Nicotinic-dopamine receptor interaction in a novel Parkinsonian mouse model.

新型帕金森病小鼠模型中烟碱-多巴胺受体的相互作用。

• 批准号: 7692288
• 负责人: ANDREW R TAPPER
• 金额: $ 32.35万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7692288
• 关键词: Acetylcholine; Address; Affect; Affinity; Age; Agonist; Animals; Basal Ganglia; Behavioral; Bilateral; Biological Assay; Bradykinesia; Brain region; Catalepsy; Cations; Cessation of life; Chemicals; Corpus striatum structure; DRD2 gene; Data; Disease; Dopamine; Dopamine Antagonists; Dopamine D2 Receptor; Dopamine Receptor; Dorsal; Engineering; Epidemiology; G-Protein-Coupled Receptors; Genetic; High Pressure Liquid Chromatography; Injection of therapeutic agent; Interneurons; Ligands; Measures; Mediating; Microdialysis; Midbrain structure; Movement; Movement Disorders; Mus; Muscle Rigidity; Mutation; Neurons; Neuroprotective Agents; Nicotine; Nicotinic Receptors; Parkinson Disease; Parkinsonian Disorders; Phenotype; Physiological; Point Mutation; Population; Presynaptic Terminals; Quinpirole; Receptor Activation; Rest Tremor; Severities; Slice; Smoker; Substantia nigra structure; Symptoms; Testing; Tobacco smoke; Tremor; Wild Type Mouse; abstracting; cholinergic; design; dopaminergic neuron; in vivo; mouse model; neuronal cell body; neurotransmission; neurotransmitter release; novel; pars compacta; receptor; receptor coupling; research study; response

DESCRIPTION (provided by applicant): Parkinson's disease is caused by the disruption of dopamine release in basal ganglia due to the progressive death of dopaminergic neurons in substantia nigra. Epidemiological data indicate Parkinson's disease is less prevalent in smokers. In addition, animal studies have found that nicotine, the addictive component of tobacco smoke, protects DAergic neurons from chemical insult and that this effect is likely mediated by neuronal nicotinic acetylcholine receptors (nAChRs). How do nAChRs modulate DA neurotransmission and which nAChR subtypes are involved? To address these questions a novel mouse line was engineered expressing a single point mutation, Leu9'Ala, within the putative pore region of the nicotinic receptor alpha-4 subunit. This mutation renders alpha-4-containing ("alpha- 4*") nAChRs 50-fold more sensitive to agonist allowing for the isolation and amplification of behavioral and physiological phenotypes that involve alpha-4* nAChRs. Recent studies suggest that alpha-4 beta- 2* nAChRs may functionally interact directly with D2-like receptors; G-protein coupled receptors that are expressed in midbrain and striatal neurons and, normally, negatively regulate activity. Preliminary data indicate that activation of D2-like receptors in Leu9'Ala mice elicits Parkinsonian symptoms that do not occur in wild-type animals. Specific aim 1 tests the hypothesis that the Leu9'Ala Parkinsonian phenotype is caused by activation of a D2-like dopamine receptor and is dependent on alpha-4* nAChR modulation. This will be done by administering different dopamine and nicotinic receptor antagonists to mice and assaying the Parkinsonian phenotype severity. Specific aim 2 tests the hypothesis that the interaction takes place in substantia nigra and/or stratum. In specific aim 3, in vivo microdialysis will be utilized to assay dopamine and acetylcholine release. Finally, specific aim 4 tests the hypothesis that D2 activation in Leu9'Ala mice uncovers a functional interaction between Gi/o coupled receptors and alpha-4* nAChRs in midbrain and/or striatal neurons. This will be achieved by measuring changes in neuron activity and nicotinic responses before and after D2 activation. It is anticipated that the results from the proposed experiments will not only provide a new pharmacological, reversible, Parkinson's disease mouse model, but, also increase understanding of nicotinic receptor mediated modulation of DAergic neurotransmission. PUBLIC HEALTH RELEVANCE It is anticipated that the results from this study will provide a new pharmacological, reversible mouse model of Parkinson's disease. In addition, this mouse model should help elucidate underlying neuronal mechanisms important for voluntary movement in normal and diseased states.

描述（由申请人提供）：帕金森氏病是由基底神经节释放的破坏引起的，这是由于黑质Nigra的多巴胺能神经元逐渐死亡。流行病学数据表明，帕金森氏病在吸烟者中的普遍性较小。此外，动物研究发现，尼古丁（烟草烟雾的成瘾成分）可以保护daergic神经元免受化学损伤的影响，并且这种作用可能是由神经元烟碱乙酰胆碱受体（NACHR）介导的。 NACHR如何调节DA神经传递和涉及哪些NACHR子类型？为了解决这些问题，在烟碱受体alpha-4亚基的推定孔区域内，设计了一个新的小鼠线，该小鼠线设计了一个点突变，即Leu9'ala。该突变使含α-4的含量（“ alpha-4*”）NACHRS对激动剂更敏感，从而使涉及alpha-4* nachrs的行为和生理表型分离和扩增。最近的研究表明，α-4β2* NACHR可能在功能上与D2样受体直接相互作用。 G蛋白偶联受体在中脑和纹状体神经元中表达，并且通常对活性负调节活性。初步数据表明，Leu9'ala小鼠中D2样受体的激活引起了野生型动物中未发生的帕金森氏症状。具体目标1检验了Leu9'ala帕金森氏菌表型的假设是由D2样多巴胺受体激活引起的，并且依赖于alpha-4* NACHR调制。这将通过对小鼠进行不同的多巴胺和烟碱受体拮抗剂并测定帕金森氏表型严重程度来完成。特定的目标2检验了相互作用在黑质和/或层中发生的假设。在特定的目标3中，体内微透析将用于测定多巴胺和乙酰胆碱释放。最后，具体目标4检验了以下假设：Leu9'ala小鼠中的D2激活发现了中脑和/或纹状体神经元中GI/O耦合受体与α-4* NACHR之间的功能相互作用。这将通过测量D2激活之前和之后的神经元活性和烟碱反应的变化来实现。可以预料，提出的实验的结果不仅会提供新的药理，可逆的帕金森氏病小鼠模型，而且还增加了对烟碱受体介导的DAergic神经传递调节的理解。公共卫生相关性可以预计，这项研究的结果将为帕金森氏病的新药理，可逆的小鼠模型提供。此外，该小鼠模型应有助于阐明对正常状态和患病状态的自愿运动重要的潜在神经元机制。