Division of Pharmacology and Toxicology, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E, P.O. Box 56, 00014 Helsinki, Finland.
Neurochem Res. 2012 Sep;37(9):2033-41. doi: 10.1007/s11064-012-0825-y. Epub 2012 Jun 23.
Prolyl oligopeptidase (PREP) is an intracellular enzyme digesting small proline-containing peptides. Since PREP resides the same brain areas as neurotensin in the nigrostriatal and mesolimbic dopaminergic pathways, we were interested to study if there is an intracellular interaction between them. A colocalization of PREP with neurotensin and neurotensin receptor 1 (NTS1) in the rat striatum, nucleus accumbens (NAcc), substantia nigra (SN) and ventral tegmental area (VTA) was studied with immunofluorescence. From the same brain areas, the levels of dopamine and its metabolites were measured 1 h after the injection of saline, NTS1 ligands (JMV-449; 5 μg) or antagonist (SR142948; 5 μg) to the rat striatum or NAcc. We also studied whether an intraperitoneal injection of a PREP inhibitor (KYP-2047; 5 mg/kg) affects the levels of dopamine and its metabolites alone or modifies the effects of the NTS1 ligands. PREP was highly colocalized with neurotensin and NTS1 in the VTA, and with NTS1 in the SN. Colocalization was moderate or low in other brain areas. When injected to the striatum, JMV-449 had a tendency to increase dopamine (p = 0.052) and metabolite levels in the striatum and SN, whereas SR142948 did not. After the injection to the NAcc, JMV-449 but not SR142948, increased dopamine levels in the VTA and dopamine metabolite levels in the NAcc and VTA. KYP-2047 decreased the dopamine levels in the striatum, but increased dopamine metabolite levels in the NAcc and VTA. Our results suggest a novel role for PREP in the modulation of dopaminergic transmission, which may be different in nigrostriatal and mesolimbic pathways.
脯氨酰寡肽酶（PREP）是一种细胞内酶，可消化含有脯氨酸的小肽。由于 PREP 与神经降压素存在于黑质纹状体和中脑边缘多巴胺能通路的相同脑区，我们有兴趣研究它们之间是否存在细胞内相互作用。使用免疫荧光法研究了 PREP 与神经降压素和神经降压素受体 1（NTS1）在大鼠纹状体、伏隔核（NAcc）、黑质（SN）和腹侧被盖区（VTA）中的共定位。从相同的脑区，在向大鼠纹状体或 NAcc 注射盐水、NTS1 配体（JMV-449；5μg）或拮抗剂（SR142948；5μg）1 小时后测量多巴胺及其代谢物的水平。我们还研究了 PREP 抑制剂（KYP-2047；5mg/kg）的腹腔内注射是否单独影响多巴胺及其代谢物的水平，或者是否改变 NTS1 配体的作用。PREP 与 VTA 中的神经降压素和 NTS1 高度共定位，与 SN 中的 NTS1 中度或低度共定位。当注射到纹状体时，JMV-449 有增加纹状体和 SN 中多巴胺（p=0.052）及其代谢物水平的趋势，而 SR142948 则没有。向 NAcc 注射后，JMV-449 但不是 SR142948 增加了 VTA 中的多巴胺水平和 NAcc 和 VTA 中的多巴胺代谢物水平。KYP-2047 降低了纹状体中的多巴胺水平，但增加了 NAcc 和 VTA 中的多巴胺代谢物水平。我们的结果表明 PREP 在调节多巴胺能传递中发挥了新的作用，这种作用在黑质纹状体和中脑边缘多巴胺能通路中可能不同。
