NEUROTENSIN AND METHAMPHETAMINE EFFECTS

神经降压素（NT）在脑缺血再灌注损伤中起重要作用， 在调节多巴胺（DA）途径;因此，NT拮抗DA的作用 当给药到脑桥核和纹状体时， 从而减弱运动反应（即，运动和 低剂量的兴奋剂滥用，如甲基苯丙胺 （METH）.以一种相互作用的方式，DA释放的增加（例如， METH诱导）深刻地改变了NT活性与多巴胺 和纹状体DA终末，引起NT浓度的相反变化 当DA D-1或D-2受体被刺激时。这些调查结果表明 NT和DA系统之间的复杂相互作用;由于 NT相互作用可能对CNS反应有重要影响 兴奋剂，如METH。因此，本提案的主要目的是 是为了确定内源性NT系统对 各种METH治疗引起的DA活性和运动行为， 阐明这些作用的机制。 本提案的目标将通过确定 拮抗内源性NT活性的后果，无论是 针对NT或非肽NT拮抗剂（SR）产生的选择性抗血清 #36892;的影响。令人惊讶的初步数据表明，NT 系统被激活，并拮抗DA和运动反应，以低（0.5 mg/kg），但是，在高浓度的 （5 mg/kg）剂量的METH。这些研究结果将得到扩展， 已识别的DA系统。其他研究结果表明，NT 参与低剂量METH的反应与增加 由DA D-2受体引起的活性。相比之下， 对高剂量METH的反应被DA D-1和N-甲基-D- 天冬氨酸（NMDA;谷氨酸亚型）受体。这些假设将 得到考验 METH或选择性D1和D2激动剂和拮抗剂的作用， 将通过用微透析测量DA和/或NT释放来确定 将探针或推拉套管植入脑桥核， 新纹状体或脑室。将评价对METH的运动反应 通过Digiscan“Micro”分析仪与训练有素的观察员盲测 到治疗。 更好地了解METH如何影响边缘系统和锥体外系NT 系统，以及它们如何反过来有助于由这一点引起的反应 兴奋剂可能会导致新的治疗急性 以及长期滥用冰毒的问题此外，这些研究将有助于 阐明重要的中脑多巴胺能 调节途径，并可能提出新的治疗方法， 相关的精神和运动障碍。

The neuropeptide, neurotensin (NT), appears to play an important role in regulating dopamine (DA) pathways; thus, NT antagonizes DA effects when administered into the nucleus accumbens and striatum and consequently attenuates the motor responses (i.e., locomotion and rearing) to low doses of stimulants of abuse, like methamphetamine (METH). In a reciprocal manner, increases in DA release (such as that induced by METH) profoundly alter NT activity associated with accumbens and striatal DA terminals, causing opposite changes in NT concentration when DA D-l or D-2 receptors are stimulated. These findings suggest a complex interaction between NT and DA systems; because of that interaction NT may have an important influence on responses to CNS stimulants, such as METH. Thus, the principal objective of this proposal is to identify the effects of endogenous NT systems on the changes in DA activity and motor behavior caused by various METH treatments and to elucidate the mechanisms of these effects. The objectives of this proposal will be achieved by determining the consequences of antagonizing endogenous NT activity, with either a selective antiserum raised against NT or a nonpeptide NT antagonist (SR 48692), on the effects of METH. Surprising initial data suggest that NT systems are activated and antagonize DA and motor responses to low (0.5 mg/kg), but, are shut down and have no effect in the presence of high (5 mg/kg) doses of METH. These findings will be extended and the involved DA systems identified. Other findings suggest that NT involvement in the response to low METH doses relates to increased activity caused by DA D-2 receptors. In contrast, NT systems in the response to high doses of METH are shut down by DA D-l and N-methyl-D- aspartate (NMDA; a glutamate subtype) receptors. These hypotheses will be tested. The effects of METH or selective Dl and D2 agonists and antagonists, will be determined by measuring DA and/or NT release with microdialysis probes or push-pull cannulae implanted into the nucleus accumbens, neostriatum or ventricles. The motor response to METH will be evaluated by a Digiscan "Micro" Analyzer combined with a trained observer blind to the treatment. A better understanding of how METH affects limbic and extrapyramidal NT systems and how they in turn contribute to the response caused by this stimulant may lead to the development of novel therapies for the acute and chronic problems of METH abuse. In addition, these studies will help elucidate the mechanisms whereby important midbrain dopaminergic pathways are regulated and possibly suggest new approaches for treating related psychiatric and motor disorders.