Parametric approaches towards understanding the effects of the preferential D3 receptor agonist pramipexole on prepulse inhibition in rats

Abstract

The preferential dopamine D3 receptor agonist pramipexole (PRA) disrupts prepulse inhibition (PPI) of acoustic startle, an operational measure of sensorimotor gating, in rats. Drug effects on PPI are sensitive to numerous experimental variables; proceeding with in-depth analyses of drug effects without a clear understanding of these variables is inefficient. The present studies characterized the impact on PRA-induced PPI deficits by a range of experimental parameters. As shown previously, PRA reduced both PPI and startle magnitude beginning 5-15 min post-injection; PRA effects on PPI were statistically significant through 35 min post-injection, while those on startle magnitude were still significant 65 min post-injection. PRA-induced PPI deficits were evident under conditions that matched startle magnitude in vehicle and PRA conditions and were independent of PRA-induced changes in prepulse-elicited motor activity. Additionally, PRA-induced PPI deficits did not differ significantly between uni- vs. cross-modal stimuli or between male vs. female rats, with no robust effect of estrous phase in females. These findings demonstrate that PRA effects on PPI are observed across several different experimental conditions and are dissociable from changes in startle magnitude or prepulse-elicited responses. Recommendations are made regarding “optimal” experimental conditions for studying the neurobiology of PRA-induced changes in PPI in rats.

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).…”

“…Several studies have assessed the regulation of PPI by specific DA receptor subtypes (Doherty et al, 2008; Peng et al, 1990; Stevenson and Gratton, 2004; Wan and Swerdlow, 1996), and the role of D1, D2 and D3 DA receptors in the regulation of PPI differs substantially across rodent strains and species, as well as across different brain regions. We and others have shown that PPI is disrupted by systemic treatment with D3-preferential agonists such as pramipexole (PPX) and PD128907 (Chang et al, 2010b; Weber et al, 2008, 2009; Zhang et al, 2007). 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).…”

“…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). …”