Perry William, Minassian Arpi, Paulus Martin P, Young Jared W, Kincaid Meegin J, Ferguson Eliza J, Henry Brook L, Zhuang Xiaoxi, Masten Virginia L, Sharp Richard F, Geyer Mark A
Department of Psychiatry, University of California, San Diego, 9500 Gilman Dr, MC 0804, La Jolla, CA 92093-0804, USA.
Arch Gen Psychiatry. 2009 Oct;66(10):1072-80. doi: 10.1001/archgenpsychiatry.2009.58.
Bipolar mania and schizophrenia are recognized as separate disorders but share many commonalities, which raises the question of whether they are the same disorder on different ends of a continuum. The lack of distinct endophenotypes of bipolar mania and schizophrenia has complicated the development of animal models that are specific to these disorders. Exploration is fundamental to survival and is dysregulated in these 2 disorders. Although exploratory behavior in rodents has been widely studied, surprisingly little work has examined this critical function in humans.
To quantify the exploratory behavior of individuals with bipolar mania and schizophrenia and to identify distinctive phenotypes of these illnesses.
Static group comparison by the use of a novel human open field paradigm, the human Behavioral Pattern Monitor (BPM).
Psychiatric hospital.
Fifteen patients with bipolar mania and 16 patients with schizophrenia were compared with 26 healthy volunteers in the human BPM. The effects of amphetamine sulfate, the selective dopamine transporter inhibitor GBR12909, and the genetic knockdown of the dopamine transporter were compared with controls in the mouse BPM.
The amount of motor activity, spatial patterns of activity, and exploration of novel stimuli were quantified in both the human and mouse BPMs.
Patients with bipolar mania demonstrated a unique exploratory pattern, characterized by high motor activity and increased object exploration. Patients with schizophrenia did not show the expected habituation of motor activity. Selective genetic or pharmacologic inhibition of the dopamine transporter matched the mania phenotype better than the effects of amphetamine, which has been the criterion standard for animal models of mania.
These findings validate the human open field paradigm and identify defining characteristics of bipolar mania that are distinct from those of schizophrenia. This cross-species study of exploration calls into question an accepted animal model of mania and should help to develop more accurate human and animal models, which are essential to the identification of the neurobiological underpinnings of neuropsychiatric disorders.
双相躁狂症和精神分裂症被认为是不同的疾病，但存在许多共性，这就引发了一个问题，即它们是否是同一疾病在连续谱两端的表现。双相躁狂症和精神分裂症缺乏明确的内表型，这使得针对这些疾病的特异性动物模型的开发变得复杂。探索行为对于生存至关重要，而在这两种疾病中其调节出现异常。尽管啮齿动物的探索行为已得到广泛研究，但令人惊讶的是，针对人类这一关键功能的研究却很少。
量化双相躁狂症和精神分裂症患者的探索行为，并确定这些疾病的独特表型。
使用新型人类旷场范式——人类行为模式监测仪（BPM）进行静态组间比较。
精神病医院。
将15名双相躁狂症患者和16名精神分裂症患者与26名健康志愿者在人类BPM中进行比较。在小鼠BPM中，将硫酸苯丙胺、选择性多巴胺转运体抑制剂GBR12909以及多巴胺转运体基因敲低的效果与对照组进行比较。
在人类和小鼠BPM中，对运动活动量、活动的空间模式以及对新刺激的探索进行量化。
双相躁狂症患者表现出独特的探索模式，其特征为高运动活动和增加的物体探索。精神分裂症患者未表现出预期的运动活动习惯化。多巴胺转运体的选择性基因或药物抑制比苯丙胺的效果更能匹配躁狂症表型，而苯丙胺一直是躁狂症动物模型的标准。
这些发现验证了人类旷场范式，并确定了双相躁狂症有别于精神分裂症的特征。这项跨物种的探索研究对一种公认的躁狂症动物模型提出了质疑，并应有助于开发更准确的人类和动物模型，这对于确定神经精神疾病的神经生物学基础至关重要。
