Department of Pharmacology, FMRP, University of São Paulo, Av. Bandeirantes 3900, 14049-900 Ribeirão Preto, Brazil.
Behav Brain Res. 2009 Dec 28;205(2):475-81. doi: 10.1016/j.bbr.2009.08.003. Epub 2009 Aug 7.
Drugs that facilitate dopaminergic neurotransmission induce cognitive and attentional deficits which include inability to filter sensory input measured by prepulse inhibition (PPI). Methylphenidate, an amphetamine analog is used in the treatment of attention deficit hyperactivity disorder. Given that nitric oxide (NO) modulates dopamine effect our aim is to analyze the nitric oxide synthase (NOS) and soluble guanylate cyclase (sGC) inhibitors effect on PPI disruption induced by methylphenidate. The inhibitors effects were compared to those produced by haloperidol and clozapine. Male Swiss mice received a first i.p. injection (one hour before testing), of either saline, or N(G) nitro l-arginine (10, 40 or 90 mg/kg), or 7-Nitroindazole (3, 10, 30 or 60 mg/kg), or oxadiazolo-quinoxalin (5 or 10 mg/kg), or haloperidol (1 mg/kg), or clozapine (5 mg/kg). Thirty min later mice received the second injection of either saline or methylphenidate (20 or 30 mg/kg) or amphetamine (5 or 10 mg/kg). One group of mice received intracerebroventricular 7-Nitroindazole (50 or 100 nM) followed by systemic administration of saline or methylphenidate (30 mg/kg). The results revealed a methylphenidate dose-dependent disruption of PPI comparable to amphetamine. The effect was prevented by either nitric oxide synthase or guanilate cyclase inhibitors or clozapine or haloperidol. In conclusion, methylphenidate induced a dose-dependent PPI disruption in Swiss mice modulated by dopamine and NO/sGC. The results corroborate the hypothesis of dopamine and NO interacting to modulate sensorimotor gating through central nervous system. It may be useful to understand methylphenidate and other psychostimulants effects.
促进多巴胺能神经传递的药物会导致认知和注意力缺陷，包括无法过滤感觉输入，这可以通过前脉冲抑制（PPI）来衡量。哌醋甲酯是一种安非他命类似物，用于治疗注意力缺陷多动障碍。鉴于一氧化氮（NO）调节多巴胺的作用，我们的目的是分析一氧化氮合酶（NOS）和可溶性鸟苷酸环化酶（sGC）抑制剂对哌醋甲酯引起的 PPI 破坏的影响。将抑制剂的作用与氟哌啶醇和氯氮平产生的作用进行了比较。雄性瑞士小鼠接受了第一次腹腔注射（测试前一小时），或生理盐水，或 N（G）-硝基-L-精氨酸（10、40 或 90mg/kg），或 7-硝基吲唑（3、10、30 或 60mg/kg），或恶二唑并喹喔啉（5 或 10mg/kg），或氟哌啶醇（1mg/kg），或氯氮平（5mg/kg）。30 分钟后，小鼠接受第二次注射生理盐水或哌醋甲酯（20 或 30mg/kg）或安非他命（5 或 10mg/kg）。一组小鼠接受了脑室 7-硝基吲唑（50 或 100nM），随后系统给予生理盐水或哌醋甲酯（30mg/kg）。结果显示，哌醋甲酯呈剂量依赖性破坏 PPI，与安非他命相当。该作用可被一氧化氮合酶或鸟苷酸环化酶抑制剂或氯氮平或氟哌啶醇预防。总之，哌醋甲酯在瑞士小鼠中引起了一种剂量依赖性的 PPI 破坏，这种破坏由多巴胺和 NO/sGC 调节。这些结果证实了多巴胺和 NO 相互作用通过中枢神经系统来调节感觉运动门控的假设。这对于理解哌醋甲酯和其他精神兴奋剂的作用可能是有用的。
