Department of Neurobiology and Neuropsychology, Institute of Applied Psychology, Jagiellonian University, Poland.
Department of Molecular Neuropharmacology, Institute of Pharmacology, Polish Academy of Sciences, Poland.
Addict Biol. 2018 Mar;23(2):596-609. doi: 10.1111/adb.12514. Epub 2017 Jun 21.
Exposure to drug-associated cues evokes drug-seeking behavior and is regarded as a major cause of relapse. Conditional stimulus upregulates noradrenaline (NA) system activity, but the drug-seeking behavior depends particularly on phasic dopamine signaling downstream from the ventral tegmental area (VTA). The VTA dopamine-ergic activity is regulated via the signaling of alpha -adrenergic and alpha -adrenergic receptors (α -ARs and α -ARs); thus, the impact of the conditional stimulus on drug-seeking behavior might involve NAergic signaling in the VTA. To date, the role of VTA ARs in regulating cocaine seeking was not studied. We found that cocaine seeking under extinction conditions in male Sprague-Dawley rats was attenuated by intra-VTA prazosin or terazosin-two selective α -AR antagonists. In contrast, cocaine seeking was facilitated by intra-VTA administration of the selective α -AR agonist phenylephrine as well as α -AR antagonist RX 821002, whereas the selective β-AR antagonist propranolol had no effects. In addition, blockade of α -AR in the VTA prevented α -AR antagonist-induced enhancement of cocaine seeking. Importantly, the potential non-specific effects of the VTA AR blockade on cocaine seeking could be excluded, because none of the AR antagonists influenced sucrose seeking under extinction conditions or locomotor activity in the open field test. These results demonstrate that NAergic signaling potently and selectively regulates cocaine seeking during early cocaine withdrawal via VTA α -AR and α -AR but not β-AR. Our findings provide new insight into the NAergic mechanisms that underlie cocaine craving.
暴露于与药物相关的线索会引发觅药行为，被认为是复吸的主要原因。条件性刺激会上调去甲肾上腺素（NA）系统的活性，但觅药行为尤其依赖于腹侧被盖区（VTA）下游的多巴胺信号传递。VTA 多巴胺能活动通过α-肾上腺素能和α-肾上腺素能受体（α-ARs 和 α-ARs）的信号传递来调节；因此，条件性刺激对觅药行为的影响可能涉及 VTA 中的 NA 能信号传递。迄今为止，尚未研究 VTA AR 在调节可卡因觅药中的作用。我们发现，在雄性 Sprague-Dawley 大鼠的可卡因消退条件下，VTA 内给予普萘洛尔或特拉唑嗪这两种选择性α-AR 拮抗剂可减弱可卡因觅药。相比之下，VTA 内给予选择性α-AR 激动剂苯肾上腺素以及 α-AR 拮抗剂 RX 821002 可促进可卡因觅药，而选择性β-AR 拮抗剂普萘洛尔则没有影响。此外，VTA 中的α-AR 阻断可防止 α-AR 拮抗剂增强可卡因觅药。重要的是，可以排除 VTA AR 阻断对可卡因觅药的潜在非特异性影响，因为 AR 拮抗剂均未影响消退条件下的蔗糖觅药或在开放场测试中的运动活动。这些结果表明，NA 能信号通过 VTA α-AR 和 α-AR 而非β-AR 强烈且选择性地调节可卡因戒断早期的可卡因觅药。我们的研究结果为可卡因渴求的 NA 能机制提供了新的见解。
