Regulation of Dopamine Neuron Excitability

多巴胺神经元兴奋性的调节

• 批准号: 7028920
• 负责人: EDWIN S LEVITAN
• 金额: $ 30.14万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7028920
• 关键词: action potentials; antipsychotic agents; calcium flux; clozapine; dopamine; dopamine receptor; electrophysiology; gene expression; haloperidol; laboratory rat; messenger RNA; neurons; neuropharmacology; neuroregulation; nimodipine; polymerase chain reaction; potassium channel; second messengers; substantia nigra; tegmentum; tetrodotoxin; tissue /cell culture; voltage /patch clamp; voltage gated channel

DESCRIPTION (provided by applicant): Midbrain dopamine neurons express inhibitory D2 dopamine autoreceptors. Therefore, D2 receptor antagonists such as the antipsychotic drug haloperidol act acutely to excite these cells. However, chronic haloperidol acts after a delay to decrease dopamine release and dopamine dependent behavior. The long-term regulation of dopamine neuron activity, which might contribute to the therapeutic action of antipsychotic drugs, has been a source of controversy because of the confounding effects of general anesthetics present during in vivo recording. We have used an experimental approach that bypasses the need for anesthetics to demonstrate that chronic haloperidol dampens the intrinsic excitability of young rat midbrain dopamine neurons. This is caused by upregulation of Kv4.3 A-type K+ channels. Furthermore, we find that this effect can be recapitulated in cell culture with chronic exposure to the D2 receptor antagonist sulpiride. In this proposal, we will determine: (i) whether Kv4.3 auxiliary subunit expression is also regulated by the antipsychotic drug, (ii) the ionic basis for irregular pacemaker activity induced by chronic haloperidol, (iii) whether an atypical antipsychotic drug acts similarly to remodel dopamine neuron excitability, (iv) the role of D2 receptors and second messengers in the long-term effect in vitro, and (v) how remodeling of dopamine neuron excitability depends on age and duration of antipsychotic drug treatment. These experiments will determine how D2 receptors and clinically used antipsychotic drugs remodel dopamine neuron intrinsic pacemaker activity. This long-term regulation may operate during normal development and in response to changes in D2 receptor activity induced by addictive and antipsychotic drugs.

描述（由申请人提供）：中脑多巴胺神经元表达抑制性 D2 多巴胺自身受体。因此，D2 受体拮抗剂（例如抗精神病药物氟哌啶醇）可迅速激发这些细胞。然而，慢性氟哌啶醇在延迟后起作用，减少多巴胺释放和多巴胺依赖性行为。多巴胺神经元活性的长期调节可能有助于抗精神病药物的治疗作用，但由于体内记录过程中全身麻醉药存在的混杂效应而引起争议。我们使用了一种无需麻醉剂的实验方法来证明长期氟哌啶醇会抑制幼鼠中脑多巴胺神经元的内在兴奋性。这是由 Kv4.3 A 型 K+ 通道上调引起的。此外，我们发现这种效应可以在长期暴露于 D2 受体拮抗剂舒必利的细胞培养物中重现。在本提案中，我们将确定：（i）Kv4.3辅助亚基表达是否也受到抗精神病药物的调节，（ii）慢性氟哌啶醇诱导的不规则起搏器活动的离子基础，（iii）非典型抗精神病药物是否起作用与重塑多巴胺神经元兴奋性类似，（iv）D2受体和第二信使在体外长期效应中的作用，以及（v）如何重塑多巴胺神经元兴奋性取决于年龄和抗精神病药物治疗的持续时间。这些实验将确定 D2 受体和临床使用的抗精神病药物如何重塑多巴胺神经元内在起搏器活性。这种长期调节可能在正常发育过程中发挥作用，并对成瘾药物和抗精神病药物引起的 D2 受体活性变化作出反应。