Acute D2/D3 dopaminergic agonism but chronic D2/D3 antagonism prevents NMDA antagonist neurotoxicity
Acute D2/D3 dopaminergic agonism but chronic D2/D3 antagonism prevents NMDA antagonist neurotoxicity
复制标题
DOI：
10.1016/j.biopsych.2006.02.019
复制
发表时间：
2006-09-15
影响因子：
10.6
通讯作者：
Noguchi, Kevin K.
中科院分区：
文献类型：
--
作者：
Farber, Nuri B.;Nemmers, Brian;Noguchi, Kevin K.
背景。n -甲基- d -天冬氨酸（NMDA）谷氨酸受体拮抗剂，最有可能通过在复杂回路中产生去抑制作用，在人类中急性产生精神病和认知障碍，并在啮齿动物中产生神经毒性。因此，研究NMDA受体功能低下（NRHypo）对动物的神经毒性，可能为精神障碍的病理生理学提供见解。多巴胺能D-2和/或D-3药物可以在数天到数周内改变精神病，表明这些递质系统参与其中。方法：我们研究了D-2/D-3激动剂和拮抗剂在一次性急性暴露和慢性每日暴露后改变NRHypo神经毒性的能力。结果：本研究报告了D-2/D-3多巴胺激动剂（可能通过P受体）在急性给予时可预防NRHypo神经毒性。长期每日给药后，D-2/D-3激动剂的保护作用未见。相反，抗精神病药氟哌啶醇在急性给予致死剂量时不会影响NRHypo神经毒性。然而，长期每日给药1、3或5周后，氟哌啶醇确实能预防NRHypo神经毒性，且持续时间越长，保护作用越大。了解慢性暴露于多巴胺能药物后NRHypo回路发生的变化可以为精神障碍的病理生理学提供重要线索。
Background. Antagonists of the N-methyl-D-aspartate (NMDA) glutamate receptor, most likely by producing disinhibtion in complex circuits, acutely produce psychosis and cognitive disturbances in humans, and neurotoxicity in rodents. Studies examining NMDA Receptor Hypofunction (NRHypo) neurotoxicity in animals, therefore, may provide insights into the pathophysiology of psychotic disorders. Dopaminergic D-2 and/or D-3 agents can modify psychosis over days to weeks, suggesting involvement of these transmitter system(s).Methods: we studied the ability of D-2/D-3 agonists and antagonists to modify NRHypo neurotoxicity both after a one-time acute exposure and after chronic daily exposure.Results: Here we report that D-2/D-3 dopamine agonists, probably via P, receptors, prevent NRHypo neurotoxicity when given acutely. The protective effect with D-2/D-3, agonists is not seen after chronic daily dosing. In contrast, the antipsycbotic haloperidol does not affect NRHypo neurotoxicity when given acutely at DIE, doses. However, after chronic daily dosing of 1, 3, or 5 weeks, haloperidol does prevent NRHypo neurotoxicity with longer durations producing greater protection.Conclusions. Under-standing the changes that occur in the NRHypo circuit after chronic exposure to dopaminergic agents could provide important clues into the pathophysiology of psychotic disorders.