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激活 D1 受体而非 D2 受体可增强地佐环平介导的惊吓前脉冲抑制的破坏作用。

Activation of D1, but not D2 receptors potentiates dizocilpine-mediated disruption of prepulse inhibition of the startle.

作者信息

Bortolato Marco, Aru Gian Nicola, Fà Mauro, Frau Roberto, Orrù Marco, Salis Paola, Casti Alberto, Luckey Grant Christopher, Mereu Giampaolo, Gessa Gian Luigi

机构信息

Guy Everett Laboratory, Department of Neuroscience, Center of Excellence, Neurobiology of Dependence, Monserrato (CA), Italy.

出版信息

Neuropsychopharmacology. 2005 Mar;30(3):561-74. doi: 10.1038/sj.npp.1300547.

Abstract

Although substantial evidence has shown interactions between glutamatergic and dopaminergic systems play a cardinal role in the regulation of attentional processes, their involvement in informational filtering has been poorly investigated. Chiefly, little research has focused on functional correlations between the dopaminergic system and the mechanism of action of N-methyl-D-aspartate (NMDA) receptor antagonists on sensorimotor gating. The present study was targeted at evaluating whether the activation of D1 and D2 receptors is able to interact with the disruption of prepulse inhibition (PPI) of startle mediated by dizocilpine, a selective, noncompetitive NMDA receptor antagonist. We tested the effects of SKF 38393 ((+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol) (10 mg/kg, s.c.), a selective D1 agonist, and quinpirole (0.3, 0.6 mg/kg, s.c.), a D2 agonist, in rats, per se and in cotreatment with different doses of dizocilpine, ranging from 0.0015 to 0.15 mg/kg (s.c.). Subsequently, the effect of the D1 antagonist SCH 23390 ((R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) (0.05, 0.1 mg/kg, s.c.) on PPI disruptions mediated by dizocilpine and by combination of dizocilpine and SKF 38393 was tested. Two further experiments were performed to verify whether the synergic effect of the D1 agonist with dizocilpine was counteracted by effective doses of haloperidol (0.1, 0.5 mg/kg, i.p.) and clozapine (5, 10 mg/kg, i.p.). All experiments were carried out using standard procedures for the assessment of PPI of the acoustic startle reflex. SKF 38393, while unable to impair sensorimotor gating alone, induced PPI disruption in cotreatment with 0.05 and 0.15 mg/kg of dizocilpine, both ineffective per se. Furthermore, this effect was reversed by SCH 23390, but not by haloperidol or clozapine. Conversely, no synergistic effect was exhibited between quinpirole and dizocilpine, at any given dose. These findings suggest that D1, but not D2 receptors, enhance the disruptive effect of dizocilpine on PPI.

摘要

尽管大量证据表明谷氨酸能系统与多巴胺能系统之间的相互作用在注意力过程的调节中起关键作用,但它们在信息过滤中的作用却鲜有研究。主要是,很少有研究关注多巴胺能系统与N-甲基-D-天冬氨酸(NMDA)受体拮抗剂对感觉运动门控的作用机制之间的功能相关性。本研究旨在评估D1和D2受体的激活是否能够与地佐环平(一种选择性、非竞争性NMDA受体拮抗剂)介导的惊吓前脉冲抑制(PPI)破坏相互作用。我们测试了选择性D1激动剂SKF 38393((+/-)-1-苯基-2,3,4,5-四氢-(1H)-3-苯并氮杂卓-7,8-二醇)(10mg/kg,皮下注射)和D2激动剂喹吡罗(0.3、0.6mg/kg,皮下注射)对大鼠单独给药以及与不同剂量(0.0015至0.15mg/kg,皮下注射)地佐环平联合给药时的作用。随后,测试了D1拮抗剂SCH 23390((R)-(+)-7-氯-8-羟基-3-甲基-1-苯基-2,3,4,5-四氢-1H-3-苯并氮杂卓)(0.05、0.1mg/kg,皮下注射)对地佐环平以及地佐环平与SKF 38393联合介导的PPI破坏的影响。还进行了另外两个实验,以验证有效剂量的氟哌啶醇(0.1、0.5mg/kg,腹腔注射)和氯氮平(5、10mg/kg,腹腔注射)是否能抵消D1激动剂与地佐环平的协同作用。所有实验均采用评估听觉惊吓反射PPI的标准程序进行。SKF 38393单独使用时不会损害感觉运动门控,但与0.05和0.15mg/kg的地佐环平联合给药时会诱导PPI破坏,而这两种剂量的地佐环平单独使用时均无效。此外,这种作用被SCH 23390逆转,但未被氟哌啶醇或氯氮平逆转。相反,喹吡罗与地佐环平在任何给定剂量下均未表现出协同作用。这些发现表明,D1受体而非D2受体增强了地佐环平对PPI的破坏作用。

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