Pramipexole effects on startle gating in rats and normal men

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 modifies PPI in humans and rats. Unlike indirect DA agonists and mixed D2/D3 agonists, pramipexole increases longinterval PPI in humans, in a manner that is independent of baseline PPI and personality measures. These findings are consistent with preclinical evidence for differences in the D2-and D3-mediated regulation of sensorimotor gating.

Sensorimotor gating in healthy adults tested over a 15 year period

“…One longstanding line of inquiry in our laboratory has been the effects of drugs – particularly dopamine (DA) agonists and NMDA antagonists - on startle and PPI in healthy adults (Swerdlow et al 2002a, 2003, 2006b, 2009a,b, 2016a; Talledo et al 2009). For both clinical and scientific reasons, subjects in these studies are carefully screened to establish the absence of medical and psychiatric illness and substance use, to match experimental groups based on comparable response characteristics (Swerdlow et al 2001b), and to determine the presence of an adequately robust startle reflex to enable reliable measures of PPI.…”

Stereochemical and neuroanatomical selectivity of pramipexole effects on sensorimotor gating in rats

“…2B). As in previous studies (Chang et al, 2010b; Swerdlow et al, 2009; Weber et al 2008, 2009), to understand the relationship between the startle- and PPI-reducing effects of (S)-PPX, difference scores were calculated between startle magnitude after vehicle and after active drug doses, and an ANOVA was conducted with a median split of these difference scores in each stereoisomer group. The PPI-disruptive effects of PPX did not differ among groups that exhibited high vs. low PPX-induced startle reduction (F<1), nor was there a median split × stereoisomer interaction (F<1).…”

“…Our previous reports of the ability of PPX to disrupt PPI in rats (Weber et al, 2008, 2009; Chang et al, 2010b, 2011; Swerdlow et al, 2009) were based on the assumption that these effects were mediated by interactions between PPX and DA receptors in the forebrain. However, PPX is bioactive in other ways; it has been shown to be neuroprotective in neurodegenerative models using MPTP, apparently through DA-dependent and DA-independent mechanisms (cf.…”

“…Drug doses for systemic PPX stereoisomer salts (0, 0.47, 1.42, 4.73 µmol/kg) are molar equivalents of milligram/kilogram doses used in previous systemic studies with (S)-PPX base (Chang et al, 2010b; Swerdlow et al, 2009; Weber et al, 2008, 2009), namely 0.1, 0.3, 1.0 mg/kg, respectively. Preliminary studies tested the behavioral effects of (S)-PPX base doses compared to molar equivalents of the (S)-PPX salt and found nearly identical effect sizes on PPI and startle magnitude (data not shown).…”

“…PPX is among the most D3-selective agonists that are commercially available, with selectivity for D3 over D2 receptors reported to be between 7:1 and 160:1 (Millan et al, 2002; Piercey et al, 1996; Svensson et al, 1994). We previously reported the sensitivity of PPX-induced PPI deficits to several experimental parameters, including sex, species, stimulus modality, inter-stimulus interval, and startle-eliciting pulse magnitude, and demonstrated that PPX effects on PPI are dissociable from changes in startle magnitude or prepulse-elicited motor responses (Chang et al, 2010b; Swerdlow et al, 2009). …”