Neuropsychopharmacology Laboratory, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
Neuropeptides. 2011 Feb;45(1):9-16. doi: 10.1016/j.npep.2010.09.003. Epub 2010 Nov 2.
NT69L is a neurotensin analog that blocks nicotine-induced locomotor activity and has sustained efficacy in a rat model of nicotine-induced sensitization when administered peripherally. Additionally, NT69L attenuates food-reinforcement in rats. The present study tested the effect of acute administration of NT69L on nicotine self-infusion in Sprague-Dawley rats. Rats were trained to self-infuse nicotine intravenously (0.03mg/kg per infusion) following operant training. Once the rats acquired stable responding to nicotine self-infusion they were pretreated with NT69L (1mg/kg, i.p.) or saline 30min before being assessed for nicotine self-infusion. Pretreatment with NT69L significantly attenuated nicotine self-infusion under FR1 (fixed ratio of 1) and FR5 schedule of reinforcement as compared to saline pretreatment. Control rats that were response-independent "yoked" as well as rats that self-infused saline or NT69L showed minimal responses, indicating that nicotine served as a reinforcer. Additionally, NT69L modulated serum corticosterone; brain norepinephrine serotonin; and dopamine receptors mRNA levels altered in the nicotine self-infused rats after a 24h withdrawal period. Pretreatment with NT69L significantly decreased the nicotine-induced increase in serum corticosterone levels and striatal norepinephrine and increased the nicotine-induced reduction in serotonin in both the striatum and the prefrontal cortex (PFC). NT69L might modulate dopamine neurotransmission implicated in the reinforcing effects of nicotine by modulating tyrosine hydroxylase and dopamine receptor mRNA levels in the PFC and striatum. These data support further study of the effects of NT analogs on attenuating the reinforcing effects of psychostimulants.
NT69L 是一种神经降压素类似物，可阻断尼古丁引起的运动活动，并在外周给予时在尼古丁引起的敏化的大鼠模型中具有持续疗效。此外，NT69L 可减弱大鼠的食物强化作用。本研究测试了急性给予 NT69L 对 Sprague-Dawley 大鼠尼古丁自我输注的影响。大鼠经过操作性训练后，接受静脉内（每次输注 0.03mg/kg）自我输注尼古丁的训练。一旦大鼠获得对尼古丁自我输注的稳定反应，他们在接受尼古丁自我输注评估之前，预先给予 NT69L（1mg/kg，ip）或盐水。与盐水预处理相比，NT69L 预处理显着减弱了 FR1（固定比率 1）和 FR5 强化方案下的尼古丁自我输注。作为对照，非应答性“偶联”的大鼠以及自我输注盐水或 NT69L 的大鼠表现出最小的反应，表明尼古丁作为一种强化物。此外，NT69L 调节了血清皮质酮；脑去甲肾上腺素、血清素和多巴胺受体 mRNA 水平在 24 小时戒断期后在尼古丁自我输注大鼠中发生改变。NT69L 预处理显着降低了血清皮质酮水平升高、纹状体去甲肾上腺素增加和纹状体和前额叶皮质（PFC）中血清素减少，这是由尼古丁引起的。NT69L 可能通过调节 PFC 和纹状体中的酪氨酸羟化酶和多巴胺受体 mRNA 水平来调节多巴胺神经传递，从而调节尼古丁的强化作用。这些数据支持进一步研究 NT 类似物对减弱精神兴奋剂的强化作用的影响。
