可卡因位置条件反射、慢性递增剂量“ binge”模式可卡因给药及急性戒断对Fischer和Sprague-Dawley大鼠下丘脑外侧区食欲素/下丘脑泌素及前强啡肽原基因表达的影响
Effects of cocaine place conditioning, chronic escalating-dose "binge" pattern cocaine administration and acute withdrawal on orexin/hypocretin and preprodynorphin gene expressions in lateral hypothalamus of Fischer and Sprague-Dawley rats.
作者信息
Zhou Y, Cui C-L, Schlussman S D, Choi J C, Ho A, Han J-S, Kreek M J
机构信息
Laboratory of the Biology of Addictive Diseases, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
出版信息
Neuroscience. 2008 Jun 2;153(4):1225-34. doi: 10.1016/j.neuroscience.2008.03.023. Epub 2008 Mar 22.
Recent evidence suggests an important role for hypothalamic orexins/hypocretins in modulation of drug reward and addiction-like behaviors in rodents. Our recent study has shown that the aversive state of arousal during acute morphine withdrawal is associated with increased orexin gene expression in lateral hypothalamus (LH) of Fischer 344 (F344) inbred rats, with no change in the expression of preprodynorphin (ppDyn), a gene co-expressed with LH orexin. Therefore, we determined whether orexin and ppDyn mRNA levels in LH or medial hypothalamus (including perifornical and dorsomedial areas) of F344 or Sprague-Dawley (SD) outbred rats, are altered following: 1) cocaine (10 mg/kg, i.p.) conditioned place preference (CPP); 2) chronic (14 days) cocaine exposure using both "binge" pattern administration in steady-dose (45 mg/kg/day) and escalating-dose (45-90 mg/kg/day) regimens; and 3) acute (1 day) and chronic (14 days) withdrawal from cocaine with opioid receptor antagonist naloxone treatment (1 mg/kg). We found that orexin mRNA levels were decreased after cocaine place conditioning in the LH of SD rats. A decreased LH orexin mRNA level was also observed after chronic escalating-dose cocaine (but not CPP pattern regimen without conditioning, or steady-dose regimen) in both strains. In F344 rats only, acute withdrawal from chronic escalating-dose cocaine administration resulted in increases in both LH orexin and ppDyn mRNA levels, which were unaltered by naloxone or after chronic withdrawal. Our results suggest that (1) alteration of LH orexin gene expression is region-specific after cocaine place conditioning in SD rats and dose-dependent after chronic exposure in both strains; and (2) increased LH orexin and ppDyn gene expressions in F344 rats may contribute to negative affective states in cocaine withdrawal.
最近的证据表明，下丘脑食欲素/下丘脑泌素在调节啮齿动物的药物奖赏和成瘾样行为中发挥重要作用。我们最近的研究表明，急性吗啡戒断期间的厌恶觉醒状态与Fischer 344（F344）近交系大鼠下丘脑外侧区（LH）中食欲素基因表达增加有关，而与前强啡肽原（ppDyn）的表达变化无关，ppDyn是一种与LH食欲素共表达的基因。因此，我们确定了F344或Sprague-Dawley（SD）远交系大鼠的LH或内侧下丘脑（包括穹窿周和背内侧区域）中食欲素和ppDyn mRNA水平在以下情况后是否发生改变：1）可卡因（10 mg/kg，腹腔注射）条件性位置偏爱（CPP）；2）采用稳定剂量（45 mg/kg/天）“暴饮暴食”模式给药和递增剂量（45 - 90 mg/kg/天）方案进行慢性（14天）可卡因暴露；3）用阿片受体拮抗剂纳洛酮治疗（1 mg/kg）进行急性（1天）和慢性（14天）可卡因戒断。我们发现，在SD大鼠的LH中，可卡因位置条件化后食欲素mRNA水平降低。在两种品系中，慢性递增剂量可卡因给药后（但不是无条件的CPP模式方案或稳定剂量方案），LH食欲素mRNA水平也降低。仅在F344大鼠中，慢性递增剂量可卡因给药后的急性戒断导致LH食欲素和ppDyn mRNA水平均升高，纳洛酮或慢性戒断后这些水平未改变。我们的结果表明：（1）在SD大鼠中，可卡因位置条件化后LH食欲素基因表达的改变具有区域特异性，在两种品系中慢性暴露后具有剂量依赖性；（2）F344大鼠中LH食欲素和ppDyn基因表达增加可能导致可卡因戒断时的负性情绪状态。
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