Doherty James M, Masten Virginia L, Powell Susan B, Ralph Rebecca J, Klamer Daniel, Low Malcolm J, Geyer Mark A
Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093-0804, USA.
Neuropsychopharmacology. 2008 Oct;33(11):2648-56. doi: 10.1038/sj.npp.1301657. Epub 2007 Dec 12.
Deficits in prepulse inhibition (PPI) of startle, an operational measure of sensorimotor gating, are characteristics of schizophrenia and related neuropsychiatric disorders. Previous studies in mice demonstrate a contribution of dopamine (DA) D(1)-family receptors in modulating PPI and DA D(2) receptors (D2R) in mediating the PPI-disruptive effects of amphetamine. To examine further the contributions of DA receptor subtypes in PPI, we used a combined pharmacological and genetic approach. In congenic C57BL/6 J wild-type mice, we tested whether the D1R antagonist SCH23390 or the D2/3R antagonist raclopride would attenuate the effects of the indirect DA agonist cocaine (40 mg/kg). Both the D1R and D2/3R antagonists attenuated the cocaine-induced PPI deficit. We also tested the effect of cocaine on PPI in wild-type and DA D1R, D2R, or D3R knockout mice. The cocaine-induced PPI deficit was influenced differently by the three DA receptor subtypes, being absent in D1R knockout mice, partially attenuated in D2R knockout mice, and exaggerated in D3R knockout mice. Thus, the D1R is necessary for the PPI-disruptive effects of cocaine, while the D2R partially contributes to these effects. Conversely, the D3R appears to inhibit the PPI-disruptive effects of cocaine. Uncovering neural mechanisms involved in PPI will further our understanding of substrates of sensorimotor gating and could lead to better therapeutics to treat complex cognitive disorders such as schizophrenia.
惊吓前脉冲抑制（PPI）功能缺陷是精神分裂症及相关神经精神疾病的特征，而PPI是感觉运动门控的一项操作性指标。先前对小鼠的研究表明，多巴胺（DA）D（1）家族受体在调节PPI中发挥作用，DA D（2）受体（D2R）在介导苯丙胺对PPI的破坏作用中起作用。为了进一步研究DA受体亚型在PPI中的作用，我们采用了药理学和遗传学相结合的方法。在同基因C57BL/6 J野生型小鼠中，我们测试了D1R拮抗剂SCH23390或D2/3R拮抗剂雷氯必利是否会减弱间接DA激动剂可卡因（40毫克/千克）的作用。D1R和D2/3R拮抗剂均减弱了可卡因诱导的PPI缺陷。我们还测试了可卡因对野生型小鼠以及DA D1R、D2R或D3R基因敲除小鼠PPI的影响。可卡因诱导的PPI缺陷受到三种DA受体亚型的不同影响，在D1R基因敲除小鼠中不存在，在D2R基因敲除小鼠中部分减弱，在D3R基因敲除小鼠中则加剧。因此，D1R对可卡因破坏PPI的作用是必需的，而D2R部分促成这些作用。相反，D3R似乎抑制可卡因破坏PPI的作用。揭示与PPI相关的神经机制将加深我们对感觉运动门控底物的理解，并可能带来更好的疗法来治疗诸如精神分裂症等复杂的认知障碍。
