Department of Psychological Sciences, College of William and Mary, Williamsburg, VA 23187, USA; VA Boston Healthcare System and Department of Psychiatry, Harvard Medical School, West Roxbury, MA 02132, USA.
Center for Translational Social Neuroscience, Emory National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
Behav Brain Res. 2023 Jul 26;450:114497. doi: 10.1016/j.bbr.2023.114497. Epub 2023 May 16.
Schizophrenia is a neuropsychiatric condition that is associated with impaired attentional processing and performance. Failure to support increasing attentional load may result, in part, from inhibitory failure in attention-relevant cortical regions, and available antipsychotics often fail to address this issue. Orexin/hypocretin receptors are found throughout the brain and are expressed on neurons relevant to both attention and schizophrenia, highlighting them as a potential target to treat schizophrenia-associated attentional dysfunction. In the present experiment, rats (N = 14) trained in a visual sustained attention task that required discrimination of trials which presented a visual signal from trials during which no signal was presented. Once trained, rats were then co-administered the psychotomimetic N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801: 0 or 0.1 mg/kg, intraperitoneal injections) and the dual orexin receptor antagonist filorexant (MK-6096: 0, 0.1, or 1 mM, intracerebroventricular infusions) prior to task performance across six sessions. Dizocilpine impaired overall accuracy during signal trials, slowed reaction times for correctly-responded trials, and increased the number of omitted trials throughout the task. Dizocilpine-induced increases in signal trial deficits, correct response latencies, and errors of omission were reduced following infusions of the 0.1 mM, but not 1 mM, dose of filorexant. As such, orexin receptor blockade may improve attentional deficits in a state of NMDA receptor hypofunction.
精神分裂症是一种神经精神疾病，与注意力处理和表现受损有关。无法支持注意力负荷的增加，可能部分是由于注意力相关皮质区域的抑制失败，而现有的抗精神病药物通常无法解决这个问题。食欲素/下丘脑分泌素受体存在于整个大脑中，并在与注意力和精神分裂症都相关的神经元上表达，这突出了它们作为治疗与精神分裂症相关的注意力功能障碍的潜在靶点。在本实验中，大鼠（N=14）在视觉持续注意力任务中接受训练，该任务需要区分呈现视觉信号的试验和没有信号呈现的试验。一旦接受训练，大鼠随后在进行六次任务表现之前，接受 N-甲基-D-天冬氨酸（NMDA）受体拮抗剂地佐西平（MK-801：0 或 0.1mg/kg，腹腔注射）和双重食欲素受体拮抗剂氟雷西坦（MK-6096：0、0.1 或 1mM，侧脑室输注）的联合给药。地佐西平在有信号的试验中损害了整体准确性，减慢了正确反应试验的反应时间，并在整个任务中增加了遗漏试验的数量。氟雷西坦 0.1mM 剂量而非 1mM 剂量的输注可降低地佐西平诱导的信号试验缺陷、正确反应潜伏期和遗漏错误的增加。因此，食欲素受体阻断可能会改善 NMDA 受体功能低下状态下的注意力缺陷。
