Karl Tim, Hoffmann Torsten, Pabst Reinhard, von Hörsten Stephan
Department of Functional and Applied Anatomy, Hannover Medical School, Germany.
Pharmacol Biochem Behav. 2003 Jul;75(4):869-79. doi: 10.1016/s0091-3057(03)00154-0.
Dipeptidyl-peptidase IV (DPPIV/CD26) is involved in several physiological functions by cleavage of dipeptides with a Xaa-Pro or Xaa-Ala sequence of regulatory peptides such as neuropeptide Y (NPY). Cleavage of NPY by DPPIV results in NPY(3-36), which lacks affinity for the Y(1) but not for other NPY receptor subtypes. Among other effects, the NPY Y(1) receptor mediates anxiolytic-like effects of NPY. In previous studies with F344 rat substrains lacking endogenous DPPIV-like activity we found a reduced behavioral stress response, which might be due to a differential degradation of NPY. Here we tested this hypothesis and administered intracerebroventricularly two different doses of NPY (0.0, 0.2, 1.0 nmol) in mutant and wildtype-like F344 substrains. NPY dose-dependently stimulated food intake and feeding motivation, decreased motor activity in the plus maze and social interaction test, and exerted anxiolytic-like effects. More important for the present hypothesis, NPY administration was found to be more potent in the DPPIV-negative substrains in exerting anxiolytic-like effects (increased social interaction time in the social interaction test) and sedative-like effects (decreased motor activity in the elevated plus maze). These data demonstrate for the first time a differential potency of NPY in DPPIV-deficient rats and suggest a changed receptor-specificity of NPY, which may result from a differential degradation of NPY in this genetic model of DPPIV deficiency. Overall, these results provide direct evidence that NPY-mediated effects in the central nervous system are modulated by DPPIV-like enzymatic activity.
二肽基肽酶IV（DPPIV/CD26）通过切割具有Xaa-Pro或Xaa-Ala序列的调节肽（如神经肽Y（NPY））中的二肽，参与多种生理功能。DPPIV切割NPY会产生NPY(3 - 36)，其对Y(1)受体缺乏亲和力，但对其他NPY受体亚型具有亲和力。在其他作用中，NPY Y(1)受体介导NPY的抗焦虑样作用。在先前对缺乏内源性DPPIV样活性的F344大鼠亚系的研究中，我们发现行为应激反应降低，这可能是由于NPY的降解差异所致。在此，我们对这一假设进行了测试，向突变型和野生型样F344亚系脑室内注射两种不同剂量的NPY（0.0、0.2、1.0 nmol）。NPY剂量依赖性地刺激食物摄入和进食动机，在十字迷宫和社交互动测试中降低运动活动，并发挥抗焦虑样作用。对当前假设更重要的是，发现NPY给药在DPPIV阴性亚系中发挥抗焦虑样作用（社交互动测试中社交互动时间增加）和镇静样作用（高架十字迷宫中运动活动减少）方面更有效。这些数据首次证明了NPY在DPPIV缺陷大鼠中的效力差异，并表明NPY的受体特异性发生了变化，这可能是由于在这种DPPIV缺陷的遗传模型中NPY的降解差异所致。总体而言，这些结果提供了直接证据，表明中枢神经系统中NPY介导的作用受DPPIV样酶活性的调节。
