Probing the molecular basis for an inherited sensitivity to the startle-gating disruptive effects of apomorphine in rats

Abstract

Background Prepulse inhibition of acoustic startle (PPI) is deficient in several heritable brain disorders. In rats, the dopamine agonist, apomorphine (APO), reduces PPI and expression of the early gene, c-fos, within the nucleus accumbens (NAC) core. Both of these effects are greater in Sprague–Dawley (SD) vs. Long Evans (LE) rats, and this PPI strain pattern is inherited. Here, we examined phosphorylation of cyclic-AMP response element-binding protein (CREB), a putative intermediary step between dopamine receptor stimulation and Fos expression, in SD and LE rats. Methods The effects of APO (vehicle vs. 0.5 mg/kg) on PPI were tested in SD and LE rats in a within-subject design. Seven days later, under conditions mimicking PPI testing, half of the rats from each strain received either vehicle or APO (0.5 mg/kg) 20 min before euthanasia. NAC CREB and phospho-CREB levels were quantified from tissue sections reacted immunohistochemically. Results APO reduced PPI in both strains, with a significantly greater effect in SD vs. LE rats. APO also significantly reduced NAC core phospho-CREB levels in both strains, with a significantly greater effect in SD vs. LE rats. Among SD rats receiving APO, the reduction in NAC core CREB phosphorylation correlated significantly with the APO-induced reduction in PPI (R=0.49). Conclusions A dose of APO that disrupts PPI of acoustic startle causes a profound suppression of CREB phosphorylation in the NAC; both dopamine-sensitive behavioral and molecular phenotypes are more robust in SD vs. LE rats, and within SD rats, they are significantly correlated.

The effect of estrogenic compounds on psychosis-like behaviour in female rats

“…In SHAM rats, our data are consistent with previous studies in both the SD and LE strain demonstrating apomorphine-induced disruption of PPI [ 29 , 60 ]. However, in the OVX group only, we observed an apomorphine-induced increase in PPI.…”

Sensorimotor gating of the startle reflex: what we said 25 years ago, what has happened since then, and what comes next

“…Palmer et al, 2000; Qu et al, 2009; Shilling et al, 2008; Swerdlow et al, 2011), and is recapitulated among mice with different genetic backgrounds (e.g. Ralph and Caine, 2005, 2007); (b) the fact that some aspects of the neural regulation of PPI can differ between two strains of mice or rats presents daunting challenges when trying to extrapolate findings from rodents to humans (Dulawa et al, 2000).…”

Fronto-temporal-mesolimbic gene expression and heritable differences in amphetamine-disrupted sensorimotor gating in rats

“…Swerdlow et al 2001a). Changes in NAC D2-linked G-protein signaling appear to mediate the impact of DA agonists on PPI (Swerdlow et al 2006, 2011). Studies are explicating the molecular genetics of PPI as a vehicle to understand the genetics of PPI deficits in human brain disorders, including schizophrenia (Braff et al 1978; Greenwood et al 2011, 2012).…”

“…The stability of this phenotype was intact through >15 years of breeding stock (Swerdlow et al 2001), with Mendelian patterns of inheritance in F1 and N2 generations that could not be explained by strain differences in maternal behavior (Swerdlow et al 2004a, c) or regional drug levels (Swerdlow et al 2002). Strain-related differences in PPI sensitivity to DA agonists were significantly associated with levels of D2-linked GTPγS binding (Swerdlow et al 2006) and reduced CREB-phosphorylation in the NAC core (Swerdlow et al 2011); they were evident from the earliest testable age (day 16) and were neurochemically specific (Swerdlow et al 2003a). We reported highly significant differences in expression of specific NAC genes in SD vs.…”