NEUROTENSIN AND METHAMPHETAMINE EFFECTS

神经肽，神经降压素(NT)，似乎扮演着重要的角色 调节多巴胺(DA)途径；因此，NT拮抗DA效应 当注射到伏隔核和纹状体时， 因此减弱了马达响应(即，运动和 养育)低剂量的滥用兴奋剂，如甲基苯丙胺 (冰毒)。以一种对等的方式，DA释放的增加(如 冰毒诱导)深刻改变与伏隔相关的NT活性 和纹状体DA终末，引起NT浓度的相反变化 当刺激DA、D-L或D-2受体时。这些发现表明， NT和DA系统之间的复杂相互作用；因此 相互作用NT可能对中枢神经系统的反应有重要影响 兴奋剂，如冰毒。因此，这项提案的主要目标是 就是确定内源性NT系统对 不同冰毒治疗引起的DA活动和运动行为 阐明这些影响的机制。 这项提案的目标将通过确定 拮抗内源性NT活性的后果， 针对NT或非肽NT拮抗剂(SR)制备的选择性抗血清 48692)，关于冰毒的影响。令人惊讶的初步数据表明，NT 系统被激活，并对抗DA和运动对LOW(0.5)的反应 Mg/kg)，但在存在高电平的情况下关闭，并且不起作用 (5毫克/公斤)冰毒剂量。这些调查结果将得到扩展， 已确定涉及DA系统。其他研究结果表明，NT 参与对低剂量冰毒的反应与增加 由多巴胺D-2受体引起的活动。相比之下，NT系统在 对高剂量冰毒的反应被DA、D-L和N-甲基-D-D-关闭 天冬氨酸(NMDA；谷氨酸亚型)受体。这些假设将 接受测试。 冰毒或选择性的DL和D2激动剂和拮抗剂的作用， 将通过用微透析法测量DA和/或NT释放来确定 将探头或推拉管植入伏隔核， 新纹状体或脑室。将对冰毒的运动反应进行评估 由Digiscan“Micro”分析仪和受过训练的盲人观察者相结合 为治疗干杯。 更好地了解冰毒如何影响边缘和锥体外区NT 系统以及它们如何反过来对由此引起的响应做出贡献 兴奋剂可能会导致急性白血病的新疗法的发展 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 通路是受调控的，可能会为治疗提供新的方法 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.