Clare Kevin, Pan Chelsea, Kim Gloria, Park Kicheon, Zhao Juan, Volkow Nora D, Lin Zhicheng, Du Congwu
Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, United States.
Laboratory of Psychiatric Neurogenomics, Basic Neuroscience Division, McLean Hospital, Belmont, MA, United States.
Front Pharmacol. 2021 Apr 12;12:624127. doi: 10.3389/fphar.2021.624127. eCollection 2021.
Addiction to cocaine is associated with dysfunction of the dopamine mesocortical system including impaired dopamine-2 receptor (D2r) signaling. However, the effects of chronic cocaine on neuronal adaptations in this system have not been systematically examined and data available is mostly from males. Here, we investigated changes in the total neuronal density and relative concentration of D2r-expressing neurons in the medial prefrontal cortex (mPFC), dorsal striatum (Dstr), nucleus accumbens (NAc), and ventral tegmental area (VTA) in both male and female mice passively exposed to cocaine for two weeks. In parallel experiments, we measured mRNA levels for and for opioid peptides (m and m). Through a combination of large field of view fluorescent imaging with BAC transgenic D2r-eGFP mice and immunostaining, we observed that cocaine exposed mice had a higher density of D2r-positive cells that was most prominent in mPFC and VTA and larger for females than for males. This occurred amidst an overall significant decrease in neuronal density (measured with NeuN) in both sexes. However, increases in mRNA levels with cocaine were only observed in mPFC and Dstr in females, which might reflect the limited sensitivity of the method. Our findings, which contrast with previous findings of cocaine-induced downregulation of D2r binding availability, could reflect a phenotypic shift in neurons that did not previously express and merits further investigation. Additionally, the neuronal loss particularly in mPFC with chronic cocaine might contribute to the cognitive impairments observed with cocaine use disorder.
可卡因成瘾与多巴胺中脑皮质系统功能障碍有关，包括多巴胺 -2 受体（D2r）信号传导受损。然而，慢性可卡因对该系统中神经元适应性的影响尚未得到系统研究，现有数据大多来自雄性。在此，我们研究了被动暴露于可卡因两周的雄性和雌性小鼠内侧前额叶皮质（mPFC）、背侧纹状体（Dstr）、伏隔核（NAc）和腹侧被盖区（VTA）中表达 D2r 的神经元的总神经元密度和相对浓度的变化。在平行实验中，我们测量了 以及阿片肽（m 和 m）的 mRNA 水平。通过结合使用 BAC 转基因 D2r - eGFP 小鼠的大视野荧光成像和免疫染色，我们观察到暴露于可卡因的小鼠中 D2r 阳性细胞密度更高，在 mPFC 和 VTA 中最为明显，且雌性比雄性更高。这发生在两性神经元密度（用 NeuN 测量）总体显著下降的背景下。然而，仅在雌性小鼠的 mPFC 和 Dstr 中观察到可卡因使 mRNA 水平升高，这可能反映了该方法的有限敏感性。我们的发现与先前可卡因诱导 D2r 结合可用性下调的发现形成对比，可能反映了先前未表达 的神经元的表型转变，值得进一步研究。此外，慢性可卡因导致的神经元损失，尤其是 mPFC 中的神经元损失，可能导致可卡因使用障碍中观察到的认知障碍。
