ELECTROPHYSIOLOGY OF CNS DOPAMINE RECEPTOR KNOCKOUT

大脑中的多巴胺能神经传递调节许多 重要的认知和行为功能。例如，精神分裂症 据信是由于前脑多巴胺系统失衡所致。 分子生物学的最新进展导致了对5种病毒的鉴定 多巴胺受体的两个主要家族的不同编码基因 D2。虽然激动剂和拮抗剂区分 D1和D2家族存在，但尚不存在选择性药物 在家庭成员中(例如，D2对D3对D4或D1对D5)。这有 导致对多巴胺的作用部位和作用机制的混淆 在大脑中，关于哪些受体亚型确切地介导了哪些 细胞效应，可能也有助于混合治疗 抗精神分裂症药物使用中的疗效及不良反应 今天。 我们已经证明了在体内注入专门设计的反义 与编码不同基因的mRNA互补的寡脱氧核苷酸 多巴胺受体产生高度区域和受体特异性的前... 或突触后“敲除”多巴胺D2或D3受体 通过受体放射自显影。体内和体外电生理 将使用技术来确定D2和D3多巴胺的作用 受体在调节脑实质电活动中的作用 黑质多巴胺能神经元和新纹状体神经元。随后的实验 将利用类似的方法实现对d1和d4的击倒 感受器。 多巴胺受体的位置和受体亚型，它介导 苯丙胺对黑质细胞放电的抑制作用将是 下定决心。活体细胞外和体外细胞内记录 将被用于确认黑质躯体树突状细胞的身份 并确定它在控制血管紧张素转换酶中的作用。 黑质多巴胺神经元的放电率和放电模式。体内和体内 体外细胞内记录将用于确定受体亚型- 多巴胺对新纹状体神经元的特异性作用，并确定 介导多巴胺作用的受体的位置和亚型 皮质纹状体突触传递。 这项研究与基础神经科学和应用神经科学都高度相关。 选择性受体反义敲除方法在体内的验证 通过电生理手段是迈向 这项技术在各种研究问题上的应用。这个 特定多巴胺受体亚型(S)的鉴定 介导了许多具有良好特征的生理反应 多巴胺可能提供的信息将指导未来的研究 新一代抗精神病药物的设计 同时更有效，而且没有经常具有破坏性的副作用 目前正在使用的抗精神病药。

Dopaminergic neurotransmission in the brain modulates a number of important cognitive and behavioral functions. For example, schizophrenia is believed to result from an imbalance in forebrain dopamine systems. Recent advances in molecular biology have led to the identification of 5 different genes coding for dopamine receptors of 2 main families, D1 and D2. Although agonists and antagonists that discriminate between members of the D1 and D2 families exist, drugs do not yet exist that are selective among family members (e.g., D2 vs. D3 vs. D4 or D1 vs. D5). This has resulted in confusion about the sites and mechanisms of action of dopamine in the brain, about precisely which receptor subtypes mediate which cellular effects, and likely also contributes to the mixed therapeutic efficacy and unwanted side effects of antischizophrenic drugs in use today. We have shown that in vivo infusion of specifically designed antisense oligodeoxynucleotides complementary to the mRNA coding for different dopamine receptors produces a highly regional- and receptor-specific pre- or postsynaptic "knockout" of the dopamine D2 or D3 receptors as indexed by receptor autoradiography. In vivo and in vitro electrophysiological techniques will be used to determine the roles that D2 and D3 dopamine receptors play in the modulation of the electrical activity of substantia nigra dopaminergic neurons and neostriatal neurons. Subsequent experiments will utilize similar methods to achieve knockout of the D1 and D4 receptors. The site and receptor subtype of the dopamine receptor that mediates the inhibitory effects of amphetamine on nigral cell firing will be determined. In vivo extracellular and in vitro intracellular recordings will be used to confirm the identity of the nigral somadendritic autoreceptor and determine the role that it plays in the control of the rate and pattern of firing of nigral dopamine neurons. In vivo and in vitro intracellular recordings will be used to define receptor subtype- specific actions of dopamine on neostriatal neurons, and determine the site and subtype of the receptor that mediates dopamine's effect on corticostriatal synaptic transmission. This research is highly relevant to both basic and applied neuroscience. Validating the antisense approach to selective receptor knockout in vivo by electrophysiological means is a necessary first step towards the application of this technique to a variety of research issues. The identification of the particular dopamine receptor subtype(s) that mediates a number of well-characterized physiological responses to dopamine may provide information that will direct future research towards the design of a new generation of antipsychotic drugs that are simultaneously more effective and lack the often devastating side effects of the neuroleptics in use today.