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首页> 外文期刊>Pharmacology, Biochemistry and Behavior >Time course of prepulse inhibition disruption induced by dopamine agonists and NMDA antagonists: effects of drug administration regimen.
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Time course of prepulse inhibition disruption induced by dopamine agonists and NMDA antagonists: effects of drug administration regimen.

机译：多巴胺激动剂和NMDA拮抗剂诱导的前脉冲抑制破坏的时程：药物给药方案的影响。

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Prepulse inhibition (PPI) of acoustic startle response is impaired in patients with schizophrenia and in animals acutely treated with dopamine agonists and NMDA antagonists. In this study, we investigated the time course of PPI disruption induced by repeated amphetamine, quinpirole, phencyclidine (PCP), and dizocilpine (MK-801) treatment. We focused on how PPI disruption development was influenced by drug administration regimens, comparing a constant versus an escalating dosing regimen. Male Sprague-Dawley rats were repeatedly treated with amphetamine (1.25-5.0 mg/kg, or constant 5.0 mg/kg, sc), PCP (0.50-2.0 mg/kg, or constant 0.5, 1.0 or 2.0 mg/kg, sc), quinpirole (0.03-0.12 mg/kg, or constant 0.12 mg/kg, sc), MK-801 (0.025-0.10 mg/kg, or constant 0.10 mg/kg, sc) or vehicle (saline) and tested for PPI once daily for 6 consecutive days. When amphetamine 5.0 mg/kg or quinpirole 0.12 mg/kg was administrated on a constant dosing schedule, both drugs disrupted PPI upon acute administration, but had no effect after repeated treatment and testing (days 2-5). However, when amphetamine 5.0 mg/kg or quinpirole 0.12 mg/kg was preceded by two lower doses in an escalating dosing regimen, both drugs still disrupted PPI on days 5 and 6 when the constant amphetamine and quinpirole had no effect. For PCP and MK-801, repeated treatment under both regimens produced a stable and persistent disruption of PPI. Startle magnitude increased progressively and dose-dependently under both regimens for all drugs except for quinpirole, which caused a decrease. These results suggest that the drug dosing schedule, rather than the absolute amount of drug that an animal receives, has a greater impact on the development of PPI-disruptive effect of dopamine agonists than NMDA antagonists. Thus, in order to mimic the emerging process of PPI deficit with dopamine agonists, an escalating dosing regimen should be used.
机译：在患有精神分裂症的患者以及接受多巴胺激动剂和NMDA拮抗剂急性治疗的动物中，声音惊吓反应的前脉冲抑制（PPI）受到损害。在这项研究中，我们调查了由反复的苯丙胺，喹吡罗，苯环利定（PCP）和地佐西平（MK-801）治疗引起的PPI破坏的时程。我们比较了恒定和逐步加药方案，重点研究了药物给药方案对PPI干扰发展的影响。雄性Sprague-Dawley大鼠反复用苯丙胺（1.25-5.0 mg / kg，或恒定的5.0 mg / kg，sc），PCP（0.50-2.0 mg / kg，或恒定的0.5、1.0或2.0 mg / kg，sc）处理，喹吡罗（0.03-0.12 mg / kg或恒定的0.12 mg / kg，sc），MK-801（0.025-0.10 mg / kg或恒定的0.10 mg / kg，sc）或赋形剂（盐水）并测试一次PPI每天连续6天。当按固定的给药时间表服用安非他明5.0 mg / kg或喹吡罗0.12 mg / kg时，两种药物在急性给药后均会破坏PPI，但在重复治疗和测试后（第2-5天）无效。但是，当在逐步增加的给药方案中先于安非他明5.0 mg / kg或喹吡罗0.12 mg / kg服用两次较低剂量时，两种药物仍在第5天和第6天破坏了PPI，而恒定的苯丙胺和喹吡罗无效。对于PCP和MK-801，在两种方案下重复治疗都会产生稳定而持久的PPI中断。在所有方案中，除喹吡罗外，所有药物的惊吓幅度都逐渐增加，并呈剂量依赖性，喹吡罗减少了。这些结果表明，与NMDA拮抗剂相比，给药剂量的时间表而不是动物接受的绝对剂量对多巴胺激动剂的PPI破坏作用的发展具有更大的影响。因此，为了用多巴胺激动剂模拟新出现的PPI缺乏症的过程，应采用逐步加药的方案。

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