Relative to bred low-responder (bLR) rats, bred high-responder (bHR) rats have an exaggerated locomotor response to a novel environment, take more risks, are more impulsive, and more likely to exhibit compulsive drug-seeking behaviors. These phenotypic differences in addiction-related behaviors and temperament have previously been associated with differences in neurotransmitter signaling, including the mesolimbic dopamine system. In this study, we applied advanced in vivo microdialysis sampling in the nucleus accumbens of bHRs and bLRs to assess differences in basal and stimulated neurochemical efflux more broadly. We used liquid chromatography–mass spectrometry measurements of dialysate samples to quantify a panel of 17 neurochemicals, including dopamine, norepinephrine, serotonin, histamine, glutamate, GABA, acetylcholine, adenosine, DOPAC, 3-MT, HVA, 5-HIAA, normetanephrine, taurine, serine, aspartate, and glycine. We also applied a stable isotope labeling technique to assess absolute baseline concentrations of dopamine and norepinephrine in the nucleus accumbens. Finally, we investigated the role of norepinephrine tone in the nucleus accumbens on the bHR phenotype. Our findings show that bHRs have elevated basal and cocaine-evoked dopamine and norepinephrine levels in the nucleus accumbens compared to those of bLRs. Furthermore, norepinephrine signaling in the nucleus accumbens appeared to be an important contributor to the bHR phenotype because bilateral perfusion of the α1 adrenergic receptor antagonist terazosin (10 μM) into the nucleus accumbens abolished the response of bHRs to novelty. These findings are the first to demonstrate a role for norepinephrine in the bHR phenotype. They reveal a positive relationship between dopamine and norepinephrine signaling in the nucleus accumbens in mediating the exaggerated response to novelty and point to norepinephrine signaling as a potential target in the treatment of impulse control disorders.

中文翻译：

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选择性繁殖的高反应和低反应大鼠的体内神经化学概况揭示了单胺能系统中基线、可卡因诱发和新奇诱发的差异。

相对于繁殖的低反应 (bLR) 大鼠，繁殖的高反应 (bHR) 大鼠对新环境有夸张的运动反应，承担更多风险，更冲动，更可能表现出强迫性寻求药物的行为。这些与成瘾相关的行为和气质的表型差异以前与神经递质信号传导的差异有关，包括中脑边缘多巴胺系统。在这项研究中，我们在 bHRs 和 bLRs 的伏隔核中应用先进的体内微透析取样，以更广泛地评估基础和刺激神经化学外排的差异。我们使用透析液样品的液相色谱-质谱测量来量化一组 17 种神经化学物质，包括多巴胺、去甲肾上腺素、血清素、组胺、谷氨酸、GABA、乙酰胆碱、腺苷、DOPAC、3-MT、HVA、5-HIAA、去甲肾上腺素、牛磺酸、丝氨酸、天冬氨酸和甘氨酸。我们还应用稳定同位素标记技术来评估伏隔核中多巴胺和去甲肾上腺素的绝对基线浓度。最后，我们研究了伏隔核中去甲肾上腺素张力对 bHR 表型的作用。我们的研究结果表明，与 bLRs 相比，bHRs 在伏隔核中基础和可卡因诱发的多巴胺和去甲肾上腺素水平升高。此外，伏隔核中的去甲肾上腺素信号似乎是 bHR 表型的重要贡献者，因为双侧灌注 α1 肾上腺素能受体拮抗剂特拉唑嗪 (10 μM) 到伏隔核中消除了 bHR 对新奇事物的反应。这些发现首次证明了去甲肾上腺素在 bHR 表型中的作用。