g., 30 ��g/kg). Similar to acquisition, the rate of nicotine self-administration decreases across unit doses more than 30 ��g/kg and changes in infusion rate are not proportional to dose, so that intake increases with dose. The threshold reinforcing unit dose of nicotine at the low end of the dose range is rarely determined (see Table 1), but doses as low as 3 our website ��g/kg have been shown to maintain nicotine self-administration rates above those for saline in both limited and extended access studies (Brower et al., 2002; Corrigall & Coen, 1989; Cox et al., 1984; Shoaib et al., 1997; Watkins et al., 1999). Cross-study comparisons suggest that the ascending limb of the dose�Cresponse curve during maintenance of nicotine self-administration may span a wider range and result in a lower reinforcement threshold than that for acquisition.

Consistent with that observation, some research has shown that preexposure to nicotine can affect acquisition of nicotine self-administration (Adriani et al., 2003; Hanson, Ivester, & Morton, 1979; Shoaib et al., 1997). Within-subject designs that employ an ascending dose�Cresponse procedure for acquisition or reacquisition of nicotine self-administration in addition to assessing the dose�Cresponse curve for dose reduction using the same testing parameters would help clarify this issue. One variable to be particularly mindful of is the influence of response-contingent cues, which may account for sustained responding (see Data analysis considerations section).

Regardless, the lack of data directly addressing whether the threshold for acquisition and maintenance are the same, a fundamental issue facing nicotine reduction strategies, is striking and highlights how a change in perspective illuminates gaps in the literature. The data available to date, however, provide relatively little direct evidence about the threshold for nicotine reinforcement and nicotine reduction strategies for several reasons. First, studies have typically examined a limited range of doses (e.g., 3�C4), often failing to identify a subthreshold dose. Second, it is not clear that the range of doses used have been sufficient to fully characterize the dose�Cresponse curve in every subject. Quantifying and understanding individual variability is essential to deriving estimates of the reinforcement threshold and to anticipate and overcome limitations to a nicotine reduction policy (see the following sections).

Third, procedures that can influence the dose�Cresponse curve vary widely across studies along parameters that may directly impact the threshold for reinforcement. Fourth, studies have not been designed to mimic Brefeldin_A specific policy scenarios. For example, maintenance doses have often been tested in random order within subjects. It is possible that the dose�Cresponse function would differ from that in previous studies if doses were tested in a descending order within subjects (cf. Brower et al., 2002; Chen et al., 2007; Shoaib et al.