692 scores from the EPQ. VAS ratings and autonomic measures were treated as continuous variables and were analyzed with mixed-design ANOVAs, focusing on difference scores (change from pre-pill baseline to time of PPI testing). Specific post-hoc comparisons were made with one-factor ANOVAs or the Fisher’s protected least significant differ- ence test. Alpha was 0.05. In most cases, post-hoc comparisons were limited to tests of specific a priori hypotheses (e.g., that DA agonist effects on PPI would be dependent on baseline PPI) or planned comparisons (e.g., relationship of PPI pramipexole sensitivity to personality measures). Rodent testing The methods used in this study were in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals (NIH Publications no. 80-23) and approved by the UCSD Animal Subjects Committee (protocol S01221). Adult male Sprague–Dawley rats (225–250 g; Harlan Laboratories, San Diego, CA, USA) were housed in groups of two to three animals per cage and maintained on a reversed light/dark schedule with water and food available ad libitum. Rats were handled within 2 days of arrival. Testing occurred during the dark phase. Pramipexole (Toronto Research Chemicals, North York, Ontario, Canada) was dissolved in saline vehicle and administered subcutane- ously in doses of 0 or 0.1 mg/kg (n= 8), 0 or 0.3 mg/kg (n= 8), or 0 or 1.0 mg/kg (n=8), with the same parallel within- subject dose design used in humans (doses from Weber et al. 2008). Startle chambers (San Diego Instruments, San Diego, CA, USA) were housed in a sound-attenuated room and consisted of a Plexiglas cylinder 8.2 cm in diameter resting on a 12.5× 25.5 cm Plexiglas frame within a ventilated enclosure. Noise bursts were presented via a speaker mounted 24 cm above the cylinder. A piezoelectric acceler- ometer mounted below the Plexiglas frame detected and transduced motion from within the cylinder. Stimulus delivery was controlled by the SR-LAB microcomputer and interface assembly, which also digitized (0–4095), rectified, and recorded stabilimeter readings. One hundred 1-ms readings were collected beginning at stimulus onset. Startle amplitude was defined as the average of the 100 readings. Approximately 7 days after shipment arrival, rats were exposed to a short “matching” startle session. They were placed in the startle chambers for a 5-min acclimation period with a 70 dB(A) background noise and then exposed to a total of 17 P-alone trials (40 ms–120 dB(A) noise bursts) that were interspersed with three PP12dB + P-alone trials [P-alone preceded 100 ms (onset-to-onset) by a 20-ms noise burst of 12dB above background]. Rats were assigned to dose order groups based on average %PPI from the matching session to ensure similar baseline PPI levels between groups. Four days later, rats were injected with Psychopharmacology (2009) 205:689–698 pramipexole (vehicle or active dose) and, 15 min later, placed in the startle chambers for a 5-min acclimation period with a 70-dB(A) background noise. They were then exposed to a series of trial types within a test session identical to that used in testing humans (see above, “Human testing”). Three days later, testing was repeated, with pramipexole dose reversed. Statistical analyses of startle magnitude and PPI were structured identically to those used in humans. Results Human testing Demographic variables and personality scale scores for all subjects are seen in Table 1. Effects of pramipexole on autonomic and self-rating measures are seen in Fig. 1 and Table 2. The only robust evidence of bioactivity of these doses of pramipexole came in significant increases in self-rated “drowsiness” (Fig. 1). ANOVA of the change in ratings from pre-pill baselines for all subjects revealed a significant effect of pramipexole (F = 8.16, df 1,38, p < 0.007), no significant effect of dose group (F < 1), and no significant interaction of pramipexole × dose group (F = 1.04). Analysis limited to 0.125 mg pramipexole revealed no significant effect of pramipexole on drowsiness (F = 2.94, df 1,19, ns), while analysis limited to 0.1875 mg pramipexole revealed a significant increase in drowsiness at the time of PPI testing [mean (SEM) increase in VAS after pramipexole = 23.6 (6.02) vs. placebo = 5.05 (5.50); F = 5.27, df 1,19, p < 0.035]. In contrast, no significant effects of pramipexole were detected for either dose in measures of Fig. 1 Self-rated drowsiness VAS scores after placebo (open circles), 0.125 mg or 0.1875 mg pramipexole (closed circles), compared to pre- pill baselines (mean ±SEM). Time of PPI testing is indicated by arrow. Number sign Significantly greater increase in drowsiness at time of PPI testing, pramipexole vs. placebo (p<0.007) by ANOVA; post-hoc individual comparisons detected significant effects only for the 0.1875 mg dose (p<0.035)