690 ropinirole to healthy men whose baseline PPI was >30%, and we reported similar baseline-dependent effects of amphetamine on PPI in healthy men (Swerdlow et al. 2003b) and women (Talledo et al. 2009). Furthermore, amphetamine has been reported to disrupt PPI only among normal subjects with high scores on measures of novelty- or sensation-seeking (Hutchison et al. 1999; Talledo et al. 2009). In some subgroups of normal humans (e.g., those characterized by low baseline PPI or novelty seeking), DA agonists can actually increase PPI (Talledo et al. 2009). Some evidence suggests that differences in PPI sensitivity to DA agonists in rats and humans may be mediated in part by differences in brain regional activity of catechol-O-methyl transferase (Shilling et al. 2008; Roussos et al. 2008b; Talledo et al. 2009). The present study tested the effects of pramipexole, a non-ergot preferential D3 agonist, on PPI. While the vast majority of studies of the DAergic regulation of PPI in rats and humans focus on the role of D1 and D2 receptors, more recent evidence suggests that PPI in both species may also be regulated by D3 receptors. For example, Roussos et al. (2008a) reported that PPI differed significantly across humans characterized by Gly/Gly vs. Ser/Ser variants of the D3 receptor Ser9Gly polymorphism. Pramipexole has preferential affinity for D3 vs. D2 receptors, with an in vitro D3/D2 preference of 7.8:1 (Piercey et al. 1996, Svensson et al. 1994; cf. Kvernmo et al. 2006) relative to the high affinity state of the D2 receptor. Millan et al. (2002) determined the D3/D2 preference of pramipexole to be 90:1 relative to the short isoform of the human receptor (D2S) and 160:1 relative to the long isoform (D2L). In compar- ison, ropinirole is relatively less preferential for D3 receptors [e.g., in vitro D3/D2 preference = 1.3:1 (cf. Kvernmo et al. 2006), with preference of 18:1 relative to D2S and 25:1 relative to D2L (Millan et al. 2002)]. Table 1 Subject characteristics Subject characteristics Age (mean (range), years) Weight (mean (range), kg) Dose PRAM (mean (range), mg/kg x 103) Daily caffeine intake (mean (range), mg) Personality scale scores (mean (range)) TPQ Novelty seeking Harm avoidance Reward dependence SSS Total score EPQ Total score Psychopharmacology (2009) 205:689–698 Our group reported that pramipexole disrupts PPI in laboratory rats and that this effect is relatively insensitive to selective D2 blockade but is opposed by functional D3 antagonists (Weber et al. 2008, 2009). In addition, strain differences in the PPI-disruptive effects of indirect DA agonists (amphetamine, Swerdlow et al. 2003a), mixed D1/ D2 agonists (APO, Swerdlow et al. 2001), and D2- preferential agonists (quinpirole, Swerdlow et al. 2001) are not detected with pramipexole (Weber et al. 2008), suggesting that its PPI-disruptive effects are mediated differently from those of non-D3 DA agonists. In this study, we examined the effects of pramipexole on PPI in normal men, also assessing the potential moderating impact of baseline PPI and personality scale scores. Materials and methods Human testing The methods used in these studies were very similar to those used in studies described in recent reports (Swerdlow et al. 2003b), were approved by the UCSD Human Subjects Institutional Review Board, and were approved and supported by the National Institute of Mental Health. Forty right-handed men (Table 1) completed testing; the study involved a phone contact and three laboratory visits. Phone screening procedures were identical to those described in previous reports from our group (Swerdlow et al. 2003b). After passing a telephone interview, subjects came to the laboratory for a screening examination, during which the senior investigator (NRS) informed subjects of the potential risks and benefits of the study. Subjects read and signed a consent form for study participation, underwent a physical examination and electrocardiogram to rule out exclusionary 0.125 mg dose 21.9 (18–30) 76.8 (59.4–122.5) 1.67 (1.02–2.10) 138.5 (0.0-615.2) 17 (8–23) 8 (0–19) 19 (9–27) 21 (10–28) 21 (9–29) 0.1875 mg dose 22.5 (18.0–33.0) 72.3 (56.7–89.8) 2.63 (2.08–3.30) 62.3 (0.0–280.0) 15 (4–25) 8 (0–18) 19 (10–26) 20 (8–31) 20 (7–32)