Sex differences in voluntary oral nicotine consumption by adolescent mice: a dose-response experiment

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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.

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 smokers initiate cigarette smoking before the age of 20 (i.e., adolescence; Gilpin et al., 1999, United States Department of Health and Human Services, 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 Centers for Disease Control and Prevention, 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 experimentation 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 experiment 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 biobehavioral support for this “critical period” hypothesis Abreu-Villaca et al., 2003, Adriani et al., 2002, Klein, 2001, Laviola et al., 2003, Miao et al., 1998, Trauth et al., 2000a, Trauth et al., 2001. These adolescent rodent models include several rat (e.g., Wistar, Sprague–Dawley, Brown Norway, Wistar Kyoto) and mouse (e.g., CD-1, C57BL/6, NMRI) strains (e.g., Adriani et al., 2002, Faraday et al., 2001, Faraday et al., 2003, Gäddnäs et al., 2001, Kelley and Middaugh, 1999, Klein, 2001, Klein et al., 2003, Levin et al., 2003, Lopez et al., 2001, Pekonen et al., 1993, Todte et al., 2001, Trauth et al., 2000a, Trauth et al., 2000b), with ages spanning preweaning, periadolescence (around postnatal age 30 days; Spear and Brake, 1983), and postadolescence (around postnatal age 60 days; e.g., Adriani et al., 2003, Hatchell and Collins, 1980, Klein et al., 2003, Petersen et al., 1984, Robinson et al., 1996). These models also incorporate various nicotine administration methods previously used with adults including osmotic minipump and continuous infusion methods (e.g., Bhat et al., 1994, Faraday et al., 2001, Klein, 2001, Trauth et al., 2000a), repeated injections (e.g., Hatchell and Collins, 1980, Miao et al., 1998), oral consumption (e.g., Adriani et al., 2002, Flynn et al., 1989, Gäddnäs et al., 2001, Klein et al., 2003, Pekonen et al., 1993, Todte et al., 2001), and, most recently, intravenous self-administration in rats (Levin et al., 2003). These studies offer important data for understanding the biobehavioral effects of nicotine exposure in adolescence. For example, recent findings suggest that adolescent male rats exposed to nicotine are at risk for increased opioid (Wistar; Klein, 2001) and nicotine consumption in adulthood (Sprague–Dawley; Adriani et al., 2003). There also are reports of dramatic, neurobiological effects of adolescent nicotine exposure in rats, which include immediate and long-term changes in the central nervous system dopaminergic and catecholaminergic functioning (Trauth et al., 2001), and long-lasting cellular and neuronal damage in the midbrain, hippocampus, and cerebral cortex (Abreu-Villaca et al., 2003). As this field of adolescent nicotine research continues to develop, however, new studies are needed to test the validity and parameters of adult models adapted for use with adolescent animals, particularly because the biological and behavioral characteristics of adolescence appear to be quite different than those observed in adulthood (e.g., Laviola et al., 2003).

