Minneapolis Medical Research Foundation, 914 S 8th Street, Minneapolis, MN 55404, USA.
Psychopharmacology (Berl). 2010 Apr;209(2):203-12. doi: 10.1007/s00213-010-1792-0. Epub 2010 Feb 24.
The hypocretin (hcrt) system has been implicated in addiction-relevant effects of several drugs, but its role in nicotine dependence has been little studied.
These experiments examined the role of the hcrt system in nicotine reinforcement.
Rats were trained for nicotine self-administration (NSA) on fixed-ratio schedules. The effects of acute, presession treatments with the hcrtR1 antagonist SB334867 and the hcrtR1/2 antagonist almorexant were examined on NSA maintained on a fixed-ratio (FR) 5 schedule. Gene expression for the hcrt system (mRNA for hcrt, hcrtR1, and hcrtR2) was measured in animals following NSA on a FR 1 schedule for a 19-day period.
The hcrtR1 antagonist SB334867 and the hcrtR1/2 antagonist almorexant both reduced NSA dose-dependently (significantly at doses of 30 and 300 mg/kg, respectively); SB334867 did not affect food-maintained responding whereas almorexant (at the 300 mg/kg) did. Tissue from animals collected 5 h after self-administration showed an increase in hcrtR1 mRNA in the arcuate nucleus compared to control subjects. In tissue collected immediately after a similar 19-day self-administration period, mRNA for hcrtR1 was decreased in the rostral lateral hypothalamus compared to controls.
These data confirm a previous report (Hollander et al., Proc Natl Acad Sci U S A 105:19480-19485, 2008) that the hypocretin receptor hcrtR1 is activated in nicotine reinforcement and in addition show that both the arcuate nucleus and lateral hypothalamus are sites at which hcrt receptor mechanisms may influence reinforcement. Different patterns of mRNA expression at different times after NSA suggest that changes in the hcrt system may be labile with time.
下丘脑泌素（hcrt）系统与几种药物的成瘾相关效应有关，但它在尼古丁依赖中的作用研究甚少。
这些实验研究了 hcrt 系统在尼古丁强化中的作用。
大鼠接受尼古丁自我给药（NSA）训练，采用固定比率程序。在固定比率（FR）5 程序下维持 NSA 时，检测 hcrtR1 拮抗剂 SB334867 和 hcrtR1/2 拮抗剂 almorexant 的急性、会前处理对 NSA 的影响。在 19 天的 FR1 方案 NSA 后，测量动物的 hcrt 系统基因表达（hcrt、hcrtR1 和 hcrtR2 的 mRNA）。
hcrtR1 拮抗剂 SB334867 和 hcrtR1/2 拮抗剂 almorexant 均剂量依赖性地降低 NSA（分别在 30 和 300mg/kg 时显著）；SB334867 不影响食物维持反应，而 almorexant（300mg/kg）则影响。与对照相比，在自我给药后 5 小时采集的动物组织中，弓状核中的 hcrtR1 mRNA 增加。在经过类似的 19 天自我给药后立即采集的组织中，与对照相比，前外侧下丘脑的 hcrtR1 mRNA 减少。
这些数据证实了先前的报告（Hollander 等人，Proc Natl Acad Sci U S A 105:19480-19485，2008），即下丘脑泌素受体 hcrtR1 在尼古丁强化中被激活，此外还表明，弓状核和外侧下丘脑都是 hcrt 受体机制可能影响强化的部位。NSA 后不同时间的 mRNA 表达模式不同，表明 hcrt 系统的变化可能随时间而不稳定。
