Increased consumption but not operant self-administration of ethanol in mice lacking the RIIβ subunit of protein kinase A
Increased consumption but not operant self-administration of ethanol in mice lacking the RIIβ subunit of protein kinase A
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DOI：
10.1111/j.1530-0277.2006.00096.x
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发表时间：
2006-05-01
影响因子：
3.2
通讯作者：
Thiele, TE
中科院分区：
文献类型：
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作者：
Ferraro, FM;Sparta, DR;Thiele, TE
背景：越来越多的证据表明，单磷酸腺苷 (cAMP) 依赖性蛋白激酶 A (PKA) 参与对乙醇的神经生物学反应。先前的报告表明，使用 2 瓶测试程序，缺乏 PKA 的 RII β 亚基 (RII β(+)) 的小鼠比野生型对照 (RII β(+/+)) 自愿消耗更多的乙醇。尽管此类程序主要测量完成行为，但操作性自我管理程序允许分析完成行为以及食欲或“寻找乙醇”行为（即......需要按下杠杆才能获得乙醇溶液）。因此，我们确定了 RII beta(-/-) 小鼠的高乙醇消耗特征是否会在操作范式中通过增加食欲性乙醇寻求行为来补充。方法：RII beta(-/-) (n = 8) 和 RII beta(+/+) (n = 8) 小鼠最初进行蔗糖褪色，直到它们对不加糖的乙醇产生杠杆反应 （10%、14% 和 18%）。自我给药测试后，RII beta(+/+) 和 RII beta(-/-) 小鼠被给予 2 个瓶子，一个装有水，另一个装有乙醇，以复制我们实验室之前自愿饮用乙醇的数据。最后，在自愿消耗后立即再次测试所有小鼠的10%乙醇的自我施用。还探索了强化计划的改变，因为 RII beta(+/+) 和 RII beta(-/-) 小鼠在 FR-3 和 FR-5 计划中测试了自我施用 10% 乙醇。结果：与 RII beta(+/+) 对照相比，RII beta(-/-) 小鼠对乙醇和食物强化的操作反应较低。然而，这种效应是由雌性 RII beta(+/+) 小鼠的杠杆反应显着增加驱动的。当考虑到雌性 RII beta(+/+) 小鼠的过度杠杆反应时，RII beta(-/-) 小鼠表现出与对照组相当的乙醇杠杆反应。经过操作性自我给药测试，在 2 瓶测试中，与 RII beta(+/+) 小鼠相比，两种性别的 RII beta(-/-) 小鼠消耗了更多的乙醇溶液。结论：RII beta(-/-) 小鼠乙醇摄入量增加可能是控制乙醇完成行为的神经元通路中 PKA 活性改变的结果。相反，PKA 的 RII β 亚基似乎在调节旨在获得乙醇的食欲行为的神经元通路中不起关键作用。最后，雌性野生型小鼠对食物和乙醇的操作性自我管理在雌性 RII beta(-/-) 小鼠中不存在，这表明正常的 PKA 信号传导可能是与寻求强化行为有关的一般性、性别依赖性机制的一部分。
Background: Accumulating evidence indicates that adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) is involved in the neurobiological responses to ethanol. Previous reports indicate that mice lacking the RII beta subunit of PKA (RII beta(+)) voluntarily consume more ethanol than wild-type controls (RII beta(+/+)) using 2-bottle testing procedures. Although such procedures primarily measure consummatory behavior, operant self-administration procedures allow analysis of consummatory as well as appetitive or "ethanol-seeking" behavior (i.e... lever pressing is required to gain access to the ethanol solution). Therefore, we determined whether the high ethanol consumption characteristic of RII beta(-/-) mice would be complemented by increased appetitive ethanol-seeking behavior in an operant paradigm.Methods: RII beta(-/-) (n = 8) and RII beta(+/+) (n = 8) mice were initially sucrose-faded until they were lever responding for nonsweetened ethanol (10, 14, and 18%). Following the self-administration testing, RII beta(+/+) and RII beta(-/-) mice were given access to 2 bottles, one containing water and the other ethanol to replicate the voluntary ethanol drinking data previously from our laboratory. Finally, immediately after Voluntary consumption all mice were again tested for self-administration of 10% ethanol. Alterations in the reinforcement schedule were also explored as RII beta(+/+) and RII beta(-/-) mice were tested for self-administration of 10% ethanol at FR-3 and FR-5 schedules.Results: The RII beta(-/-) mice displayed lower operant responding for ethanol and food reinforcement compared with RII beta(+/+) controls. However, this effect was driven by a significant increase in lever responses made by female RII beta(+/+) mice. When the excessive lever responses of the female RII beta(+/+) mice are accounted for, the RII beta(-/-) mice show ethanol lever responses comparable to controls. Following operant self-administration testing, RII beta(-/-) mice of both sexes Consumed more ethanol Solution compared with RII beta(+/+) mice during 2-bottle testing.Conclusions: Increased ingestion of ethanol by RII beta(-/-) mice is likely the result of altered PKA activity within neuronal pathways that control ethanol-consummatory behaviors. Conversely, the RII beta subunit of PKA appears not to play a critical role in neuronal pathways that regulate appetitive behaviors directed at obtaining ethanol. Finally, increased operant self-administration of food and ethanol by female wild-type mice was absent in female RII beta(-/-) mice, suggesting that normal PKA signaling may be part of a general, and sex-dependent, mechanism involved with reinforcement-seeking behavior.