Strain differences in the disruption of prepulse inhibition of startle after systemic and intra-accumbens amphetamine administration

Abstract

Background Sprague Dawley (SD) rats are significantly more sensitive than Long Evans (LE) rats to the disruption of prepulse inhibition (PPI) by systemically-administered dopamine (DA) agonists. This strain difference is heritable and insensitive to cross-fostering. Inherited differences in the ability of elevated DA activity to disrupt PPI may be useful for understanding the neural basis for PPI deficits in schizophrenia and other neuropsychiatric disorders. Methods PPI was tested in male SD and LE rats after amphetamine (AMPH) was administered: 1) subcutaneously (sc), or intra-cerebrally (ic) into 2) the nucleus accumbens core (NACc; medial or lateral subregions) or the NAC shell; 3) the anteromedial striatum (AMS) or 4) the posterior striatum (PS). Results SD and LE rats had comparable PPI levels after sc vehicle injection. PPI was disrupted in SD but not LE rats after sc AMPH injection. LE insensitivity to AMPH was confirmed after sc injection into non-pigmented dermis, demonstrating that it did not reflect melanocyte sequestration of AMPH. PPI was also disrupted in SD rats after ic infusion into the NACc (medial core: p < 0.005; lateral core: p < 0.001); in LE rats, these effects only approached threshold levels (medial core: p < 0.06; lateral core: p < 0.051). In SD rats, the highest dose of AMPH (40 μg) tended to reduce PPI after infusion into the AMS or PS, while in LE rats, this dose potentiated PPI after PS infusion. Comparisons of PPI in SD vs. LE rats revealed significant main effects of strain (SD > LE) after vehicle infusions into the NACc subregions and the PS. Comparisons of pre-infusion “matching” data, data from the first infusion day, and data from separate rats in a “mock-infusion” paradigm is consistent with the possibility that SD > LE PPI after ic vehicle infusion reflects the impact of restraint stress on PPI in LE rats. Conclusions PPI is disrupted by AMPH administered sc or into the NACc in SD but not LE rats. Reduced PPI after ic vehicle infusion in LE vs. SD rats may reflect greater PPI-reducing effects of restraint stress in LE rats. The differential impact of restraint on PPI in SD vs. LE rats complicates the interpretation of strain differences in the effects of ic manipulations, but may provide an avenue for investigating the basis for differences in vulnerability to the gating-disruptive effects of stress. Supported by MH68366, MH01436.