Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, College of Medicine, Rochester, MN 55905, USA.
Pharmacol Biochem Behav. 2010 Apr;95(2):235-41. doi: 10.1016/j.pbb.2010.01.012. Epub 2010 Feb 1.
Neurotensin receptor type 1 (NTS1) is known to mediate a variety of biological functions of neurotensin (NT) in the central nervous system. In this study, we found that NTS1 null mice displayed decreased sensitivity to the ataxic effect of ethanol on the rotarod and increased ethanol consumption when given a free choice between ethanol and tap water containing bottles. Interestingly, the administration of NT69L, a brain-permeable NT analog, increased ethanol sensitivity in wild-type littermates but had no such effect in NTS1 null mice, suggesting that NTS1 contributes to NT-mediated ethanol intoxication. Furthermore, the daily treatment of NT69L, for 4 consecutive days, significantly reduced alcohol preference and consumption in wild-type littermates but had no such effects in NTS1 null mice in a two-bottle drinking experiment. Our study provides evidence for possible pharmacological roles of NT69L in which it increases sensitivity to the ataxic effect, and decreases voluntary consumption, of ethanol. Our study also demonstrates NTS1-mediated behavioral effects of NT69L. Therefore, our findings will be useful for understanding some aspects of alcoholism as well as to develop novel pharmacological therapeutic options for humans.
神经降压素受体 1（NTS1）已知在中枢神经系统中介导神经降压素（NT）的多种生物学功能。在这项研究中，我们发现 NTS1 敲除小鼠在旋转棒上对乙醇引起的共济失调效应的敏感性降低，并且在自由选择乙醇和含有瓶子的自来水之间时，乙醇消耗量增加。有趣的是，脑渗透性 NT 类似物 NT69L 的给药增加了野生型同窝仔鼠对乙醇的敏感性，但在 NTS1 敲除小鼠中没有这种作用，表明 NTS1 有助于 NT 介导的乙醇中毒。此外，在为期 4 天的每天 NT69L 处理后，在双瓶饮酒实验中，野生型同窝仔鼠的酒精偏好和消耗量显著降低，但在 NTS1 敲除小鼠中没有这种作用。我们的研究为 NT69L 的可能药理学作用提供了证据，即它增加了对乙醇引起的共济失调效应的敏感性，并减少了自愿消耗。我们的研究还证明了 NT69L 对 NTS1 的行为作用。因此，我们的发现将有助于理解酒精中毒的某些方面，并为人类开发新的药理学治疗选择。
