Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, USA.
Department of Pharmacology and Toxicology, Jacobs School of Medicine, State University of New York at Buffalo, Buffalo, NY, USA.
Addict Biol. 2018 Sep;23(5):1032-1045. doi: 10.1111/adb.12553. Epub 2017 Oct 2.
The hypocretin receptor 1 (HCRTr1) is a critical participant in the regulation of motivated behavior. Previous observations demonstrate that acute pharmacological blockade of HCRTr1 disrupts dopamine (DA) signaling and the motivation for cocaine when delivered systemically or directly into the ventral tegmental area (VTA). To further examine the involvement of HCRTr1 in regulating reward and reinforcement processing, we employed an adeno-associated virus to express a short hairpin RNA designed to knock down HCRTr1. We injected virus into the VTA and examined the effects of HCRTr1 knockdown on cocaine self-administration and DA signaling in the nucleus accumbens (NAc) core. We determined that the viral approach was effective at reducing HCRTr1 expression without affecting the expression of hypocretin receptor 2 or DA-related mRNAs. We next examined the effects of HCRTr1 knockdown on cocaine self-administration, observing delayed acquisition under a fixed-ratio schedule and reduced motivation for cocaine under a progressive ratio schedule. These effects did not appear to be associated with alterations in sleep/wake activity. Using fast-scan cyclic voltammetry, we then examined whether HCRTr1 knockdown alters DA signaling dynamics in the NAc core. We observed reduced DA release and slower uptake rate as well as attenuated cocaine-induced DA uptake inhibition in rats with knockdown of HCRTr1. These observations indicate that HCRTr1 within the VTA influence the motivation for cocaine, likely via alterations in DA signaling in the NAc.
孤啡肽受体 1（HCRTr1）是调节动机行为的关键参与者。先前的观察表明，急性药理学阻断 HCRTr1 会破坏多巴胺 (DA) 信号传递和可卡因的动机，无论是系统给药还是直接给药到腹侧被盖区 (VTA)。为了进一步研究 HCRTr1 在调节奖励和强化处理中的作用，我们使用腺相关病毒表达短发夹 RNA 来敲低 HCRTr1。我们将病毒注射到 VTA 中，并检查 HCRTr1 敲低对可卡因自我给药和伏隔核 (NAc) 核心中 DA 信号的影响。我们确定该病毒方法可有效降低 HCRTr1 的表达，而不影响孤啡肽受体 2 或与 DA 相关的 mRNA 的表达。接下来，我们检查了 HCRTr1 敲低对可卡因自我给药的影响，观察到在固定比率方案下获得时间延迟，在递增比率方案下可卡因的动机降低。这些影响似乎与睡眠/觉醒活动的改变无关。使用快速扫描循环伏安法，我们然后检查了 HCRTr1 敲低是否改变了 NAc 核心中的 DA 信号动力学。我们观察到 HCRTr1 敲低大鼠的 DA 释放减少、摄取率减慢以及可卡因诱导的 DA 摄取抑制减弱。这些观察结果表明，VTA 中的 HCRTr1 影响可卡因的动机，可能通过改变 NAc 中的 DA 信号传递。
