Vadnie Chelsea A, Hinton David J, Choi Sun, Choi YuBin, Ruby Christina L, Oliveros Alfredo, Prieto Miguel L, Park Jun Hyun, Choi Doo-Sup
Neurobiology of Disease Program, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Neuropharmacology. 2014 Oct;85:482-92. doi: 10.1016/j.neuropharm.2014.05.046. Epub 2014 Jun 11.
Intracerebroventricular administration of neurotensin (NT) suppresses locomotor activity. However, the brain regions that mediate the locomotor depressant effect of NT and receptor subtype-specific mechanisms involved are unclear. Using a brain-penetrating, selective NT receptor type 1 (NTS1) agonist PD149163, we investigated the effect of systemic and brain region-specific NTS1 activation on locomotor activity. Systemic administration of PD149163 attenuated the locomotor activity of C57BL/6J mice both in a novel environment and in their homecage. However, mice developed tolerance to the hypolocomotor effect of PD149163 (0.1 mg/kg, i.p.). Since NTS1 is known to modulate dopaminergic signaling, we examined whether PD149163 blocks dopamine receptor-mediated hyperactivity. Pretreatment with PD149163 (0.1 or 0.05 mg/kg, i.p.) inhibited D2R agonist bromocriptine (8 mg/kg, i.p.)-mediated hyperactivity. D1R agonist SKF-81297 (8 mg/kg, i.p.)-induced hyperlocomotion was only inhibited by 0.1 mg/kg of PD149163. Since the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) have been implicated in the behavioral effects of NT, we examined whether microinjection of PD149163 into these regions reduces locomotion. Microinjection of PD149163 (2 pmol) into the NAc, but not the mPFC suppressed locomotor activity. In summary, our results indicate that systemic and intra-NAc activation of NTS1 is sufficient to reduce locomotion and NTS1 activation inhibits D2R-mediated hyperactivity. Our study will be helpful to identify pharmacological factors and a possible therapeutic window for NTS1-targeted therapies for movement disorders.
脑室内注射神经降压素（NT）可抑制运动活性。然而，介导NT运动抑制作用的脑区以及所涉及的受体亚型特异性机制尚不清楚。我们使用一种可穿透大脑的、选择性1型NT受体（NTS1）激动剂PD149163，研究了全身及脑区特异性NTS1激活对运动活性的影响。腹腔注射PD149163可减弱C57BL/6J小鼠在新环境和其笼内的运动活性。然而，小鼠对PD149163（0.1 mg/kg，腹腔注射）的低运动效应产生了耐受性。由于已知NTS1可调节多巴胺能信号传导，我们研究了PD149163是否会阻断多巴胺受体介导的多动。用PD149163（0.1或0.05 mg/kg，腹腔注射）预处理可抑制D2R激动剂溴隐亭（8 mg/kg，腹腔注射）介导的多动。D1R激动剂SKF-81297（8 mg/kg，腹腔注射）诱导的运动亢进仅被0.1 mg/kg的PD149163抑制。由于伏隔核（NAc）和内侧前额叶皮质（mPFC）与NT的行为效应有关，我们研究了向这些区域微量注射PD149163是否会降低运动。向NAc而非mPFC微量注射PD149163（2 pmol）可抑制运动活性。总之，我们的结果表明，全身及NAc内NTS1的激活足以降低运动，且NTS1的激活可抑制D2R介导的多动。我们的研究将有助于确定针对运动障碍的NTS1靶向治疗的药理学因素和可能的治疗窗口。
