Heritable Differences in the Dopaminergic Regulation of Behavior in Rats: Relationship to D2-Like Receptor G-Protein Function

Abstract

We reported heritable differences between Sprague-Dawley (SD) and Long Evans (LE) rats in their sensitivity to the disruption of prepulse inhibition of startle (PPI) by dopamine (DA) agonists, and in their basal levels and turnover of forebrain DA. In an effort to better understand these differences, we assessed strain patterns in the efficacy of D 2 -like receptor-G-protein coupling using [35 S]GTPgS binding in brain regions that contribute to the dopaminergic regulation of PPI. Sensitivity to the PPI-disruptive effects of apomorphine (APO) was examined in SD, LE, and F1 (SD Â LE) rats. Basal and DA-stimulated [35 S]GTPgS binding were then assessed in these rats using conditions that preferentially exclude Gs proteins to favor visualization of D2-like receptors. To explore the behavioral specificity of these strain differences, locomotor responses to APO and amphetamine (AMPH) were also assessed in SD, LE, and F1 rats. Strain differences were evident in the PPI-disruptive effects of APO (SD4F14LE), and in the locomotor responses to AMPH (LE4F14SD) and APO (SD exhibited motor suppression, LE exhibited motor activation). Compared to SD rats, LE rats exhibited greater DAstimulated [35 S]GTPgS binding in nucleus accumbens and caudatoputamen, while F1 progeny had intermediate levels.In conclusion, SD and LE rats exhibit heritable differences in D2-mediated behavioral and biochemical measures. Conceivably, genes that regulate heritable differences in forebrain D2 function may contribute to heritable differences in PPI in patients with specific neuropsychiatric disorders, including schizophrenia and Tourette Syndrome.

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

“…For example, after localized intra-NACc AMPH infusion, SDxLE F1 rats exhibit a PPI phenotype comparable to SD rats ( Figure 4A), while systemic AMPH injection yields an F1 phenotype that is intermediate between parental strains (Swerdlow et al 2003a). We can speculate that dopaminergic changes within multiple subregions contribute to strain differences in reduced PPI after systemic drug administration, even though in isolation (after localized infusion), the contribution of any single region does not achieve statistical significance; this speculation would be consistent with our findings that differences in DA-stimulated GTPγS binding between SD and LE rats are observed not only within the NAC, but also within the AMS and cortical regions (Swerdlow et al 2006a), consistent with anatomically distributed genetically-based differences in dopaminergic function. In fact, one could argue that the strain differences observed after systemic AMPH administration are best reproduced by an (admittedly artificial) integration of AMPH effects across all of the infusion sites in the present study ( Figure 6B), although even this artificial reconstruction omits brain regions (eg.…”

“…Animal studies have begun to focus on the genetics of brain substrates that regulate PPI (Arguello and Gogos 2006;Petryshen et al 2005;Shilling et al 2006;Swerdlow et al 2006a). For example, there are heritable differences in the dopaminergic regulation of PPI in both mice (Ralph & Caine 2005) and rats (Swerdlow etal.…”

“…amphetamine: AMPH), compared to hooded Long Evans rats from Harlan Laboratories (LE) (Swerdlow et al 2003a(Swerdlow et al ,2004a. These differences are innate (Swerdlow et al 2004a,c) and neurochemically specific (Swerdlow et al 2003(Swerdlow et al ,2004b, follow relatively simple inheritance patterns (Swerdlow et al 2003a(Swerdlow et al ,2004c, cannot be explained by differences in maternal behavior (Swerdlow et al 2004a), and appear to be linked to the inheritance of coat pigmentation (Swerdlow et al 2004c and DA-linked G-protein function (Swerdlow et al 2006a).…”

Effect of social isolation on CB1 and D2 receptor and fatty acid amide hydrolase expression in rats

“…This may be due in part to the use of different strains of rat in social isolation experiments including Lister hooded (Jones et al 1992), Fawn hooded (Djouma et al 2006), Wistar (Guisado et al 1980) and Sprague-Dawley (Del Arco et al 2004). Similarly, differences in the affinity state of the D 2 receptor have been shown using [ 35 S]GTPγS binding in different strains of rats, thus making a comparison between radioligand binding and immunohistochemistry studies problematic (Swerdlow et al, 2006). In the same strain of rats (Sprague Dawley) used in the present study, it has been reported that social isolation did not alter [ 3 H]-raclopride binding to D 2 receptors in the dorsal or ventral striatum (Del Arco et al, 2004).…”

A novel rat strain with enhanced sensitivity to the effects of dopamine agonists on startle gating

“…In outbred SD, LE and F1 (SD × LE) strains, the inherited phenotype of PPI sensitivity to DA agonists is mediated by DA-linked signal transduction pathways within the ventral forebrain (Swerdlow et al 2006a;Saint Marie et al 2007). Clearly, pedigrees from different strains demonstrate different patterns of inheritance of PPI phenotypes, and the present findings demonstrate that patterns of generational transmission of the PPI APO sensitivity phenotype cannot be generalized across all rat strains.…”