NEUROTENSIN AND METHAMPHETAMINE EFFECTS

描述：(申请人摘要) 与滥用甲基苯丙胺(冰毒)有关的问题有所增加 由于不断升级的非法使用，它在美国戏剧性地出现了。为了澄清 对这种药物的反应，并可能发现新的治疗方法 处理这些问题的策略，之间的关系 锥体外区神经肽系统及其强效刺激剂的作用 已被研究过。据观察，低剂量的冰毒(0.5毫克/公斤) 选择性影响尾状背外侧核的神经降压素(NT)系统 通过激活多巴胺D-2受体。相比之下，高剂量的冰毒 (10-15毫克/公斤)选择性改变与 通过激活多巴胺D-1受体激活内侧/腹侧尾状核。因为D-2 和D-1多巴胺受体选择性地在 纹状体-苍白球神经元和纹状体-黑质神经元，这些发现 导致假设低剂量和高剂量冰毒优先 影响间接(纹状体-苍白球)和直接(纹状体-黑质) 分别向基底节输出核的传出通路。这 将通过实现以下具体目标来检验假设： A.确定低剂量的冰毒是否优先改变脑组织的活性 通往苍白球的间接纹状体传出通路。这个 效果 相关发射机系统上的低剂量冰毒(即，NT， 甲硫氨酸脑啡肽[M-Enk]和GABA)将通过测量 药物诱发 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)，以及(C)体内释放(NT， M-Enk 和GABA)。D-2受体在这些效应中的作用将是 已澄清。 B.确定大剂量冰毒是否优先改变直接纹状体 向黑质的传出投射。HIGH的影响 剂量 相关发射器系统上的冰毒(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)。这个 角色 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该效应中的作用 将研究从具体目标A和B中确定的目标。 这些研究可能有助于更好地理解这些生物的神经生物学。 针对与滥用冰毒有关的问题的系统和改进的治疗方法 以及锥体外系/边缘功能障碍。

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.