With regard to nicotine consumption models, there is a growing interest in adapting the oral nicotine consumption method for use with adolescent rodents to examine nicotine's biobehavioral effects given the ease of administration, opportunity for continuous nicotine exposure, and production of acceptable levels of nicotine bioavailability through this administration route (Le Houezec et al., 1989). The mouse is an important model for examining the development of nicotine consumption in periadolescence. Adult mouse models of nicotine exposure have been used effectively to demonstrate nicotine's effects in reward-relevant regions of the brain (e.g., Collins et al., 1989, Mansvelder et al., 2002, Marks and Collins, 1982, Pauly et al., 1996), as well as the behavioral effects of nicotine (e.g., Hatchell and Collins, 1977, Hatchell and Collins, 1980). Adult and adolescent mice will readily consume nicotine in drinking water (e.g., Klein et al., 2003, Meliska et al., 1995, Robinson et al., 1996, Rowell et al., 1983, Sparks and Pauly, 1999), in amounts that yield serum nicotine, serum cotinine (nicotine's primary active metabolite), and brain tissue distribution levels comparable with the human smoker. In light of the recent mapping of the mouse genome, mouse models provide a unique opportunity to reveal genetic contributions to drug abuse. The importance of outlining the parameters of voluntary nicotine consumption in adolescent mice is highlighted by reports that genetic variability accounts for the biobehavioral differences in responses to nicotine across mouse strains Hatchell and Collins, 1977, Smolen et al., 1994, Meliska et al., 1995, as well as in sex differences in response to nicotine Hatchell and Collins, 1980, Rosecrans, 1972. For example, the alcohol-preferring mouse strain, C57BL/6, also prefers nicotine, relative to mice that demonstrate a low preference for alcohol (DBA/2; Meliska et al., 1995). C57BL/6 mice also prefer amphetamine more than DBA/2 mice do, suggesting that genetic factors may contribute to the use of a wide range of psychoactive drugs including nicotine. The handful of studies that have tested voluntary nicotine consumption in periadolescent mice (e.g., Adriani et al., 2002, Klein et al., 2003, Robinson et al., 1996) suggest that this method can be valuable for understanding adolescent nicotine intake behavior, and that additional studies are needed to clarify this paradigm in male and female mice. The present experiment was designed to examine potential sex differences in nicotine consumption based on earlier reports of differential sensitivity to nicotine in periadolescent male and female rodents (e.g., Faraday et al., 2001, Hatchell and Collins, 1980). In addition, we sought to determine the parameters of oral nicotine consumption by testing voluntary nicotine intake in periadolescent C57BL/6 mice across six different nicotine concentrations.

Section snippets

Animals

One hundred twenty-one male and 125 female periadolescent C57BL/6J mice (Jackson Laboratory, Bar Harbor, ME) were individually housed under standard housing conditions to allow for accurate measurement of liquid and food intake. Mice were 32 days old and weighed approximately 15.81±0.10 g (standard error of the mean) at the beginning of the experiment (males: 16.80±0.15 g; females: 15.79±0.10 g). This age is defined as early adolescence by Spear (2000), Spear and Brake (1983), and Laviola et

Baseline body weight, food consumption, and water intake

There were no significant nicotine group differences in body weight, food consumption, or water intake on the last day of the baseline period, prior to nicotine-treatment group randomization (i.e., 10, 25, 50, 75, 100, or 200 μg nicotine/ml treatment group). However, males weighed more [17.9±0.1 vs. 15.6±0.1 g, respectively; F(1,232)=220.8, P<.0001], ate more food [4.3±0.1 vs. 4.1±0.1 g, respectively; F(1,231)=6.98, P<.01], and drank more water [7.1±0.1 vs. 6.5±0.1 ml, respectively; F

Discussion

The present experiment examined voluntary nicotine consumption by male and female periadolescent mice across six different nicotine concentrations. Consistent with adult studies of male mice, results suggest that both male and female periadolescent C57BL/6J mice will voluntarily consume nicotine across a wide range of nicotine concentrations (Robinson et al., 1996), and that this consumption results in a measurable increase in serum cotinine levels. With regard to adolescent versus adult

Summary

The present findings suggest important sex differences in nicotine self-administration, nicotine pharmacokinetics, and the effects of nicotine on body weight in adolescent C57BL/6J mice across six nicotine concentrations, using a voluntary oral nicotine consumption paradigm. To the extent that this model predicts nicotine consumption by adolescent humans, it could be used to understand why adolescent humans begin to smoke, and how smoking might increase the propensity to consume other addictive

Acknowledgements

This research was conducted at The Pennsylvania State University and was supported by NIDA grant 1RO3DA015114-01 (LCK). HMK now is in the Department of Behavioral Neuroscience at Oregon Health & Science University. Portions of this work were presented at the annual meetings of the Society for Research on Nicotine and Tobacco, Savannah, GA, February 2002, the Society of Biological Psychiatry, Philadelphia, PA, May 2002, and the American Psychological Association, Toronto, Ontario, Canada, August

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