Swerdlow Neal R, Krupin Alison S, Bongiovanni Michele J, Shoemaker Jody M, Goins Jana C, Hammer Ronald P
Department of Psychiatry, University of California School of Medicine, San Diego, La Jolla, CA 92093, USA.
Neuropsychopharmacology. 2006 Apr;31(4):721-9. doi: 10.1038/sj.npp.1300877.
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]GTPgammaS 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 x LE) rats. Basal and DA-stimulated [35S]GTPgammaS 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]GTPgammaS 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.
我们报告了斯普拉格-道利（SD）大鼠和朗·埃文斯（LE）大鼠在对多巴胺（DA）激动剂破坏惊吓前脉冲抑制（PPI）的敏感性、前脑DA的基础水平及更新率方面存在可遗传差异。为了更好地理解这些差异，我们利用[35S]GTPγS结合法评估了在对PPI进行多巴胺能调节的脑区中D2样受体-G蛋白偶联功效的品系模式。在SD、LE和F1（SD×LE）大鼠中检测了对阿扑吗啡（APO）破坏PPI作用的敏感性。然后在这些大鼠中使用优先排除Gs蛋白以利于观察D2样受体的条件，评估基础和DA刺激的[35S]GTPγS结合。为了探究这些品系差异的行为特异性，还在SD、LE和F1大鼠中评估了对APO和苯丙胺（AMPH）的运动反应。APO破坏PPI的作用（SD>F1>LE）以及对AMPH（LE>F1>SD）和APO（SD表现出运动抑制，LE表现出运动激活）的运动反应存在明显的品系差异。与SD大鼠相比，LE大鼠伏隔核和尾壳核中DA刺激的[35S]GTPγS结合更强，而F1后代的水平处于中间。总之，SD和LE大鼠在D2介导的行为和生化指标上表现出可遗传差异。可以想象，调节前脑D2功能可遗传差异的基因可能导致包括精神分裂症和妥瑞氏综合征在内的特定神经精神疾病患者PPI的可遗传差异。
