CHRONIC DRUGS: C N S BIOCHEMISTRY AND BEHAVIOR

人类长期服用苯丙胺(Amph)会导致 对药物所产生的情绪提升的耐受性，但可能导致 对其精神特性的敏感化。同样，慢性病 给大鼠注射安非他明可产生定性的行为特征 根据受监视的行为进行更改。的某些组件 行为反应表现出耐受性，而其他组件表现出 增强(反向容差)。后者可以进一步分离 至少分成三个不同的部分。尽管多巴胺(DA)似乎 在AMPH的所有急性行为效应中起着关键作用 多巴胺能生化与安非他明的慢性效应相关 已被确认身份。这些观察结果，加上明显的差异 在文献中，AMPH的假定作用机制和 药物的生化和电生理后果，表明 DA在AMPH诱导的行为改变中的作用需要重新评估。 由于神经传递的动态性质，这样的重新评估 应在清醒的、自由活动的动物中进行，并应考虑 与DA神经传递最相关的参数，即 到达突触间隙的递质及其功能后果 突触后功能的递质-受体相互作用。最后，一个 重新评估应考虑替代神经化学底物 AMPH的作用，我们最近的数据表明这可能是5-羟色胺(5-羟色胺)。 拟议的研究首先是有针对性的，重新评估 AMPH对纹状体多巴胺能和5-羟色胺能突触前和 突触后功能；第二，确定Amph-DA和Amph-DA的作用(S) AMPH-5HT相互作用在急、慢性行为后果中的作用 AMPH管理。这些目标将通过以下方式实现：(1)直接 通过推-拉法评估细胞外DA水平对AMPH的响应 纹状体灌注术，作为获得新的 AMPH与多巴胺能相互作用机制的研究进展 系统；(2)共同评估灌流液中的5-羟色胺水平，以允许描绘 Amph与神经递质相互作用的程度；(3)评估 纹状体胆碱能反应作为一种直接的生理指标 多巴胺和5-羟色胺功能改变对突触后的影响；及 量化相同动物的行为反应，以建立 安非他明给药的最准确的生化行为相关性。

The chronic administration of amphetamine (AMPH) to humans results in tolerance to the mood elevation produced by the drug, but can result in sensitization to its psychotic properties. Similarly, the chronic administration of AMPH to rats produces qualitatively distinct behavioral changes depending on the behavior which is monitored. Some components of the behavioral response exhibit tolerance, whereas other components exhibit augmentation (reverse tolerance). The latter can be further dissociated into at least three distinct components. Although dopamine (DA) appears to play a crucial role in all of the acute behavioral effects of AMPH, a dopaminergic biochemical correlate to the chronic effects of AMPH has not been identified. These observations, coupled with apparent discrepancies in the literature between the presumed mechanisms of action of AMPH and the biochemical and electrophysiological consequences of the drug, suggest that the role of DA in AMPH-induced behavioral changes requires reevaluation. Because of the dynamic nature of neurotransmission, such a reevaluation should be performed in the awake, freely-moving animal, and should consider those parameters most relevant to DA neurotransmission, i.e., the amount of transmitter reaching the synaptic cleft, and the functional consequences of transmitter-receptor interactions for post-synaptic function. Finally, a reevaluation should consider alternative neurochemical substrates for AMPH's action, which our recent data suggest may be serotonin (5HT). The proposed research is directed at first, reevaluating consequences of AMPH for striatal dopaminergic and serotonergic presynaptic and postsynaptic function, and second, defining the role(s) of the AMPH-DA and AMPH-5HT interactions in the behavioral consequences of acute and chronic AMPH administration. These objectives will be achieved by: (1) directly evaluating extracellular DA levels in response to AMPH, through push-pull perfusion of the striatum, as the most appropriate approach to gain new insights into the mechanism of interaction of AMPH with dopaminergic systems; (2) coevaluating 5HT levels in perfusate to allow a delineation of the degree to which AMPH can interact with neurotransmitter; (3) evaluating the striatal cholinergic response to AMPH as a direct physiological measure of the postsynaptic consequences of changes in DA and 5HT function; and (4) quantitating the behavioral response in the same animals to establish the most accurate biochemical-behavioral correlates of AMPH administration.