Chartoff Elena H, Ebner Shayla R, Sparrow Angela, Potter David, Baker Phillip M, Ragozzino Michael E, Roitman Mitchell F
Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, USA.
Department of Psychology, University of Illinois at Chicago, Chicago, IL, USA.
Neuropsychopharmacology. 2016 Mar;41(4):989-1002. doi: 10.1038/npp.2015.226. Epub 2015 Aug 4.
Negative affective states can increase the rewarding value of drugs of abuse and promote drug taking. Chronic cocaine exposure increases levels of the neuropeptide dynorphin, an endogenous ligand at kappa opioid receptors (KOR) that suppresses dopamine release in the nucleus accumbens (NAc) and elicits negative affective states upon drug withdrawal. However, there is evidence that the effects of KOR activation on affective state are biphasic: immediate aversive effects are followed by delayed increases in reward. The impact of KOR-induced affective states on reward-related effects of cocaine over time is not known. We hypothesize that the initial aversive effects of KOR activation increase, whereas the delayed rewarding effects decrease, the net effects of cocaine on reward and dopamine release. We treated rats with cocaine at various times (15 min to 48 h) after administration of the selective KOR agonist salvinorin A (salvA). Using intracranial self-stimulation and fast scan cyclic voltammetry, we found that cocaine-induced increases in brain stimulation reward and evoked dopamine release in the NAc core were potentiated when cocaine was administered within 1 h of salvA, but attenuated when administered 24 h after salvA. Quantitative real-time PCR was used to show that KOR and prodynorphin mRNA levels were decreased in the NAc, whereas tyrosine hydroxylase and dopamine transporter mRNA levels and tissue dopamine content were increased in the ventral tegmental area 24 h post-salvA. These findings raise the possibility that KOR activation-as occurs upon withdrawal from chronic cocaine-modulates vulnerability to cocaine in a time-dependent manner.
消极情绪状态会增加滥用药物的奖赏价值并促进药物摄取。长期接触可卡因会增加神经肽强啡肽的水平，强啡肽是κ阿片受体（KOR）的内源性配体，可抑制伏隔核（NAc）中的多巴胺释放，并在停药时引发消极情绪状态。然而，有证据表明KOR激活对情绪状态的影响是双相的：立即产生厌恶效应，随后奖赏延迟增加。随着时间的推移，KOR诱导的情绪状态对可卡因奖赏相关效应的影响尚不清楚。我们假设KOR激活的初始厌恶效应会增加，而延迟的奖赏效应会降低可卡因对奖赏和多巴胺释放的净效应。我们在给予选择性KOR激动剂Salvinorin A（salvA）后的不同时间（15分钟至48小时）用可卡因处理大鼠。使用颅内自我刺激和快速扫描循环伏安法，我们发现当在salvA后1小时内给予可卡因时，可卡因诱导的脑刺激奖赏增加和NAc核心中诱发的多巴胺释放增强，但在salvA后24小时给予时则减弱。定量实时PCR用于显示salvA后24小时，NAc中KOR和前强啡肽mRNA水平降低，而腹侧被盖区酪氨酸羟化酶和多巴胺转运体mRNA水平以及组织多巴胺含量增加。这些发现增加了一种可能性，即从长期可卡因戒断时发生的KOR激活以时间依赖性方式调节对可卡因的易感性。
