PKC inhibition decreases amphetamine-maintained responding under a progressive-ratio schedule of reinforcement.
PKC inhibition decreases amphetamine-maintained responding under a progressive-ratio schedule of reinforcement.
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DOI：
10.1037/pha0000425
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发表时间：
2021-12
影响因子：
2.3
通讯作者：
Jutkiewicz EM
中科院分区：
文献类型：
--
作者：
Altshuler RD;Mac RC;Gnegy ME;Jutkiewicz EM
蛋白激酶C （PKC）在安非他明（AMPH）的作用机制中起重要作用。抑制PKC阻断amph刺激的细胞外多巴胺水平的增加和amph刺激的运动活动。本研究考察了PKC抑制对AMPH增强特性的影响。雄性Sprague-Dawley大鼠接受0.032 mg/kg/次AMPH输注或渐进比例（PR）强化训练。在连续的会话中记录获得的输液次数、断点和会话持续时间。一旦amph维持反应稳定，大鼠在自我给药前18小时分别接受0、10或30 pmol的enzastaurin （PKCβ选择性抑制剂）或6 mg/kg 6c（脑渗透性PKC抑制剂）治疗。用30 pmol enzastaurin或6 mg/kg 6c预处理可减少获得的AMPH输注次数和断点，但不改变糖维持行为。这些数据表明，PKC抑制降低了AMPH的动机，因此值得作为AMPH使用障碍的潜在治疗方法进行研究。
Protein kinase C (PKC) is important for the mechanism of action of amphetamine (AMPH). Inhibiting PKC blocks AMPH-stimulated increases in extracellular dopamine levels and AMPH-stimulated locomotor activity. This study examined the effects of PKC inhibition on the reinforcing properties of AMPH. Male Sprague-Dawley rats were trained to respond for infusions of 0.032 mg/kg/infusion AMPH or for sucrose pellets under a progressive-ratio (PR) schedule of reinforcement. Number of infusions earned, breakpoints, and session duration were recorded over consecutive sessions. Once AMPH-maintained responding stabilized, rats were treated with 0, 10, or 30 pmol of enzastaurin, a PKCβ-selective inhibitor, or 6 mg/kg 6c, a brain-permeable PKC inhibitor, 18 hr prior to a self-administration session. Pretreatment with 30 pmol enzastaurin or 6 mg/kg 6c decreased the number of AMPH infusions earned and breakpoints without altering sucrose-maintained behaviors. These data suggest that PKC inhibition decreases motivation for AMPH and, therefore, is worth pursuing as a potential treatment for AMPH-use disorder.
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