Nonetheless, they provide valuable information regarding the range of doses that likely encompass the reinforcement threshold in rats and highlight several variables to be discussed selleck chemicals Tofacitinib in the following sections, which may be important determinants of self-administration at low doses of nicotine. Table 1. A Representative Summary of Studies Evaluating the Impact of Dose on Acquisition and Maintenance of Nicotine Self-Administration Acquisition dose�Cresponse curves have been generated by assigning different groups of animals to different nicotine doses. On average, the dose�Cresponse curve for acquisition of intravenous nicotine self-administration under small fixed ratio (FR) schedules (fixed number of responses required per infusion) has a biphasic inverted-U shape.

The peak of the curve is around 20�C30 ��g/kg, with acquisition commonly observed at this dose in several species, including rats, dogs, monkeys, and humans (Harvey et al., 2004; Matta et al., 2007). At lower unit doses (3.75�C10 ��g/kg) on the ascending limb of the dose�Cresponse curve, mean response rates increase with dose. In this range, there is considerable individual variability in response rates and a lower proportion of rats acquire nicotine self-administration (i.e., responding greater than saline control and/or inactive operandum; Cox, Goldstein, & Nelson, 1984; Shram, Li, & Le, 2008). As such, the ascending limb of the group curve may be an averaging artifact, resulting from increasing proportions of animals acquiring, and not reflect intermediate responding by the majority of individuals.

In most studies, the average rate of self-administration for doses at or less than 10 ��g/kg is not significantly different from saline (Chen, Matta, & Sharp, 2007; Cox et al., 1984; Donny et al., 1998); however, some studies utilizing different strains and longer duration of access report self-administration at doses as low as 3.75 ��g/kg (Valentine, Hokanson, Matta, & Sharp, 1997). Although acquisition rates (i.e., latency to stable responding) tend not to improve significantly as the unit dose increases above 30 ��g/kg with the majority of animals acquiring the behavior (Donny et al., 1998; 2000; Shoaib, Schindler, & Goldberg, 1997), infusion rates decrease with dose in this range, resulting in the descending limb of the curve.

Because the decrease in infusion rate is not proportional to the increase in dose, an increase in nicotine intake is observed as dose increases (Donny et al., 1999). Similar to acquisition, the peak of the dose�Cresponse curve obtained during maintenance of nicotine self-administration is typically between 10 and 30 ��g/kg (Brower, Fu, Matta, & Sharp, 2002; Corrigall & Coen, 1989; Denoble & Mele, 2006; Drug_discovery Donny, Caggiula, Knopf, & Brown, 1995; Shoaib et al., 1997; Watkins, Epping-Jordan, Koob, & Markou, 1999).