Sex differences in voluntary oral nicotine consumption by adolescent mice: a dose-response experiment Laura Cousino Klein * , Michele M. Stine, David J. Vandenbergh, Courtney A. Whetzel, Helen M. Kamens Department of Biobehavioral Health, Center for Developmental and Health Genetics, 315 East Health and Human Development Building, The Pennsylvania State University, University Park, PA 16802, USA Received 3 September 2003; received in revised form 11 January 2004; accepted 20 January 2004 Abstract Recent studies with adolescent rodents offer valuable information regarding the neurochemical and behavioral effects of adolescent nicotine exposure. One hundred twenty-one male and 125 female adolescent (35 days of age) C57BL/6J mice were tested for voluntary nicotine consumption by providing 24-h access to both saccharin-only (SAC) and one of six nicotine-containing solutions [10, 25, 50, 75, 100, 200 ug (-)-freebase nicotine/ml in 2% SAC] in the home cage for 7 days. Although males and females drank similar volumes (ml) of nicotine, the female mice consumed more nicotine adjusted for body weight (mg/kg) and as a percentage of total fluid intake than did the male mice. In contrast, there was no sex difference in overall serum cotinine levels (adjusted for liver weight). For all mice, nicotine consumption and serum cotinine levels increased in a dose-dependent manner, and the volume of nicotine intake (ml), percent nicotine intake, and nicotine dosage (mg/kg) on the last day of the experiment were positively correlated with cotinine levels. Cotinine levels were inversely related to body weight only for females. Sex differences in nicotine consumption, but not in cotinine levels, suggest sex differences in pharmacokinetic processes that may contribute to oral nicotine consumption behavior during periadolescence. D 2004 Elsevier Inc. All rights reserved. Keywords: Sex differences; Nicotine; Mice; Voluntary oral consumption; Two-bottle; Saccharin; Periadolescent; Dose-response; Pharmacokinetics; Genetics; Cotinine; Liver 1. Introduction Cigarette smoking still is the single largest preventable cause of death and illness in the United States (Centers for Disease Control [CDC], 2003a). Nearly 90% of adult smok- ers initiate cigarette smoking before the age of 20 (i.e., adolescence; Gilpin et al., 1999; United States Department of Health and Human Services [USDHHS], 1994), and recent reports suggest that cigarette smoking rates did not change among middle-school children between 2000 and 2002 despite an increase in prevention efforts (CDC, 2003b; Chassin et al., 2003). Taken together, these data suggest that adolescent development may be a critical period during which the majority of cigarette smokers begin to smoke (Gilpin et al., 1999; USDHHS, 1994). The likelihood of quitting smoking in adulthood is decreased substantially when smoking initiation begins in adolescence. In fact, adolescents who start smoking today will smoke for as long as 20 – 30 years, on average, which means that they are more likely to experience the adverse health consequences of smoking than are those individuals who start to smoke later in life (Pierce and Gilpin, 1996). Despite these statistics, little is known about the progression from adolescent experimen- tation with cigarettes into smoking addiction. Spear (2000) and Laviola et al. (1999) suggest that there are dramatic developmental changes in the brain associated with adolescence that may predispose an individual to ex- periment with alcohol, illicit drugs, and tobacco, the primary addictive ingredient of which is nicotine (USDHHS, 1988). Animal models of nicotine exposure developed with adult rodents may be used to understand why adolescents smoke cigarettes (Smith, 2003). Indeed, recent rodent models of adolescent nicotine exposure provide mounting biobehavio- ral support for this ‘‘critical period’’ hypothesis (Abreu- 0091-3057/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.pbb.2004.01.005 * Corresponding author. Tel.: +1-814-865-8813; fax: +1-814-863- 7525. E-mail address: lcklein@psu.edu (L.C. Klein). www.elsevier.com/locate/pharmbiochembeh Pharmacology, Biochemistry and Behavior 78 (2004) 13–25