Caprioli Daniele, Sawiak Stephen J, Merlo Emiliano, Theobald David E H, Spoelder Marcia, Jupp Bianca, Voon Valerie, Carpenter T Adrian, Everitt Barry J, Robbins Trevor W, Dalley Jeffrey W
Behavioural and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
Behavioural and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom; Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, Addenbrooke's Hospital, Cambridge, United Kingdom.
Biol Psychiatry. 2014 Jan 15;75(2):115-23. doi: 10.1016/j.biopsych.2013.07.013. Epub 2013 Aug 21.
Pathological forms of impulsivity are manifest in a number of psychiatric disorders listed in DSM-5, including attention-deficit/hyperactivity disorder and substance use disorder. However, the molecular and cellular substrates of impulsivity are poorly understood. Here, we investigated a specific form of motor impulsivity in rats, namely premature responding, on a five-choice serial reaction time task.
We used in vivo voxel-based magnetic resonance imaging and ex vivo Western blot analyses to investigate putative structural, neuronal, and glial protein markers in low-impulsive (LI) and high-impulsive rats. We also investigated whether messenger RNA interference targeting glutamate decarboxylase 65/67 (GAD65/67) gene expression in the nucleus accumbens core (NAcbC) is sufficient to increase impulsivity in LI rats.
We identified structural and molecular abnormalities in the NAcbC associated with motor impulsivity in rats. We report a reduction in gray matter density in the left NAcbC of high-impulsive rats, with corresponding reductions in this region of glutamate decarboxylase (GAD65/67) and markers of dendritic spines and microtubules. We further demonstrate that the experimental reduction of de novo of GAD65/67 expression bilaterally in the NAcbC is sufficient to increase impulsivity in LI rats.
These results reveal a novel mechanism of impulsivity in rats involving gamma aminobutyric acidergic and structural abnormalities in the NAcbC with potential relevance to the etiology and treatment of attention-deficit/hyperactivity disorder and related disorders.
冲动的病理形式在《精神疾病诊断与统计手册》第5版列出的多种精神疾病中都有体现，包括注意力缺陷多动障碍和物质使用障碍。然而，冲动的分子和细胞基础仍知之甚少。在此，我们在一项五选择连续反应时任务中研究了大鼠运动冲动的一种特定形式，即过早反应。
我们使用基于体素的体内磁共振成像和体外蛋白质免疫印迹分析，来研究低冲动性（LI）和高冲动性大鼠中假定的结构、神经元和胶质蛋白标志物。我们还研究了针对伏隔核核心（NAcbC）中谷氨酸脱羧酶65/67（GAD65/67）基因表达的信使核糖核酸干扰是否足以增加LI大鼠的冲动性。
我们确定了大鼠中与运动冲动相关的NAcbC中的结构和分子异常。我们报告高冲动性大鼠左侧NAcbC的灰质密度降低，该区域的谷氨酸脱羧酶（GAD65/67）以及树突棘和微管标志物相应减少。我们进一步证明，在NAcbC中双侧实验性降低GAD65/67的从头表达足以增加LI大鼠的冲动性。
这些结果揭示了大鼠冲动性的一种新机制，涉及NAcbC中的γ-氨基丁酸能和结构异常，这可能与注意力缺陷多动障碍及相关疾病的病因和治疗有关。
