Regulation of Dopamine Neuron Excitability

多巴胺神经元兴奋性的调节

• 批准号: 7390292
• 负责人: EDWIN S LEVITAN
• 金额: $ 29.27万
• 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 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7390292
• 关键词: Age; Anesthetics; Animals; Antipsychotic Agents; Autoreceptors; Behavior; Bypass; Cells; Chronic; Cognition; Cultured Cells; Development; Dopamine; Dopamine D2 Receptor; Exposure to; Fire - disasters; General anesthetic drugs; Haloperidol; In Vitro; Life; Long-Term Effects; Midbrain structure; Pacemakers; Potassium Channel; Psychotropic Drugs; Rattus; Regulation; Rewards; Role; Second Messenger Systems; Source; Substantia nigra structure; Sulpiride; Testing; Therapeutic; Up-Regulation; Ventral Tegmental Area; Voltage-Gated Potassium Channel; atypical antipsychotic; base; day; dopaminergic neuron; in vivo; insight; mRNA Expression; patch clamp; research study; response; second messenger

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，诸如抗精神病药氟哌啶醇之类的D2受体拮抗剂敏锐地激发了这些细胞。然而，慢性氟哌啶醇在延迟后起作用以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的治疗作用，由于体内记录过程中普遍麻醉的混杂作用，因此成为了争议的根源。我们使用了一种实验方法，该方法绕过了对麻醉药的需求，以证明慢性氟哌啶醇会抑制年轻大鼠中脑多巴胺神经元的内在兴奋性。这是由KV4.3 A型K+通道的上调引起的。此外，我们发现，可以在长期暴露于D2受体拮抗剂硫酸盐的细胞培养中概括这种作用。 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长期在体外作用，以及（v）多巴胺神经元兴奋性的重塑如何取决于抗精神病药治疗的年龄和持续时间。这些实验将确定D2受体和临床使用的抗精神病药重塑多巴胺神经元内在的起搏器活性。这种长期调节可能在正常发育过程中起作用，并响应由成瘾性和抗精神病药引起的D2受体活性的变化。

项目成果

Cav1.3 channel voltage dependence, not Ca2+ selectivity, drives pacemaker activity and amplifies bursts in nigral dopamine neurons.

• DOI: 10.1523/jneurosci.4742-09.2009
• 发表时间: 2009-12-09
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Putzier I;Kullmann PH;Horn JP;Levitan ES
• 通讯作者: Levitan ES