Self-Administration of Intravenous Nicotine in Male and Female Cigarette Smokers

Neuropsychopharmacology (2008) 33, 715–720 & 2008 Nature Publishing Group All rights reserved 0893-133X/08 $30.00 www.neuropsychopharmacology.org Self-Administration of Intravenous Nicotine in Male and Female Cigarette Smokers Mehmet Sofuoglu*,1, Sonah Yoo1, Kevin P Hill1 and Marc Mooney1 1 Department of Psychiatry, School of Medicine, Yale University, VA Connecticut Healthcare System, West Haven, CT, USA Although nicotine is the main addictive chemical in tobacco, there have been few studies of pure nicotine self-administration in humans. The goal of this study was to test the parameters of an intravenous (IV) nicotine self-administration model using nicotine doses presumed to be within the range of those of average intake from cigarette smoking. Six male and four female smokers participated in a double-blind, placebo-controlled, crossover study, which consisted of one adaptation and three experimental sessions. In each experimental session, subjects were randomly assigned to one of the three doses of nicotine (0.1, 0.4, or 0.7 mg). The lowest nicotine dose, 0.1 mg, was chosen to be approximately half the amount of nicotine inhaled from one puff of a cigarette. During each experimental session, subjects first sampled the assigned nicotine dose and placebo and then had the opportunity to choose between nicotine and placebo for a total of six choices over a 90-min period. Out of six options, the average (SEM) number of nicotine choices were 3.0 (0.48) for 0.1 mg, 4.7 (0.48) for 0.4 mg and 4.5 (0.46) for 0.7 mg, indicating a significant effect of nicotine dose on nicotine choice. Both the 0.4 and 0.7, but not the 0.1 mg, nicotine doses were preferred to placebo. These higher doses also produced increases in heart rate, blood pressure, and ratings of drug liking and high. Overall, these findings indicate that smokers chose both the 0.4 and the 0.7 mg nicotine doses over placebo. Our model may be useful in the evaluation of the effects of both behavioral and pharmacological manipulations on nicotine self-administration in humans. Neuropsychopharmacology (2008) 33, 715–720; doi:10.1038/sj.npp.1301460; published online 30 May 2007 Keywords: nicotine; self-administration; choice; IV nicotine; nicotine abstinence INTRODUCTION There have been few studies of pure nicotine self-administration in humans despite the fact that nicotine is the main addictive chemical in tobacco (Rose and Corrigall, 1997; Benowitz, 1999; Rose et al, 2001; Le Foll and Goldberg 2006). Two paradigms have used nicotine replacement therapy (NRT) products, nicotine nasal spray, and nicotine gum, to assess preference for nicotine over placebo in abstinent smokers evaluated in human laboratory settings (Perkins et al, 1996; Hughes et al, 2000). These experiments have not shown consistent preferences for nicotine over placebo. In contrast, users of other drugs of abuse, including cocaine, amphetamines, benzodiazepines, and alcohol, consistently prefer active drug over placebo in the human laboratory context (de Wit and McCracken, 1990; Foltin and Fischman, 1992; Troisi II et al, 1993; Hatsukami et al, 1994; Tancer and Johanson, 2003; Stoops et al, 2005). *Correspondence: Dr M Sofuoglu, Department of Psychiatry, School of Medicine, Yale University, VA Connecticut Healthcare System, 950 Campbell Ave., Building 36/116A4, West Haven, CT 06516, USA, Tel: + 1 203 937 4809, Fax: + 1 203 937 3478, E-mail: Received 19 December 2006; revised 20 April 2007; accepted 23 April 2007 Two important factors could account for the lack of nicotine preference in the well-controlled studies of Perkins et al (1996) and Hughes et al (2000). First, the two routes of nicotine used could lead to aversive effects including local irritation and nasal burning (nasal spray) or taste, local irritation, and hiccups (nicotine gum). In recent studies of preferences for NRTs, substantial proportions of smokers do not prefer nicotine gum or nasal spray (West et al, 2001; Schneider et al, 2004, 2005). Second, the slower nicotine delivery via nicotine gum, compared to cigarette smoking, may diminish reinforcing effects (de Wit et al, 1992; Nelson et al, 2006).Thus, other routes, such as the intravenous (IV) one, may be more optimum for nicotine self-administration studies. A series of studies have tested IV nicotine self-administration in smokers (Henningfield and Goldberg, 1983; Henningfield et al, 1983; Harvey et al, 2004). In the Harvey et al (2004) study, during 3 h sessions, IV nicotine (0.75, 1.5, and 3.0 mg/injection) and saline were available concurrently for abstinent male cigarette smokers who, on average, smoked 29 cigarettes/day. To receive the injections, smokers had to pull a lever according to a fixed-ratio requirement ranging from 10 to 1600 (Harvey et al, 2004). Smokers preferred nicotine injections over saline administration for all three nicotine doses. Moreover, when the IV nicotine in male and female smokers M Sofuoglu et al 716 work requirement was higher, fixed-ratio values equal or over 200 lever pulls, rates of responding were significantly greater for nicotine than for saline. Importantly, the nicotine doses used in the Harvey et al study delivered higher than the usual nicotine intake of an average smoker, which is, on average, 1–2 cigarettes/h or 1–4 mg nicotine/h (Benowitz and Jacob, 1990). Nicotine dose may be a critical factor since in a previous study, IV nicotine doses over 1.5 mg were rated similar to cocaine or amphetamines by smokers who have used stimulants (Chausmer et al, 2003). Thus, whether smokers prefer IV nicotine over placebo in nicotine doses within the range of those of average intake from smoking remains to be determined. To address this question, this study used a choice procedure in which smokers were able to choose between various IV nicotine doses or saline. The nicotine doses chosen were 0.1, 0.4, and 0.7 mg, relative to placebo (saline). The 0.1 mg dose is less than the amount of nicotine inhaled from one puff of a cigarette (Djordjevic et al, 2000). The 0.7 mg is close to the minimum nicotine dose that has been shown to be selfadministered in the Harvey et al (2004). Thus, this study extended earlier IV nicotine self-administration studies by testing lower doses of nicotine presumed to be within the range of nicotine doses delivered with cigarette puffs and including both male and female smokers, who were less heavy cigarette smokers and without a history of any drug and alcohol dependence. METHODS sessions, subjects were instructed not to smoke after midnight the night before sessions. Smoking abstinence was verified using breath carbon monoxide levels (o10 parts per million (ppm)) and plasma nicotine levels o5 ng/ ml. Before the beginning of each session, an indwelling IV catheter was placed in the subject’s antecubital vein for nicotine infusion, blood drawing and as a safety precaution. In the adaptation session, subjects first received an IV saline injection followed by three (...truncated)