Boekhoudt Linde, Omrani Azar, Luijendijk Mieneke C M, Wolterink-Donselaar Inge G, Wijbrans Ellen C, van der Plasse Geoffrey, Adan Roger A H
Brain Center Rudolf Magnus, Department of Translational Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
Brain Center Rudolf Magnus, Department of Translational Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
Eur Neuropsychopharmacol. 2016 Nov;26(11):1784-1793. doi: 10.1016/j.euroneuro.2016.09.003. Epub 2016 Oct 4.
Hyperactivity is a core symptom in various psychiatric disorders, including attention-deficit/hyperactivity disorder, schizophrenia, bipolar disorders, and anorexia nervosa. Although hyperactivity has been linked to dopaminergic signalling, the causal relationship between midbrain dopamine neuronal activity and locomotor hyperactivity remains unknown. In this study, we test whether increased dopamine neuronal activity is sufficient to induce locomotor hyperactivity. To do so, we used designer receptors exclusively activated by designer drugs (DREADD) to chemogenetically enhance neuronal activity in two main midbrain dopamine neuron populations, i.e. the ventral tegmental area (VTA) and substantia nigra pars compacta (SN), in TH:Cre rats. We found that activation of VTA dopamine neurons induced a pronounced and long-lasting hyperactive phenotype, whilst SN dopamine neuron activation only modestly increased home cage locomotion. Furthermore, this hyperactive phenotype was replicated by selective activation of the neuronal pathway from VTA to the nucleus accumbens (NAC). These results show a clear functional difference between neuronal subpopulations in the VTA and SN with regards to inducing locomotor hyperactivity, and suggest that the dopaminergic pathway from VTA to NAC may be a promising target for the treatment of hyperactivity disorders.
多动是多种精神疾病的核心症状，包括注意力缺陷多动障碍、精神分裂症、双相情感障碍和神经性厌食症。尽管多动与多巴胺能信号传导有关，但中脑多巴胺神经元活动与运动性多动之间的因果关系仍不清楚。在本研究中，我们测试多巴胺神经元活动增加是否足以诱发运动性多动。为此，我们使用仅由设计药物激活的设计受体（DREADD），通过化学遗传学方法增强TH:Cre大鼠两个主要中脑多巴胺神经元群体，即腹侧被盖区（VTA）和黑质致密部（SN）的神经元活动。我们发现，激活VTA多巴胺神经元会诱发明显且持久的多动表型，而激活SN多巴胺神经元只会适度增加笼内活动。此外，通过选择性激活从VTA到伏隔核（NAC）的神经元通路，也能复制这种多动表型。这些结果表明，VTA和SN中的神经元亚群在诱发运动性多动方面存在明显的功能差异，并表明从VTA到NAC的多巴胺能通路可能是治疗多动障碍的一个有前景的靶点。
