Regulation of Dopamine Neuron Excitability

描述(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，如抗精神病药物氟哌啶醇，会强烈地刺激这些细胞。然而，慢性氟哌啶醇在延迟一段时间后起作用，减少多巴胺的释放和多巴胺依赖行为。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，由于在活体记录过程中存在的全身麻醉药的混杂作用，一直是争议的来源。我们使用了一种不需要麻醉药的实验方法来证明慢性氟哌啶醇抑制年轻大鼠中脑多巴胺神经元的内在兴奋性。这是由于Kv4.3A型K+通道上调所致。此外，我们发现，这种作用可以在长期暴露于D2受体拮抗剂舒必利的细胞培养中重现。在这个方案中，我们将确定：(I)Kv4.3辅助亚基的表达是否也受抗精神病药物的调节；(Ii)慢性氟哌啶醇诱导的不规则起搏活动的离子基础；(Iii)非典型抗精神病药物是否类似于重塑多巴胺神经元的兴奋性；(Iv)D2受体和第二信使在体外长期作用中的作用；以及(V)多巴胺神经元兴奋性的重塑如何依赖于年龄和抗精神病药物治疗的时间。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的内在起搏器活性。这一长期调节可能在正常发育过程中起作用，并对成瘾和抗精神病药物引起的D2受体活性变化做出反应。

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.