NEUROTENSIN AND METHAMPHETAMINE EFFECTS

描述：（申请人摘要） 与甲基安非他明（METH）滥用有关的问题有所增加 在美国，由于其非法使用的不断升级， 阐明 对这种药物的反应，并可能确定新的治疗 处理这些问题的战略， 锥体外系神经肽系统和这种强效兴奋剂的作用 本文研究了 观察到低剂量的METH（0.5mg/kg） 选择性影响尾状核背外侧的神经降压素（NT）系统 通过激活多巴胺D-2受体。 相比之下，高剂量的甲基苯丙胺 （10-15 mg/kg）选择性改变了与 通过激活多巴胺D-1受体来激活内侧/腹侧尾状核。 因为D-2 和D-1多巴胺受体选择性地表达于 纹状体苍白球和纹状体黑质神经元，分别，这些结果 导致了一种假设，即低剂量和高剂量的甲基， 间接影响（纹状体-苍白球）和直接影响（纹状体-黑质） 传出通路的基底神经节输出核，分别。 这 将通过实现以下具体目标来检验假设： A.确定低剂量的METH是否优先改变 间接纹状体传出途径苍白球。 的 影响 相关发射器系统上的低剂量METH（即，NT， 甲硫氨酸脑啡肽[M-enk]和GABA）将通过测量 药物性 神经递质的变化（a）组织含量（NT和M-enk），（B） 前体mRNA水平（NT和M-enk），和（c）体内释放（NT， M-enk GABA）。 D-2受体在这些效应中的作用将是 阐明。 B。确定高剂量的METH是否优先改变直接纹状体 向黑质的传出投射。 高的影响 剂量 相关发射机系统上的METH（即，NT，P物质[SP] 和GABA）将通过测量药物诱导的 神经递质（a）组织含量（NT和SP），（B）前体mRNA 水平（NT和SP），和（c）体内释放（NT、SP和GABA）。 的 作用 D-1受体在这些作用中的作用将被阐明。 此外，纹状体胆碱能中间神经元在这种效应中的作用 将研究从特定目的A和B中确定的药物。 这些研究可能会导致更好地了解这些神经生物学。 系统和改进的治疗方法，以解决与甲基苯丙胺滥用有关的问题， 以及锥体外系/边缘系统功能障碍。

DESCRIPTION: (Applicant's Abstract) Problems associated with methamphetamine (METH) abuse have increased dramatically in the U.S. due to its escalating illicit use. To elucidate the responses to this drug and possibly identify novel therapeutic strategies for dealing with these problems, the relationship between extrapyramidal neuropeptide systems and the effects of this potent stimulant has been studied. It was observed that a low dose of METH (0.5 mg/kg) selectively influenced neurotensin (NT) systems in the dorsolateral caudate by activating dopamine D-2 receptors. In contrast, high doses of METH (10-15 mg/kg) selectively altered NT systems associated with the medial/ventral caudate by activating dopamine D-1 receptors. Because D-2 and D-1 dopamine receptors are selectively expressed in the striatal-pallidal and striatal-nigral neurons, respectively, these findings led to the hypothesis that low and high doses of METH preferentially influence the indirect (striatal-pallidal) and direct (striatal-nigral) efferent pathways to the basal ganglia output nuclei, respectively. This hypothesis will be tested by achieving the following Specific Aims: A. Determine if low doses of METH preferentially alter the activity of the indirect striatal efferent pathway to the globus pallidus. The effects of low doses of METH on associated transmitter systems (i.e., NT, met-enkephalin [M-enk] and GABA) will be monitored by measuring drug-induced changes in neurotransmitter (a) tissue content (NT and M-enk), (b) precursor mRNA levels (NT and M-enk), and (c) in vivo release (NT, M-enk and GABA). The role of the D-2 receptor in these effects will be elucidated. B. Determine if high doses of METH preferentially alter the direct striatal efferent projection to the substantia nigra. The effects of high doses of METH on associated transmitter systems (i.e., NT, substance P [SP] and GABA) will be monitored by measuring drug-induced changes in neurotransmitter (a) tissue content (NT and SP), (b) precursor mRNA levels (NT and SP), and (c) in vivo release (NT, SP and GABA). The role of the D-1 receptor in these effects will be elucidated. In addition, the role of striatal cholinergic interneurons in the effects identified from Specific Aims A and B will be studied. These studies may lead to a better appreciation of the neurobiology of these systems and improved therapies for problems associated with METH abuse as well as extrapyramidal/limbic dysfunctions.