Laboratory of Molecular Pharmacology, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, 920-1192, Japan.
Laboratory of Molecular Pharmacology, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, 920-1192, Japan; Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, 060-0812, Japan.
Neuropharmacology. 2020 Apr;166:107968. doi: 10.1016/j.neuropharm.2020.107968. Epub 2020 Feb 6.
Stress augments the rewarding memory of cocaine, which plays a critical role in inducing cocaine craving. However, the neurobiological mechanisms underlying the enhancing effect of stress remain unclear. Here, we show that noradrenaline (NA) transmission in the medial prefrontal cortex (mPFC) mediates stress-induced enhancement of cocaine craving. When mice were exposed to acute restraint stress immediately before the posttest session of the cocaine-induced conditioned place preference (CPP) paradigm, the CPP score was significantly higher than that in non-stressed mice. Because extracellular NA levels have been reported to be increased in the mPFC during stress exposure, we assessed the effects of NA on mPFC layer 5 pyramidal cell activity. Whole-cell recordings revealed that NA application induces depolarization and a concomitant increase in spontaneous excitatory postsynaptic currents (sEPSCs). The NA effects were inhibited by terazosin, but not by yohimbine or timolol, and the sEPSC increase was not observed in the presence of tetrodotoxin, suggesting the involvement of postsynaptic α, but not α or β, adrenoceptors in the NA effects. Additionally, intra-mPFC injection of terazosin before stress exposure attenuated the stress-induced increase in cocaine CPP. Intra-mPFC injection of phenylephrine, an α adrenoceptor agonist, before the posttest session without stress exposure significantly enhanced cocaine CPP. Furthermore, chemogenetic suppression of mPFC pyramidal cells with inhibitory DREADD (designer receptors exclusively activated by designer drugs) also suppressed the stress-induced CPP enhancement. These findings suggest that the stress-induced increase in NA transmission activates mPFC pyramidal cells via α adrenoceptor stimulation, leading to enhancement of cocaine craving-related behavior.
应激增强了可卡因的奖赏记忆，而可卡因的奖赏记忆在诱导可卡因渴望中起着关键作用。然而，应激增强可卡因渴望的神经生物学机制仍不清楚。在这里，我们表明，去甲肾上腺素（NA）在中前额叶皮层（mPFC）中的传递介导了应激诱导的可卡因渴望增强。当小鼠在可卡因诱导的条件性位置偏好（CPP）范式的后测回合之前立即暴露于急性束缚应激时，CPP 评分明显高于非应激小鼠。由于据报道在应激暴露期间 mPFC 中的细胞外 NA 水平增加，我们评估了 NA 对 mPFC 第 5 层锥体神经元活动的影响。全细胞记录显示，NA 应用诱导去极化和伴随的自发性兴奋性突触后电流（sEPSC）增加。terazosin 抑制了 NA 的作用，但 yohimbine 或 timolol 没有抑制，并且在存在河豚毒素的情况下没有观察到 sEPSC 增加，这表明 NA 作用涉及突触后α，但不是α或β肾上腺素受体。此外，在应激暴露之前在 mPFC 内注射 terazosin 可减弱应激诱导的可卡因 CPP 增加。在没有应激暴露的后测回合之前，在 mPFC 内注射苯肾上腺素，一种α肾上腺素受体激动剂，可显著增强可卡因 CPP。此外，通过抑制性 DREADD（专门被设计药物激活的设计受体）对 mPFC 锥体神经元的化学遗传抑制也抑制了应激诱导的 CPP 增强。这些发现表明，应激诱导的 NA 传递增加通过α肾上腺素受体刺激激活 mPFC 锥体神经元，导致可卡因渴望相关行为增强。
