CNS Biology, Worldwide Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA.
Psychopharmacology (Berl). 2010 Aug;211(3):325-36. doi: 10.1007/s00213-010-1901-0. Epub 2010 Jun 12.
Dopamine (DA) agonists decrease prepulse inhibition (PPI) and are widely used in translational models for the sensorimotor gating deficits in schizophrenia. Reductions in PPI induced by DA agonists are routinely reversed by antipsychotics in these translational models. Nevertheless, under conditions of low-baseline PPI, DA agonists may increase PPI in humans and experimental animals. DBA/2 mice have naturally low-baseline PPI, which as in the drug-induced translational models, is increased by antipsychotics.
Determine whether DBA/2 mice respond like other models of low-baseline PPI by evaluating the effect of psychostimulants (caffeine, 30-100 mg/kg IP) and the indirect DA agonists d-amphetamine (0.3-10 mg/kg IP), methylphenidate (10-100 mg/kg IP), and sydnocarb (10-30 mg/kg IP), a selective DA transporter inhibitor on PPI. Furthermore, baseline PPI in DBA/2 mice was increased by noise exposure and the effect of d-amphetamine was assessed.
PPI was increased at one dose for each of the psychostimulants when baseline PPI was low in naïve DBA/2 mice. Effective doses were 3 mg/kg of d-amphetamine, 30 mg/kg of methylphenidate, 30 mg/kg of sydnocarb, and 100 mg/kg of caffeine. Higher doses of d-amphetamine (10 mg/kg) and methylphenidate (100 mg/kg IP) decreased PPI. When the baseline PPI was increased by noise exposure, 10 mg/kg of d-amphetamine only reduced PPI.
Lower doses of psychostimulants increased PPI in naïve DBA/2 mice in a manner consistent with their naturally low-baseline PPI, and higher doses decreased PPI, consistent with effects observed in most mouse strains.
多巴胺（DA）激动剂可降低前脉冲抑制（PPI），并广泛用于精神分裂症感觉门控缺陷的转化模型。在这些转化模型中，抗精神病药物通常可逆转 DA 激动剂引起的 PPI 降低。然而，在 PPI 基线较低的情况下，DA 激动剂可能会增加人类和实验动物的 PPI。DBA/2 小鼠的 PPI 基线自然较低，与药物诱导的转化模型一样，抗精神病药物可增加 PPI。
通过评估精神兴奋剂（咖啡因，30-100mg/kg IP）和间接 DA 激动剂 d-苯丙胺（0.3-10mg/kg IP）、哌甲酯（10-100mg/kg IP）和西地那卡林（10-30mg/kg IP）对 PPI 的影响，确定 DBA/2 小鼠是否像其他低 PPI 基线模型一样做出反应。此外，评估噪声暴露对 DBA/2 小鼠基线 PPI 的影响和 d-苯丙胺的作用。
在未接受处理的 DBA/2 小鼠的 PPI 基线较低时，每种精神兴奋剂都增加了 PPI 的一个剂量。有效剂量分别为 3mg/kg 的 d-苯丙胺、30mg/kg 的哌甲酯、30mg/kg 的西地那卡林和 100mg/kg 的咖啡因。更高剂量的 d-苯丙胺（10mg/kg）和哌甲酯（100mg/kg IP）降低了 PPI。当基线 PPI 通过噪声暴露增加时，只有 10mg/kg 的 d-苯丙胺降低了 PPI。
在未接受处理的 DBA/2 小鼠中，较低剂量的精神兴奋剂可增加 PPI，与它们自然较低的 PPI 基线一致，而较高剂量则降低 PPI，与大多数小鼠品系观察到的效果一致。
