PERMANENT DOPAMINE HYPERSENSITIVITY-A UNIQUE MODEL

广泛的长期目标是：(I)在分子水平上理解 行为超敏(SS)对神经递质的水平 例如纹状体多巴胺(DA)可能成为永久性的，特别是 通过上调D2DA受体(DA-R)：两种突触前 自身受体(DA-R AUT)和突触后DA-R(DA-R POST) (2)制定旨在降低管制的药物发展战略 两种SS DA-R。在啮齿动物中，纹状体D2的延长阻断 抗真菌药物氟哌啶醇(HAL)引起的DA-R 补偿性上调这些DA-R员额，并导致 对DA激动剂的暂时性行为SS。慢性神经衰弱患者也 导致人类迟发性运动障碍(TD)。然而，TD症状可能会变成 在停用抗精神病药后很长时间内永久保留。 我们解释表面不可逆性的假设是：(1) 补偿DA-R员额SS。DA释放减少；(2)DA-R自动， 抑制DA的合成和释放，也因HAL上调 和不断下降的DA水平；(3)这种DA-R AUTO SS现在 在新的、更低的设定点关闭DA释放，这进一步 进一步增加DA-R AUTO SS；(4)这种恶性循环 在DA释放的恒定(较低)水平上“外”和“内”；(5) 现在，随着DA-R员额的a增加，因为没有办法 增加以进一步减少DA释放；(6)系统保持 永久SS，因为也没有办法增加DA的释放 下调SS DA-R；(7)仅人工(药理) 临时增加DA裂隙的动作可以打破这个循环。 我们的模型是去卵巢(OVX)大鼠暴露于Hal，这是 迅速发展一个永久性的DA SS；对照是非OVX，HAL- 暴露的大鼠，只产生一过性SS。这一模式 永久性DA-R SS的独特之处在于黑质纹状体DA神经元 存活(不同于60HDA病变的SS)和代偿性变化 被跟踪。我们将展示一个永久性的突触前DA的SS- R AUTO先于或至少伴随着DA的永久阶段- 这些研究只模拟了TD的一个方面-- 党卫军的永恒性。但这一方面对理性来说是必不可少的 药物开发。其他模型，例如慢性抗精神病药物- 治疗后的猴子，似乎更接近于许多行为 TD的某些方面(如自发性、解剖学)，但不经济 对我们的研究来说是可行的。 具体目标是：(I)确定 妊娠一过性行为SS-DA激动剂的开发； (Ii)评估发育和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： DA-R结合(B)突触前：(1)DA-R自动SS(抑制， (3)从切片中释放DA)；(2)DA释放(3MT水平；体内 (C)黑质机制：DA-R结合GAD 活动；(Iii)确定是否有逆转 去卵巢大鼠(Cyclo(Leucyl-Glycyl，DA))的永久性行为SS 激动剂)通过逆转相同的神经化学变化来实现这一点(上图) 似乎会导致永久性党卫军。

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.