Wagstaff J D, Gibb J W, Hanson G R
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, USA.
J Pharmacol Exp Ther. 1996 Aug;278(2):547-54.
Stimulants of abuse such as cocaine and methamphetamine (METH) have dramatic effects on tissue neurotensin (NT) levels in the striatum and nucleus accumbens. Presumably these effects are due to the ability of such drugs to increase dopamine transmission. Because changes in dopamine activity appear to influence NT systems, we examined the effects of increasing doses of METH on extracellular NT levels in the medial striatum and nucleus accumbens using in vivo microdialysis in conscious rats. At the lowest dose tested (0.5 mg/kg), METH almost doubled the extracellular concentration of NT in both regions. When the dose of METH was increased to 5.0 mg/kg, extracellular NT concentration was elevated, but only to approximately 150% of control. At the highest dose examined (15.0 mg/kg), extracellular NT was not altered compared to pretreatment control levels. The role of DA D-1 and D-2 receptors in mediating these effects was determined by combining specific antagonists with the low dose of METH. The D-1 antagonist SCH 23390 blocked the METH-induced increase in extracellular NT levels in the striatum, but not in the nucleus accumbens. Pretreatment with the D-2 antagonist, eticlopride, blocked the increase in extracellular NT in both regions. Changes in striatal NT extracellular levels after a single METH injection were compared to the alterations in tissue NT levels following multiple administrations of the same doses of METH. Tissue levels were significantly elevated with 5 or 15 mg/kg METH in the medial, but not the lateral, striatum. There was not a clear correlation observed between the METH effects on striatal NT tissue levels and extracellular NT concentration.
可卡因和甲基苯丙胺（METH）等滥用兴奋剂对纹状体和伏隔核中的组织神经降压素（NT）水平有显著影响。据推测，这些影响是由于此类药物增加多巴胺传递的能力所致。由于多巴胺活性的变化似乎会影响NT系统，我们使用清醒大鼠体内微透析技术，研究了递增剂量的METH对内侧纹状体和伏隔核细胞外NT水平的影响。在测试的最低剂量（0.5mg/kg）下，METH使两个区域的NT细胞外浓度几乎增加了一倍。当METH剂量增加到(5.0mg/kg)时，细胞外NT浓度升高，但仅达到对照的约(150%)。在检查的最高剂量（(15.0mg/kg)）下，与预处理对照水平相比，细胞外NT没有改变。通过将特异性拮抗剂与低剂量的METH联合使用，确定了DA D-1和D-2受体在介导这些作用中的作用。D-1拮抗剂SCH 23390阻断了METH诱导的纹状体中细胞外NT水平的升高，但未阻断伏隔核中的升高。用D-2拮抗剂依替必利预处理可阻断两个区域细胞外NT的升高。将单次注射METH后纹状体NT细胞外水平的变化与多次给予相同剂量METH后组织NT水平的变化进行了比较。内侧纹状体中，(5)或(15mg/kg)的METH可使组织水平显著升高，但外侧纹状体则不然。未观察到METH对纹状体NT组织水平和细胞外NT浓度的影响之间存在明显的相关性。
