A primary question raised by the prospect of nicotine regulation is whether reducing nicotine delivery below the reinforcement threshold in established adult smokers would be sufficient to prevent the development of nicotine addiction in nicotine naive individuals. Almost invariably, smoking starts during adolescence. Therefore, research is needed to examine the extent to which adolescents would selleck bio initiate and continue using nicotine at doses below those that maintain behavior in adults. Research on the differential effects of nicotine in adolescents compared with adults is mixed. Several studies suggest that adolescent rats self-administer more nicotine (30 ��g/kg) and acquire stable behavior faster than adults (Chen et al., 2007; Levin, Rezvani, Montoya, Rose, & Swartzwelder, 2003; Levin et al.

, 2011). However, relatively little attention has been given to acquisition of self-administration at low doses. Compared with rats in early adolescence (starting PND 31), adult male rats are more likely to acquire nicotine self-administration at a low dose (15 ��g/kg; Shram et al., 2008). These data are limited, however, both in terms of the age of initiation and the exclusive focus on males. Several studies have reported sex differences in the acquisition of nicotine self-administration during adolescence (Chen et al., 2007; Levin et al., 2011), including a greater likelihood of females acquiring at a low dose (5 ��g/kg; Lynch, 2009).

Likewise, other work has suggested that adolescents may be more sensitive to the potentiating effects of acetaldehyde (a tobacco constituent discussed in the Could other constituents of tobacco impact the threshold for self-administration? section) on nicotine self-administration (Belluzzi, Wang, & Leslie, 2005). Clearly, much work remains to be done determining the potential impact of nicotine reduction on adolescent initiation of nicotine self-administration. Data Analysis Considerations Animal researchers typically analyze nicotine self-administration dose response data via statistical comparisons of group mean response rates for a given nicotine dose to that for saline. Accordingly, the nicotine reinforcement threshold would be the lowest dose that maintains a significantly higher mean rate of responding when compared with saline. However, threshold estimates based on group averages may be of limited use for setting nicotine performance standards.

Regulatory agencies will likely be more interested in knowing the proportion of individuals showing different patterns of behavior (e.g., how many individuals Drug_discovery fail to change or even increase use) at a given nicotine dose (Hatsukami et al., 2010). This is consistent with the FDA��s current practice of setting the acceptable daily intake or tolerable daily intake for other regulated substances (e.g.