Heritable strain differences in sensitivity to the startle gating-disruptive effects of D2 but not D3 receptor stimulation

Abstract

Prepulse inhibition of the startle reflex (PPI) is an operational measure of sensorimotor gating that is deficient in several brain disorders and is disrupted in rats by dopamine agonists. There are robust heritable strain differences between Sprague Dawley (SD) and Long Evans (LE) strains in the sensitivity to the PPI-disruptive effects of dopamine agonists associated with differential gene expression in the nucleus accumbens. Here we compared the contribution of D2 vs. D3 receptors to this heritable difference, using the D3-preferential agonist, pramipexole, the mixed D3/D2 agonist, quinpirole, the mixed D1/D2-like agonist, apomorphine, and the preferential D2 antagonist L741,626. All DA agonists disrupted PPI in SD and LE rats. Greater SD than LE sensitivity for this effect was evident with apomorphine and quinpirole, but not pramipexole. The selective D2 antagonist L741,626 preferentially reversed apomorphine-induced PPI deficits at a dose that did not alter pramipexole-induced PPI deficits. We conclude that the heritable pattern of greater PPI “disruptability” by DA agonists in SD vs. LE rats reflects differences in D2 but not D3 receptor-associated mechanisms.

Adenosine Receptor Antagonists Do Not Disrupt Rodent Prepulse Inhibition: An Improved Side Effect Profile in the Treatment of Parkinson's Disease

“…The A 2A antagonists SCH 412348 (Figure 2(a)) and istradefylline (Figure 2(b)) did not impair rat PPI (SCH 412348: F (3, 28) = 0.57, P > 0.05; istradefylline: F (3, 28) = 1.18, P > 0.05) or startle magnitude (SCH 412348: F (3, 28) = 0.31, P > 0.05; istradefylline: F (3, 28) = 0.20, P > 0.05) at any doses tested. Pramipexole (Figure 2(c)) significantly reduced PPI at all doses tested (0.3, 1, and 3 mg/kg) ( F (3, 60) = 4.47, P < 0.01) but also significantly reduced startle magnitude at all doses tested ( F (3, 60) = 5.24, P < 0.01) compared to vehicle, which is consistent with previous findings [11]. Pergolide (Figure 2(d)) impaired PPI at 0.3 and 3 mg/kg ( F (3, 60) = 5.64, P < 0.01) but did not affect startle ( F (3, 60) = 1.29, P > 0.05).…”

Modulation of prepulse inhibition and stereotypies in rodents: no evidence for antipsychotic-like properties of histamine H3-receptor inverse agonists

“…4d). To assess the impact of the startle-modulating effects of drugs on PPI, a separate analysis was conducted for subsets of animals that were constructed by eliminating the extreme responders, such as the effects of drugs on startle were balanced between the various groups (Weber et al 2008). Mean startle amplitudes were then as follows: saline (n=8)=120±4, MK-801 (n=6)=151±38, MK-801 + haloperidol (n=10)=149±22, MK-801 + BF2-649 (n=7)= 162±34, and MK-801 + haloperidol + BF2-649 (n=8)= 148±19 (Fig.…”

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.…”

“…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).…”