1. ¹Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA
2. ²Department of Psychiatry and Neuroscience, Tufts University School of Medicine, Medford, MA, USA

Correspondence: Dr NR Swerdlow, Department of Psychiatry, UCSD School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0804, USA. Tel: +1 619 543 6270; Fax: +1 619 543 2493; E-mail: nswerdlow@ucsd.edu

Received 22 April 2005; Revised 5 July 2005; Accepted 11 July 2005; Published online 17 August 2005.

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 D₂-like receptor-G-protein coupling using [³⁵S]GTPS 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 LE) rats. Basal and DA-stimulated [³⁵S]GTPS 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 (SD>F1>LE), and in the locomotor responses to AMPH (LE>F1>SD) and APO (SD exhibited motor suppression, LE exhibited motor activation). Compared to SD rats, LE rats exhibited greater DA-stimulated [³⁵S]GTPS 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.