Psychopharmacology (2009) 205:689–698 the PPI-enhancing effects of 0.1875 mg appeared to be more robust than those of 0.125 mg (d = 0.48 vs. 0.20). We examined whether the PPI-enhancing effects of 0.1875 mg pramipexole were independent of the modest startle- reducing effects of this dose on pulse-alone trials, using the same subgroup of 17 subjects (described above) for whom this dose of pramipexole did not reduce pulse-alone startle magnitude. The PPI-enhancing effects of 0.1875 mg pramipexole were highly significant in this subgroup (F = 10.53, df 1,16, p = 0.005; d = 0.79; Fig. 3b). Thus, pramipexole increased PPI at 120-mg prepulse intervals, particularly at the 0.1875 mg dose, and this effect was independent of changes in pulse-alone startle magnitude. Spearman rank correlations assessed relationships be- tween the PPI-enhancing effects of 0.1875 mg pramipexole at 120-ms prepulse intervals [calculated as a difference score: PPI (pramipexole) minus PPI (placebo)] and scores for novelty-seeking (TPQ total NS scale), sensation-seeking (SSS total score and DIS subscale score), and extraversion (EPQ-E subscale score). No correlations approached statis- tical significance (−0.27 < Rs < 0.05). Simple regression analyses revealed no correlation between these PPI- enhancing effects of pramipexole at 120-ms prepulse intervals and baseline startle magnitude (r =0.02) or the impact of pramipexole on drowsiness (r= 0.03). Pramipexole had no significant effects on startle latency, latency facilitation (reduction in latency caused by pre- pulses), or habituation (Table 3). Rodent testing The highest dose of pramipexole (1.0 mg/kg) reduced startle magnitude on pulse-alone trials (Fig. 4a). ANOVA of startle magnitude across all dose groups revealed no significant effect of group (F<1), a significant effect of pramipexole dose (vehicle vs. active dose; F= 10.91, df 1,21, p < 0.004), and no interaction of group ×dose (F= 1.45, df, 2,21, ns). Post-hoc comparison revealed significant startle-reducing effects limited to the 1.0 mg/kg group (p< 0.035). Pramipexole had dose- and interval-dependent effects on PPI in rats (Fig. 4b). ANOVA across all groups revealed near significant effects of group (F= 3.32, df 2,21, p< 0.056) and dose (F= 3.28, df 1,21, p <0.085), a near-significant interaction of group × dose (F = 3.24, df 2,21, p < 0.06), significant effects of prepulse interval (F= 25.70, df 4,84, p <0.0001), and a significant interaction of dose× interval (F= 3.60, df 4,84, p <0.01), but no significant three-way interaction. In three rats from the high-dose group, mean startle values on prepulse+ pulse trials for some prepulse intervals greatly exceeded startle values on pulse alone trials, yielding large negative values for %PPI (i.e., prepulse 695 potentiation) and thus accounting for the large error bars demonstrated in Fig. 4b; capping these values (e.g., at −100%) did not alter the statistical outcome. Inspection of the data revealed dose-dependent PPI-reducing effects of pramipexole at the 120-ms prepulse interval and PPI- increasing effects of lower doses of pramipexole at short (10–20 ms) prepulse intervals. Post-hoc comparisons for the 120-ms prepulse interval revealed significant effects of group (F= 4.15, df 2,21, p< 0.035) and dose (F= 15.04, df 1,21, p< 0.001) and a significant group × dose interaction (F = 3.45, df 2,21, p = 0.05). Pramipexole significantly reduced 120 ms PPI at the 0.3 and 1.0 mg/kg doses (p< 0.008 and 0.03, respectively) but not at the 0.1 mg/kg dose. Post-hoc comparisons for the 10–20-ms intervals revealed significant PPI-increasing effects of the 0.1 and 0.3 mg/kg doses (main effect of dose, F=6.81, df 1,14, p =0.02; no effect of group, F<1; no dose ×group interaction, F< 1). While significant PPI-reducing and PPI-increasing effects of pramipexole were detected at doses that did not significantly reduce startle magnitude on pulse alone trials, we nonetheless examined whether drug effects on startle magnitude and PPI could be more completely dissociated. This was done in two ways. First, difference scores (vehicle minus active dose) were calculated for pramipexole effects on pulse-alone startle magnitude for each rat, and median splits were used to divide each dose group into rats with the least vs. most startle-reducing effects of pramipexole. Using this median split as a grouping factor, ANOVAs confirmed both the PPI-reducing effects of 0.3 and 1.0 mg/kg doses at 120-ms prepulse intervals and PPI-enhancing effects of 0.1 and 0.3 mg/kg doses at 10–20-ms intervals, with no significant interactions of dose ×median splits (all F’s< 1.75, 1, 1, and 1, respectively). Next, simple regression analyses revealed no significant correlations between startle magnitude difference scores (i.e., the effect of pramipexole on startle magnitude) and PPI difference scores (i.e., the effect of pramipexole on PPI) at either the short (10–20 ms) or long (120 ms) prepulse intervals (r’s < 0.30, ns). Lastly, we examined the potential relationship between baseline PPI (during the dose-matching session) and pramipexole effects on PPI. Baseline PPI did not correlate significantly with the effect of pramipexole on PPI at either the short (10–20 ms) or long (120 ms) prepulse intervals (r’s< 0.18, ns). Discussion In the present study, pramipexole, a D3-preferential agonist, increased long interval PPI in clinically normal men, and had biphasic dose effects on PPI in rats—increasing short interval PPI at low doses and decreasing long interval PPI at higher doses. Unlike the PPI-enhancing or reducing