Neurochemical studies on pathophysiology and treatment of attention deficit hyperactivity disorder

为探讨注意缺陷多动障碍（ADHD）的神经化学机制，我们测定了尿中β-苯乙胺（PEA）等单胺类物质的含量。ADHD患者（n=37）的PEA水平显著低于对照组（n=21）。22例ADHD患儿用哌醋甲酯治疗。哌甲酯治疗后，应答者（n=18）的PEA水平显著增加，而非应答者则没有增加。为了开发治疗ADHD的新方法，我们采用细胞内和全细胞膜片钳技术研究了选择性5-羟色胺和去甲肾上腺素（NA）再摄取抑制剂米那昔普兰（MIL）对大鼠蓝斑（LC）神经元兴奋性和突触传递的影响。我们比较了MIL和哌甲酯（MPH）。应用MPH和MIL的人工CSF产生超极化反应，LC神经元在浓度依赖性的方式。LC神经元自发放电在超极化过程中被阻断。在全细胞膜片钳条件下，长时间应用MIL可使ACSF产生持续时间与MIL存在时间相同的外向电流。在LC神经元上，MIL可增强NA诱导的外向电流。MIL使抑制性突触后电位的幅度和时程增加，而使兴奋性突触后电位的幅度和时程降低。结果表明，MIL和MPH对大鼠LC神经活动和突触传递的影响几乎相同。提示MIL通过抑制大鼠LC NA重摄取系统，增加突触间隙NA含量。

We measured the urine levels of β-phenylethylamine (PEA) and other monoamines to clarify the neurochemical mechanism in attention deficit hyperactivity disorder (ADHD). PEA levels were significantly lower in ADHD individuals (n=37) than in controls (n=21). The 22 children with ADHD were treated with methylphenidate. PEA levels significantly increased after methylphenidate therapy in responders (n=18), whereas they did not increase in non-responders. To develop new treatment for ADHD, we examined effects of milnaciplan (MIL), a selective serotonin and noradorenaline (NA) reuptake inhibitor, on the neuronal excitability and synaptic transmission in the rat locus ceruleus (LC) by intracellular and whole-cell patch-clamp recording techniques. We compared MIL and methylphenidate (MPH). Application of MPH and MIL to artificial CSF produced a hyperpolarizing response in LC neurons in a concentration-dependent manner. Spontaneous firing of LC neurons was blocked during the hyperpolarization. Under the whole-cell patch-clamp condition, prolonged application of MIL produced an outward current which lasted as long as MIL existed in the ACSF. The outward current induced by NA was enhanced by MIL in LC neurons. MIL enhanced the amplitude and duration of the inhibitory postsynaptic potential, while it depressed the excitatory postsynaptic potential. The results indicated that both MIL and MPH showed almost the same effects on neural activity and synaptic transmission in the rat LC. These results suggest that MIL increases the concentration of NA at synaptic cleft by inhibiting the NA reuptake system in the rat LC.