio et al , 2015; Rollema et al , 2007; Scuppa et al , 2015; Wouda et al , 2011). Similarly, some studies have reported reduced intake of ethanol(see Table 2; Feduccia et al , 2014; Ginsburg and Lamb, 2013; Hendrickson et al , 2010; Kamens et al , 2010; Kaminski and Weerts, 2014; Randall et al , 2015; Sotomayor-Zárate et al , 2013; Steensland et al , 2007; Wouda et al , 2011).…”

Role of GABA-active neurosteroids in the efficacy of metyrapone against cocaine addiction

“…We have recently focused on metyrapone, both alone and in combination with oxazepam, as possible therapeutics for drug dependence [18,[29][30][31]33]. The experiments described herein demonstrate that metyrapone pretreatment resulted in a dose-dependent decrease in cocaine-reinforced responding.…”

“…For example, rats subjected to noncontingent electric footshock acquire stable cocaine self-administration, responding at lower doses than nonstressed rats [5]. Similarly, pharmacological modulators of HPA axis methamphetamine and nicotine-taking and nicotine-seeking behaviors in rats [18,29,30]. Furthermore, this MET/OX combination is effective in reducing craving and decreasing urinary cocaine metabolites in cocaine-dependent human subjects [31].…”