Durston Sarah, Fossella John A, Mulder Martijn J, Casey B J, Ziermans Tim B, Vessaz M Nathalie, VAN Engeland Herman
Drs. Durston, Mulder, Ziermans, Vessaz, and Van Engeland are with the Department of Child and Adolescent Psychiatry, Rudolf Magnus Institute for Neurosciences; Drs. Casey and Durston are with the Sackler Institute for Developmental Psychobiology; and Dr. Fossella is with Mount Sinai Hospital, New York.
Drs. Durston, Mulder, Ziermans, Vessaz, and Van Engeland are with the Department of Child and Adolescent Psychiatry, Rudolf Magnus Institute for Neurosciences; Drs. Casey and Durston are with the Sackler Institute for Developmental Psychobiology; and Dr. Fossella is with Mount Sinai Hospital, New York.
J Am Acad Child Adolesc Psychiatry. 2008 Jan;47(1):61-67. doi: 10.1097/chi.0b013e31815a5f17.
The dopamine transporter (DAT1) gene has been implicated in attention-deficit/hyperactivity disorder (ADHD), although the mechanism by which it exerts its effects remains unknown. The polymorphism associated with ADHD has been shown to affect expression of the transporter in vitro and in vivo. Dopamine transporters are predominantly expressed in the striatum, but also in the cerebellar vermis. Stimulant medication is often effective in ADHD and is believed to exert its effects by blocking dopamine transporters in the striatum. We set out to investigate the effect of the DAT1 genotype in ADHD in a small, preliminary study. We hypothesized that the DAT1 genotype would affect brain activation patterns in a manner similar to that of stimulant medication, with the lesser expressing allele mirroring its effects.
We investigated DAT1 gene effects on brain activation patterns in an all-male sample of sibling pairs discordant for ADHD (n = 20) and controls (n = 9). All of the subjects participated in a functional magnetic resonance imaging session using a go/no-go paradigm and provided a DNA sample for analysis.
DAT1 genotype affected activation in the striatum and cerebellar vermis. The genotype interacted with familial risk of ADHD in the striatum but not the vermis.
These preliminary results suggest that the DAT1 gene effects in the striatum are involved in translating the genetic risk of ADHD into a neurobiological substrate. As such, this study represents a first step in elucidating the neurobiological mechanisms underlying genetic influences in ADHD. Furthermore, these results may contribute to long-term possibilities for the development of new treatments: If the DAT1 genotype has differential effects on striatal activation, then it may be useful as a surrogate endpoint in individualized treatments targeting genotype/functional magnetic resonance imaging activation profiles.
多巴胺转运体（DAT1）基因与注意力缺陷多动障碍（ADHD）有关，但其发挥作用的机制尚不清楚。已表明与ADHD相关的多态性会在体外和体内影响该转运体的表达。多巴胺转运体主要在纹状体中表达，但在小脑蚓部也有表达。兴奋剂药物通常对ADHD有效，据信其作用是通过阻断纹状体中的多巴胺转运体来实现的。我们开展了一项小型初步研究，以调查DAT1基因型在ADHD中的作用。我们假设DAT1基因型会以与兴奋剂药物类似的方式影响大脑激活模式，表达较少的等位基因会反映出其作用。
我们在一组全为男性的样本中研究了DAT1基因对大脑激活模式的影响，该样本包括20对患ADHD不一致的同胞对和9对对照组。所有受试者都参与了一项使用“执行/不执行”范式的功能磁共振成像检查，并提供了一份DNA样本用于分析。
DAT1基因型影响纹状体和小脑蚓部的激活。该基因型在纹状体中与ADHD的家族风险存在相互作用，但在蚓部不存在。
这些初步结果表明，DAT1基因在纹状体中的作用参与了将ADHD的遗传风险转化为神经生物学基础。因此，本研究是阐明ADHD遗传影响背后神经生物学机制的第一步。此外，这些结果可能有助于新治疗方法开发的长期可能性：如果DAT1基因型对纹状体激活有不同影响，那么它可能作为针对基因型/功能磁共振成像激活谱的个体化治疗中的替代终点。
