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 microg) 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.

Figure 1

A. Infusion coordinates for all sites (PS = posterior striatum; AMS = anteromedial striatum; NACcl = nucleus accumbens lateral core; NACcm = nucleus accumbens medial core; NACs = nucleus accumbens shell). Coordinates were: PS (toothbar +5.0): AP+0.4, L±4.0, DV-4.7; AMS (toothbar -3.3): AP+1.2, L±1.7, DV-5.5; NACcl (toothbar -3.3): AP+1.2, L±2.3, DV-7.0; NACcm (toothbar -3.3): AP+1.2, L±1.6, DV-7.5; NACs (toothbar -3.3): AP+1.2, L±0.8, DV-7.2. B. Distribution of injector placements for the sites that supported a significant reduction in PPI: the NACcl and NACcm. Bilateral placements for any given rat are collapsed onto one hemisphere for this plot. C. Photomicrograph of examples of injector tip placements in NACcl and NACcm from rats in these studies (ac = anterior commissure).

Figure 2

Photographs showing relevant pigmentation patterns for the present experiments: A. Albino SD rat; B. Hooded LE rat; C. F1 rat with intermediate pigmented area; and D. Ventrum of LE rat, showing unpigmented region used for sc injection in Experiment 1.

Figure 3

Effects of subcutaneous AMPH injection on PPI in SD rats (open bars) and LE rats (solid bars).A. Injections into the nape of the neck, which is pigmented in LE rats. B. Injections into the subcutaneous tissue over the abdomen, which is LE rats is unpigmented (see Figure 2). Data shown are collapsed across all prepulse intensities. * p < 0.05-0.0001, significant reduction in PPI in SD rats compared to vehicle dose, after significant strain × dose interaction by ANOVA.

Figure 4

PPI and startle magnitude after AMPH infusion in the NACcm in SD, LE and F1 rats, and into the NACcl in SD and LE rats. A. PPI is significantly reduced after AMPH infusion into the NACcm in SD rats (significant main effect of AMPH dose, p<0.005; * p<0.001 and p<0.002 for 20 and 40 μg doses, respectively). The main effect of AMPH on PPI also reached significance in F1 rats (p<0.03) but only approached significance in LE rats (p<0.06). In SD rats, PPI was also significantly reduced after AMPH infusion into the NACcl (main effect of AMPH dose, p<0.001; * p < 0.0005, p < 0.008 and p < 0.0005 for 10, 20 and 40 μg doses, respectively). After AMPH infusion into the NACcl n LE rats, the main effect of AMPH dose again marginally reached significance (p<0.051), with post-hoc comparisons revealing significantly reduced PPI after infusion of 20 μg AMPH (* p < 0.006). PPI after vehicle infusion into the NACcm or NACcl was also significantly lower in LE vs. SD rats (# p < 0.015, both sites). B. Startle magnitude is significantly reduced in SD rats after AMPH infusion into the NACcm (main effect of AMPH dose, p<0.03; * p < 0.001 and p < 0.002 for 20 and 40 μg doses, respectively).

Figure 5

Startle magnitude on P-ALONE (0 dB over background) and prepulse+PULSE trials after infusion of either vehicle or the highest AMPH dose (40 μg) in rats in which startle magnitude was not altered after AMPH infusion into the NACcm. Data shows that AMPH selectively elevates startle magnitude on prepulse+PULSE trials in SD rats, reflecting a loss of sensorimotor gating (* p < 0.05 vs. vehicle dose).

Figure 6

A. PPI after AMPH infusion into the NACs, AMS and PS. PPI was significantly lower in LE vs. SD rats after vehicle infusion into the PS (# p < 0.04), with similar trends in the AMS. B. PPI in SD and LE rats after sc injection (from Figure 3) and integrated across all ic infusion sites (* significant reduction in PPI compared to vehicle dose, p < 0.05 - 0.0001; # significantly lower PPI in LE vs. SD rats after vehicle infusion, p < 0.0007).

Figure 7

Analyses designed to clarify the basis for reduced PPI in LE vs. SD rats after ic vehicle infusion. A. Comparable levels of PPI in SD and LE rats one week after surgery, prior to ic infusions. B. Significantly reduced PPI in LE vs. SD rats (#) on the first day of ic testing, in rats from all infusion sites that received vehicle infusions. C. Significantly reduced PPI in unoperated LE vs. SD rats (#) (n = 12/strain) that underwent a “mock-infusion” procedure light restraint in the manner typically used for ic infusions for 60 sec, light pressure to top of head, noises of pumps and timers according to normal ic infusion procedures) prior to startle measures. No strain differences in PPI were detected in a control group (n = 12/strain) taken directly from a sound insulated room and placed into the startle boxes. The startle test session was identical to that used for Experiments 1-3.

Figure 8

AMPH effects on PPI in rats whose vehicle PPI levels were either below (“low gating”) or above (“high gating”) the median levels for that strain. A. Rats from Experiment 2a, that received ic infusions into the NACc (pooled from medial and lateral infusion sites). # significant main effect of strain (LEnot LE) “high gating”).