Orphanin FQ/Nociceptin Not Only Blocks but Also Reverses Behavioral Adaptive Changes Induced by Repeated Cocaine in Mice
Orphanin FQ/Nociceptin Not Only Blocks but Also Reverses Behavioral Adaptive Changes Induced by Repeated Cocaine in Mice
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DOI：
10.1016/j.biopsych.2010.02.010
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发表时间：
2010-08-01
影响因子：
10.6
通讯作者：
Lutfy, Kabirullah
中科院分区：
文献类型：
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作者：
Bebawy, David;Marquez, Paul;Lutfy, Kabirullah
背景：孤啡肽FQ/伤害素(OFQ/N)是阿片受体样受体(ORL1)的内源性配体，可阻断大鼠对可卡因的敏感性。在这项研究中，我们测试了OFQ/N是否会阻断小鼠对可卡因的运动刺激和条件性奖赏作用的敏化。我们还检测了给予可卡因致敏小鼠的OFQ/N是否能逆转致敏反应，以及它是否能阻止第二次可卡因致敏方案对致敏小鼠的放大致敏反应。方法：ORL1基因敲除和野生型小鼠在第1-3天先用生理盐水或OFQ/N处理，在第8天进行致敏测试。此外，野生型小鼠也接受类似的治疗，但测试可卡因的条件性奖赏作用，在可卡因单独作用前后测试小鼠的位置偏爱。进一步致敏，在第13~15天，先注射生理盐水或OFQ/N，再注射生理盐水或可卡因，第20天注射可卡因，以检测OFQ/N能否逆转致敏小鼠的致敏作用，或阻断第二次可卡因致敏方案对致敏小鼠的致敏反应。它还阻断了对可卡因的条件性奖赏作用的敏化，并逆转了先前存在的运动敏化反应。结论：OFQ/N不仅能阻断反复给药引起的小鼠不适应行为改变，而且还能逆转反复给药引起的小鼠适应不良行为改变。
Background: Orphanin FQ/nociceptin (OFQ/N), the endogenous ligand of the opioid receptor-like (ORL1) receptor, blocks cocaine sensitization in rats. In this study, we tested whether OFQ/N would block sensitization to the motor stimulatory and conditioned rewarding actions of cocaine in mice. We also examined whether OFQ/N, given to cocaine-sensitized mice, would reverse the sensitized response and whether it would prevent the amplified sensitized response induced by a second cocaine-sensitizing regimen in sensitized mice.Methods: ORL1 knockout and wild-type mice were treated with saline or OFQ/N before saline or cocaine on Days 1-3 and tested for sensitization on Day 8. Additionally, wild-type mice were treated similarly but tested for the conditioned rewarding action of cocaine, in which mice were tested for place preference before and after single conditioning with cocaine. Furthermore, mice were rendered sensitized, treated with saline or OFQ/N before saline or cocaine on Days 13-15, and received cocaine on Day 20 to test whether OFQ/N would reverse sensitization or block the amplified sensitized response induced by a second cocaine-sensitizing regimen in sensitized mice.Results: OFQ/N blocked cocaine-induced psychomotor sensitization in wild-type but not knockout mice. It also blocked sensitization to the conditioned rewarding action of cocaine and reversed a preexisting locomotor sensitized response. Furthermore, OFQ/N prevented the amplified sensitized response that developed following a second cocaine sensitizing regimen given to sensitized mice.Conclusions: These results illustrate that OFQ/N not only blocks but also reverses maladaptive behavioral changes induced by repeated cocaine treatment in mice.