Wan F J, Taaid N, Swerdlow N R
Department of Neuroscience, UCSD School of Medicine, La Jolla, CA 92093-0804, USA.
Neuropsychopharmacology. 1996 Apr;14(4):265-74. doi: 10.1016/0893-133X(95)00133-X.
Prepulse inhibition (PPI) of the startle reflex is an operational measure of sensorimotor gating that is reduced in schizophrenia patients and in dopamine (DA)-activated rats. We previously found that PPI is disrupted by systemic administration of the D2 agonist quinpirole, but not by the D1 agonist SKF 38393. In this report we further characterize the D1 and D2 substrates and their potential interactions in the regulation of PPI in rats. PPI is reduced by concomitant administration of the D1 agonist SKF 38393 (5 mg/kg; relative affinity D1:D2 = 50:1) and by a subthreshold dose (0.1 mg/kg) of the D2 agonist quinpirole, but not by either drug given alone at these doses. Pretreatment with the D2 antagonist raclopride (0.05 mg/kg), but not the D1 antagonist SCH 23390 (0.05 mg/kg), blocks the SKF 38393/quinpirole synergistic reduction of PPI. The relative D1 agonist SKF 82958 (5 mg/kg; relative affinity D1:D2 = 10:1) disrupts PPI, and this effect of SKF 82958 is reversed by the D2 antagonist raclopride but not by the D1 antagonist SCH 23390. Consistent with a recent report (Hoffman and Donovan 1994), the PPI-disruptive effects of the D1/D2 agonist apomorphine (0.5 mg/kg) could be blocked by pretreatment with the D1 antagonist SCH 23390. Surprisingly the PPI-disruptive effects of quinpirole are also opposed by pretreatment with SCH 23390. Our present findings confirm that D2 receptors are important for the regulation of PPI in rats, but they also suggest that there exists a synergistic interaction between D1 and D2 substrates in the regulation of PPI. D1 receptors might modulate PPI in a "rate-dependent" manner in which tonic D1 activity is essential for the full manifestation of the D2-mediated modulation of PPI. However, D1 receptors do not appear to participate in the modulatory mechanisms of sensorimotor gating as an independent substrate.
惊吓反射的前脉冲抑制（PPI）是感觉运动门控的一种操作性测量指标，在精神分裂症患者和多巴胺（DA）激活的大鼠中会降低。我们之前发现，全身给予D2激动剂喹吡罗会破坏PPI，但D1激动剂SKF 38393不会。在本报告中，我们进一步描述了大鼠中D1和D2底物及其在调节PPI中的潜在相互作用。同时给予D1激动剂SKF 38393（5毫克/千克；相对亲和力D1:D2 = 50:1）和亚阈值剂量（0.1毫克/千克）的D2激动剂喹吡罗会降低PPI，但单独给予这两种药物在这些剂量下则不会。用D2拮抗剂雷氯必利（0.05毫克/千克）预处理可阻断SKF 38393/喹吡罗对PPI的协同降低作用，但D1拮抗剂SCH 23390（0.05毫克/千克）则不能。相对D1激动剂SKF 82958（5毫克/千克；相对亲和力D1:D2 = 10:1）会破坏PPI，D2拮抗剂雷氯必利可逆转SKF 82958的这种作用，但D1拮抗剂SCH 23390则不能。与最近的一份报告（霍夫曼和多诺万，1994年）一致，D1/D2激动剂阿扑吗啡（0.5毫克/千克）对PPI的破坏作用可被D1拮抗剂SCH 23390预处理阻断。令人惊讶的是，喹吡罗对PPI的破坏作用也会被SCH 23390预处理所对抗。我们目前的研究结果证实，D2受体对大鼠PPI的调节很重要，但也表明在PPI的调节中D1和D2底物之间存在协同相互作用。D1受体可能以“速率依赖性”方式调节PPI，其中持续性D1活性对于D2介导的PPI调节的充分表现至关重要。然而，D1受体似乎并不作为独立底物参与感觉运动门控的调节机制。
