Psychopharmacology (2009) 205:689–698 DOI 10.1007/s00213-009-1577-5 ORIGINAL INVESTIGATION Pramipexole effects on startle gating in rats and normal men Neal R. Swerdlow & Sophia A. Lelham & Ashley N. Sutherland Owens & Wei-Li Chang & Sebastiaan D. T. Sassen & Jo A. Talledo Received: 23 March 2009 / Accepted: 20 May 2009 / Published online: 9 June 2009 # The Author(s) 2009. This article is published with open access at Springerlink.com Abstract Background Dopamine D3 receptors regulate sensorimotor gating in rats, as evidenced by changes in prepulse inhibition (PPI) of startle after acute administration of D3 agonists and antagonists. In this study, we tested the effects of the D3-preferential agonist, pramipexole, on PPI in normal men and Sprague–Dawley rats. Materials and Methods Acoustic startle and PPI were tested in clinically normal men, comparing the effects of placebo vs. 0.125 mg (n = 20) or placebo vs. 0.1875 mg (n= 20) pramipexole, in double blind, crossover designs. These measures were also tested in male Sprague–Dawley rats using a parallel design [vehicle vs. 0.1 mg/kg (n= 8), vehicle vs. 0.3 mg/kg (n= 8) or vehicle vs. 1.0 mg/kg pramipexole (n = 8)]. Autonomic and subjective measures of pramipexole effects and several personality instruments were also measured in humans. Results Pramipexole increased drowsiness and significantly increased PPI at 120-ms intervals in humans; the latter effect was not moderated by baseline PPI or personality scale scores. In rats, pramipexole causes a dose-dependent reduction in long-interval (120 ms) PPI, while low doses actually increased short-interval (10–20 ms) PPI. Effects of pramipexole on PPI in rats were independent of baseline PPI and changes in startle magnitude. Conclusion The preferential D3 agonist pramipexole modi- fies PPI in humans and rats. Unlike indirect DA agonists and mixed D2/D3 agonists, pramipexole increases long- interval PPI in humans, in a manner that is independent of N. R. Swerdlow (*) : S. A. Lelham : A. N. Sutherland Owens : W.-L. Chang : S. D. T. Sassen : J. A. Talledo Department of Psychiatry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA e-mail: nswerdlow@ucsd.edu baseline PPI and personality measures. These findings are consistent with preclinical evidence for differences in the D2- and D3-mediated regulation of sensorimotor gating. Keywords Dopamine . Prepulse inhibition . Pramipexole . Sensorimotor gating . Startle Introduction Prepulse inhibition (PPI) is an operational measure of sensorimotor gating, in which a startle response to an intense stimulus is automatically suppressed by a weak lead stimulus (Graham 1975). In humans, PPI is typically assessed using electromyographic measures of the blink response, while in rodents, PPI is typically assessed by measuring whole-body startle. PPI deficits are found in several neuropsychiatric disorders (Braff et al. 1978; cf. Braff et al. 2001; cf. Swerdlow et al. 2008), and the biology of these deficits has been the focus of intense study in humans and animal models. In rats, dopamine (DA) agonists generally reduce PPI, although these effects are highly strain-sensitive (Swerdlow et al. 2004b). For example, the mixed D1/D2 agonist apomor- phine (APO) disrupts PPI in albino Sprague–Dawley rats but not in pigmented ACI rats, while in hooded Long Evans rats, APO increases PPI at short prepulse intervals and reduces it at long prepulse intervals (Swerdlow et al. 2004a, b). In humans, the effects of DA agonists on PPI differ across groups distinguished by baseline PPI levels and/or person- ality dimensions. For example, Bitsios et al. (2005) reported PPI-disruptive effects of the DA agonists pergolide and amantadine only among men characterized by high baseline PPI levels, Giakoumaki et al. (2007) reported a reduction in PPI after administration of the mixed D2/D3 agonist