CNS LESIONS EFFECTS ON DRUG ACTION

描述：(申请人摘要) 我们之前的研究，使用了兔的经典条件反射 瞬膜反应表明，两者联合 学习和运动能力在很大程度上取决于正常 下橄榄核的活动。在古典音乐中学习 条件反射涉及一种精确的计时机制，由其 对刺激间隔的时间参数非常敏感。我们的 研究和其他人的研究表明，同步的振荡活动 橄榄核神经元可能提供这种计时机制。此外，5羟色胺 (5-羟色胺)已被证明调节心脏节律性活动。 下橄榄核，并测定学习速度和其 运动表情。这两种作用都是由5-HT2a介导的 受体。因此，我们假设5-羟色胺激动剂和拮抗剂可以 提高或降低学习速度和运动的最佳水平 通过作用于位于橄榄核神经元上的5-HT2A受体而发挥作用 增强橄榄协调神经网络的能力 决定着学习的效率及其运动表达。实验 将实施以产生一般或特定的5-羟色胺去神经作用 目的：评价突触前5-羟色胺释放在大鼠脑内5-羟色胺获得中的作用。 学习和运动能力。全身和脑内注射 5-HT2A激动剂和拮抗剂将使我们能够识别关键部位 在这个时候可以恢复正常的功能。其他实验将检验 5-羟色胺直接作用于致颤剂的机制 劣质橄榄损害了学习和表现。最后，我们会 检测一些5-HT2A拮抗剂是否具有延缓学习的能力 而运动功能是由于它们作为反向激动剂的作用。这些 实验将提供有关橄榄小脑作用的线索。 在学习和运动能力方面的系统，以及可能在治疗 学习和运动功能障碍。例如，5-羟色胺已经被 牵涉到特发性震颤和5-HT2A受体的阻断 已被证明足以用于抗精神病作用。

DESCRIPTION: (Applicant's Abstract) Our previous research, employing classical conditioning of the rabbit's nictitating membrane response has demonstrated that both associative learning and motor performance are critically dependent on the normal activity of the inferior olivary nucleus. Learning during classical conditioning involves a precise timing mechanism as indicated by its exquisite sensitivity to the temporal parameters of stimulus interval. Our work and that of others suggest that the synchronized oscillatory activity of olivary neurons may provide this timing mechanism. Moreover, serotonin (5-HT) has been demonstrated to regulate the rhythmic activity of the inferior olivary nucleus and also to determine the rate of learning and its motor expression. Both of these actions are mediated by the 5-HT2A receptor. Thus, we have hypothesize that 5-HT agonists and antagonists can increase or decrease the rate of learning and optimum level of motor function by acting at 5-HT2A receptors located on olivary neurons so as to enhance the ability of the olive to coordinate a neural network that determines the efficiency of learning and its motor expression. Experiments will be carried out to produce general or specific 5-HT denervations in order to assess the role of presynaptic 5-HT release on the acquisition of learning and motor performance. Systemic and intracerebral injections of 5-HT2A agonists and antagonists will allow us to identify the critical sites at which normal function can be restored. Other experiments will examine the 5-Ht mechanisms through which tremorogenic agents that act directly on the inferior olive impair learning and performance. Finally, we will examine whether the ability of some 5-HT2A antagonists to retard learning and motor function is due to their actions as inverse agonists. These experiments will provide clues concerning the role of the olivocerebellar system in learning and motor performance and possibly in the treatment of dysfunctions in learning and motor function. For example, 5-HT has been implicated in essential tremor and 5-HT2A receptor blockade has been demonstrated to be sufficient for antipsychotic action.