Initiation of alcohol and tobacco use often occurs during the early teens, whereas first use of illicit substances arise later (Kandel and Logan 1984; Chen and Kandel 1995). Early use of tobacco or alcohol is associated with increased likelihood of progressing to harder drugs. Individuals who smoke cigarettes before the age of 15 are estimated to be 80 times more likely to use illegal drugs, such as cocaine, than those who do not (Lai et al. 2000). Such findings have led to the hypothesis that early teenage tobacco use may be a “gateway” to later illegal drug use (Kandel et al. 1992).

Adolescence is the final developmental period leading to adulthood, defined as 12 to 20 years in humans and postnatal days 28 to 42 in rodents (Spear 2000). Characteristic behaviors of this period such as risk-taking, novelty-seeking, and increased social interactions are conserved across species (Spear 2000). During this period, there is marked neural maturation of the mesocorticolimbic dopamine system and its targets, which are ultimately responsible for the integration of the external environment with internal drives to produce motivated behavior (Benes et al. 2000; Chambers et al. 2003). Fiber density of amygdalocortical (Cunningham et al. 2002) and corticoaccumbens connections (Brenhouse et al. 2008) continue to increase into early adulthood. Dopaminergic innervations of the prefrontal cortex increases in density (Benes et al. 2000), and its control of prefrontal interneurons and pyramidal firing states matures during adolescence (Tseng and O'Donnell 2005). Nicotinic acetylcholine receptors are expressed on the dopamine cell bodies in the ventral tegmental area and terminals of this actively maturing circuitry (Azam et al. 2007; Wonnacott et al. 2005), and thus, nicotine exposure in adolescence may have distinct behavioral effects.

Both clinical and animal studies have shown that adolescents exhibit unique responses to addictive drugs. In animals, nicotine is more rewarding and less aversive during adolescence than at later ages (Adriani et al. 2002; Belluzzi et al. 2004; O'Dell et al. 2006). Human studies show that teenage tobacco use is more likely to produce life-long addiction and greater difficulty quitting (Breslau and Peterson 1996; Chen and Millar 1998). Animal models have clearly demonstrated that nicotine administration during adolescence causes distinct long-term neural adaptations compared to treatment in adults (Adriani et al. 2003, 2004; Abreu-Villaca et al. 2003). Together, these findings suggest that adolescents are particularly vulnerable to the addictive effects of nicotine.

Most animal studies evaluating nicotine’s effects during adolescence use moderate to high doses and treatment for an extended duration. However, smokers aged 12 to 17 consume an average of 5.2 cigarettes per day (SAMHSA 2003) and progress to nicotine dependence even before daily smoking habits form (Chen and Millar 1998; Colby et al. 2000). These findings suggest that adolescents are vulnerable to persisting behavioral and neurochemical changes from even a brief, low-dose exposure to nicotine. Recent animal studies have provided significant evidence in support of this conclusion. A single pairing with nicotine can elicit a conditioned place preference in early adolescent, but not adult rats (Belluzzi et al. 2004; Brielmaier et al. 2007). We have also recently shown that brief treatment with nicotine, using an intravenous dosing procedure that simulates the effect of smoking 3–4 cigarettes per day, enhances subsequent acquisition of cocaine self-administration in adolescence, but not adulthood, thus supporting the “gateway” hypothesis (McQuown et al. 2007). Such low doses of nicotine stimulate nicotinic acetylcholine receptors which are found within reward circuitry, possibly altering development of the late-maturing mesolimbic dopamine system (Leslie et al. 2004; Wonnacott et al. 2005).

It is widely accepted that cocaine dependence results from drug-induced neural adaptations in mesocorticolimbic dopamine pathways and associated glutamatergic circuitry (Thomas et al. 2008). Locomotor sensitization, a form of behavioral plasticity induced by repeated exposure to many classes of abused drugs, has been shown in rodents to be associated with augmented drug reward and increased vulnerability to relapse (Robinson and Berridge 1993; De Vries et al. 1998). Given prior evidence that the mechanisms underlying this form of neural plasticity have not fully matured by adolescence (Laviola et al. 1995; Collins and Izenwasser 2002; Frantz et al. 2007), the aim of the present study was to determine whether adolescents might be uniquely sensitive to the effect of brief, low-dose nicotine exposure on subsequent locomotor response to acute and repeated cocaine.