PERMANENT DOPAMINE HYPERSENSITIVITY-A UNIQUE MODEL

永久性多巴胺超敏反应——独特的模型

• 批准号: 3412293
• 负责人: JEREMY Z FIELDS
• 金额: $ 8.47万
• 依托单位: EDWARD HINES JR VA HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-04-01 至 1992-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3412293
• 关键词: adrenergic agents; antiadrenergic agents; antipsychotic agents; corpus striatum; dopamine; dopamine receptor; haloperidol; high performance liquid chromatography; laboratory rat; neurochemistry; neurons; neurotransmitter biosynthesis; neurotransmitter metabolism; receptor sensitivity; substantia nigra; synapses; tissue /cell culture

The broad long-term objectives are (i) to understand at a molecular level how a behavioral supersensitivity (SS) to a neurotransmitter such as striatal dopamine (DA) might become permanent, especially through up-regulation of D2DA receptors (DA-R): both pre-synaptic auto-receptors (DA-R auto)and post-synaptic DA-R (DA-R post), and (ii) to create drug development strategies aimed at down-regulating both kinds of SS DA-R. In rodents, prolonged block of striatal D2 DA-R by antispsychotic drugs such an haloperidol (HAL) causes a compensatory up-regulation of those DA-R post and results in a transient behavioral SS to DA agonists. Chronic neuroieptics also cause tardive dyskinesia (TD) in man. Yet TD symptoms can become permanent remaining long after neuroleptic withdrawal. Our hypothesis to explain the apparent irreversibility is: (1) to compensate for DA-R post SS. DA release decreases; (2) DA-R auto, which inhibit DA synthesis and release, also up-regulate due to HAL and to declining levels of cleft DA; (3) this DA-R auto SS now shuts off DA release at a new, lower set point which further which further increases DA-R auto SS; (4) this vicious cycle "bottoms out" and "locks in " at a constant (lower) level of DA release; (5) now, as the a of DA-R post increases because there is no way to increase to further decrease DA release; (6) the system remains permanently SS because there is also no way to increase DA release to down-regulate SS DA-R; (7) only artificial (pharmacologic) maneuvers to temporarily increase cleft DA can break the cycle. Our model is the ovariectomized (OVX) rat exposed to Hal, which rapidly develops a PERMANENT DA SS; controls are non-OVX, HAL- exposed rats, which develop only a TRANSIENT SS. This model of permanent DA-R SS is unique in that the nigrostriatal DA neurons survive (unlike SS from 60HDA lesions) and compensatory changes can be followed. We will show that a permanent SS of PRE-synaptic DA- R auto precedes or at least accompanies to permanent phase of DA- R post SS> These studies model only ONE aspect of TD - the permanence of the SS. But this one aspect is essential to rational drug development. Other models, e.g. the chronic neuroleptic- treated monkey, appear to more closely resemble many behavioral aspects of TD (e.g. spontaneity, anatomy) but are not economically feasible for our studies. The specific aims are: (I) to confirm the time course for the development of pregnant an transient behavioral SS DA agonists; (II) to evaluate specific neural mechanism during developing and maintenance phases of the permanent striatal SS: (A) postsynaptic: DA-R binding (B) presynaptic: (1) DA-R auto SS (inhibition, of (3H)DA release from slices); (2) DA release (3MT levels; in vivo microdialysis/HPLC); (C) nigral mechanisms: DA-R binding an GAD activity; (III) To determine whether agents that reverse the permanent behavioral SS in the OVX rat (Cyclo(leucyl-glycyl), DA agonist) do so by reversing the same neurochemical changes (above) that appear to cause the permanent SS.

广泛的长期目标是（i）在分子水平上理解 水平如何行为超敏（SS）的神经递质 如纹状体多巴胺（DA）可能成为永久性的，特别是 通过上调D2 DA受体（DA-R）：突触前 自身受体（DA-R auto）和突触后DA-R（DA-R post），以及 (ii)制定药物开发策略， 这两种都是党卫军 在啮齿类动物中，纹状体D2 抗精神病药物如氟哌啶醇（HAL）引起的DA-R 这些DA-R后的补偿性上调， 短暂行为SS对DA激动剂的反应。 慢性神经抑制剂也 导致迟发性运动障碍（TD）的人。然而TD症状可以成为 在精神抑制剂停药后很长一段时间仍然存在。 我们的假设来解释表观不可逆性是：（1） 补偿SS后的DA-R。DA释放减少;（2）DA-R自动， 抑制DA的合成和释放，也由于HAL而上调 和下降水平的分裂DA;（3）这种DA-R自动SS现在 在新的较低设定点关闭DA释放， 进一步增加DA-R自动SS;（4）这种恶性循环“底部 在恒定（较低）DA释放水平下的“输出”和“锁定“;（5） 现在，随着DA-R职位的增加，因为没有办法 增加以进一步减少DA释放;（6）系统仍然 因为也没有办法增加DA的释放 下调SS DA-R;（7）仅人工（药理学） 暂时增加间隙DA的策略可以打破循环。 我们的模型是卵巢切除（OVX）大鼠暴露于哈尔， 快速发展为永久性DA SS;对照为非OVX、HAL- 暴露的大鼠，仅出现一过性SS。这个型号的 永久性DA-R SS的独特之处在于黑质纹状体DA能神经元 存活（不像60 HDA病变的SS）和代偿性变化可以 被跟踪。 我们将证明突触前DA的永久SS- R自动先于或至少伴随着DA的永久阶段- R post SS>这些研究只模拟了TD的一个方面- SS的永久性。 但这一方面对于理性的 药物开发 其他模型，例如慢性神经抑制剂- 治疗过的猴子，看起来更像许多行为 TD方面（例如自发性、解剖学），但不符合经济学要求 对我们的研究是可行的。 具体目的是：（一）确定时间进程的 妊娠期短暂行为SS DA激动剂的发展; (II)评估发育过程中的特定神经机制， 永久性纹状体SS的维持阶段：（A）突触后： 突触前DA受体结合（B）：（1）DA受体自身SS（抑制， （3 H）DA从切片释放）;（2）DA释放（3 MT水平;体内 （C）黑质机制：DA-R结合GAD （三）确定是否存在逆转 OVX大鼠的永久行为SS（Cyclo（亮氨酰-甘氨酰），DA 激动剂）通过逆转相同的神经化学变化（如上所述） 导致了永久性的党卫军