Zhang Y, Brownstein A J, Buonora M, Niikura K, Ho A, Correa da Rosa J, Kreek M J, Ott J
The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY 10065, USA.
The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY 10065, USA.
Neuroscience. 2015 Jan 29;285:34-46. doi: 10.1016/j.neuroscience.2014.11.013. Epub 2014 Nov 14.
Abuse and addiction to prescription opioids such as oxycodone (a short-acting Mu opioid receptor (MOP-r) agonist) in adolescence is a pressing public health issue. We have previously shown differences in oxycodone self-administration behaviors between adolescent and adult C57BL/6J mice and expression of striatal neurotransmitter receptor genes, in areas involved in reward. In this study, we aimed to determine whether oxycodone self-administration differentially affects genes regulating synaptic plasticity in the hippocampus of adolescent compared to adult mice, since the hippocampus may be involved in learning aspects associated with chronic drug self administration. Hippocampus was isolated for mRNA analysis from mice that had self administered oxycodone (0.25 mg/kg/infusion) 2h/day for 14 consecutive days or from yoked saline controls. Gene expression was analyzed with real-time polymerase chain reaction (PCR) using a commercially available "synaptic plasticity" PCR array containing 84 genes. We found that adolescent and adult control mice significantly differed in the expression of several genes in the absence of oxycodone exposure, including those coding for mitogen-activated protein kinase, calcium/calmodulin-dependent protein kinase II gamma subunit, glutamate receptor, ionotropic AMPA2 and metabotropic 5. Chronic oxycodone self administration increased proviral integration site 1 (Pim1) and thymoma viral proto-oncogene 1 mRNA levels compared to controls in both age groups. Both Pim1 and cadherin 2 mRNAs showed a significant combined effect of Drug Condition and Age × Drug Condition. Furthermore, the mRNA levels of both cadherin 2 and cAMP response element modulators showed an experiment-wise significant difference between oxycodone and saline control in adult but not in adolescent mice. Overall, this study demonstrates for the first time that chronic oxycodone self-administration differentially alters synaptic plasticity gene expression in the hippocampus of adolescent and adult mice.
青少年滥用和成瘾于处方阿片类药物，如羟考酮（一种短效μ阿片受体（MOP-r）激动剂），是一个紧迫的公共卫生问题。我们之前已经表明，青少年和成年C57BL/6J小鼠在羟考酮自我给药行为以及奖励相关脑区纹状体神经递质受体基因表达上存在差异。在本研究中，我们旨在确定与成年小鼠相比，羟考酮自我给药是否对青少年小鼠海马体中调节突触可塑性的基因有不同影响，因为海马体可能参与与慢性药物自我给药相关的学习过程。从连续14天每天2小时自我给药羟考酮（0.25毫克/千克/输注）的小鼠或配对的生理盐水对照小鼠中分离出海马体用于mRNA分析。使用包含84个基因的市售“突触可塑性”PCR阵列通过实时聚合酶链反应（PCR）分析基因表达。我们发现，在未接触羟考酮的情况下，青少年和成年对照小鼠在几个基因的表达上存在显著差异，包括那些编码丝裂原活化蛋白激酶、钙/钙调蛋白依赖性蛋白激酶IIγ亚基、谷氨酸受体、离子型AMPA2和代谢型5的基因。与两个年龄组的对照组相比，慢性羟考酮自我给药增加了原病毒整合位点1（Pim1）和胸腺瘤病毒原癌基因1的mRNA水平。Pim1和钙黏蛋白2的mRNA均显示出药物条件和年龄×药物条件的显著联合效应。此外，钙黏蛋白2和cAMP反应元件调节剂的mRNA水平在成年小鼠的羟考酮组和生理盐水对照组之间显示出实验性显著差异，但在青少年小鼠中未显示出差异。总体而言，本研究首次证明慢性羟考酮自我给药对青少年和成年小鼠海马体中突触可塑性基因表达有不同改变。
