CHRONIC DRUGS: C N S BIOCHEMISTRY AND BEHAVIOR

对人类长期施用安非他明（AMPH）导致 对药物产生的情绪升高的耐受性，但可能导致 对它的精神病特性敏感。 同样，慢性 对大鼠施用AMPH产生定性上不同的行为 取决于被监视的行为而改变。 的一些部件 行为反应表现出耐受性，而其他成分表现出 反向公差（reverse tolerance） 后者可以进一步分离 至少分成三个不同的部分 虽然多巴胺（DA）似乎 在AMPH的所有急性行为效应中起着至关重要的作用， 与AMPH慢性效应相关的多巴胺能生物化学 被识别。 这些观察，加上明显的差异， 在文献中，AMPH的假定作用机制与 药物的生物化学和电生理学后果表明， 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特性， 应在清醒、自由移动的动物中进行，并应考虑 与DA神经传递最相关的那些参数，即，的量 传递到达突触间隙，和功能的后果， 突触后功能的递质-受体相互作用。 最后 重新评估应考虑替代的神经化学底物， AMPH的作用，我们最近的数据表明可能是5羟色胺（5 HT）。 拟议的研究是针对首先，重新评估的后果， AMPH用于纹状体多巴胺能和多巴胺能突触前， 第二，定义AMPH-DA的作用， AMPH-5 HT在急性和慢性脑缺血行为后果中的相互作用 AMPH给药。 这些目标将通过以下方式实现：（1）直接 评估细胞外DA水平对AMPH的反应，通过推拉 纹状体的灌注，作为获得新的 AMPH与多巴胺能神经元相互作用的机制 系统;（2）共同评估灌注液中的5 HT水平，以描绘 AMPH与神经递质相互作用的程度;（3）评估AMPH与神经递质相互作用的程度 纹状体对AMPH胆碱能反应作为一种直接的生理测量 DA和5 HT功能变化的突触后后果;和（4） 对相同动物的行为反应进行定量， 最准确的生物化学行为相关的AMPH管理。

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.