Cocaine self-administration enhances excitatory responses of pyramidal neurons in the rat medial prefrontal cortex to human immunodeficiency virus-1 Tat.
Cocaine self-administration enhances excitatory responses of pyramidal neurons in the rat medial prefrontal cortex to human immunodeficiency virus-1 Tat.
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DOI：
10.1111/ejn.12853
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发表时间：
2015-05
期刊：
影响因子：
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通讯作者：
Hu XT
中科院分区：
文献类型：
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作者：
Wayman WN;Chen L;Napier TC;Hu XT
内侧前额叶皮层 (mPFC) 在奖励动机行为中发挥着关键作用。反复接触可卡因会导致背侧 mPFC 失调，这被认为是导致可卡因寻求和戒毒者复吸的原因之一。 mPFC 的神经病理学也发生在人类免疫缺陷病毒 (HIV) 阳性个体中，并且在那些也滥用可卡因的人中更严重。合并症对 mPFC 神经元功能的影响尚不清楚。为了填补这一知识空白，我们利用成年雄性大鼠进行了一项行为和电生理学研究，这些大鼠通过按下控制杆每天一次的操作会话 14 次来自我注射可卡因。盐水轭（SAL-yoked）大鼠作为对照。提示反应性（CR）用于指示药物寻求，通过将大鼠重新暴露于可卡因配对提示来评估，其中在第 14 次操作后 1 天（CR1）和 18-21 天（CR2）对非强化杠杆按压进行量化。仅可卡因自我给药 (COC-SA) 大鼠显示 CR。 CR2后一天，制备脑切片用于电生理学评估。 COC-SA 大鼠背侧（前边缘）mPFC 锥体神经元的全细胞膜片钳记录显示，与 SAL 轭对照大鼠相比，去极化电流引起的放电显着增加。 Bath 使用有毒的 HIV-1 转录反式激活因子 (Tat) 也使神经元膜去极化并增加诱发放电。撤回的 COC-SA 大鼠的神经元中 Tat 诱导的兴奋程度高于对照组。 Tat 还降低了尖峰幅度，这与 CR2 期间可卡因寻求共同变化。总而言之，这些新发现在神经元水平上为以下概念提供了支持：自我施用可卡因后 mPFC 锥体神经元的兴奋性增加会驱动药物寻求并增强 HIV-1 Tat 引起的神经病理生理学。
The medial prefrontal cortex (mPFC) plays a critical role in reward-motivated behaviors. Repeated cocaine exposure dysregulates the dorsal mPFC, and this is thought to contribute to cocaine-seeking and relapse of abstinent abusers. Neuropathology of the mPFC also occurs in human immunodeficiency virus (HIV)-positive individuals, and this is exaggerated in those who also abuse cocaine. The impact of the comorbid condition on mPFC neuronal function is unknown. To fill this knowledge gap, we performed a behavioral and electrophysiological study utilising adult male rats that self-administered cocaine by pressing a lever for 14 oncedaily operant sessions. Saline-yoked (SAL-yoked) rats served as controls. Cue reactivity (CR) was used to indicate drug-seeking, assessed by re-exposing the rats to cocaine-paired cues wherein non-reinforced lever pressing was quantified 1 day (CR1) and 18–21 days (CR2) after the 14th operant session. Only cocaine self-administration (COC-SA) rats showed CR. One day after CR2, brain slices were prepared for electrophysiological assessment. Whole-cell patch-clamp recordings of dorsal (prelimbic) mPFC pyramidal neurons from COC-SA rats showed a significant increase in firing evoked by depolarizing currents as compared with those from SAL-yoked control rats. Bath application of the toxic HIV-1 protein transactivator of transcription (Tat) also depolarized neuronal membranes and increased evoked firing. The Tat-induced excitation was greater in the neurons from withdrawn COC-SA rats than in controls. Tat also reduced spike amplitude, and this co-varied with cocaine-seeking during CR2. Taken together, these novel findings provide support at the neuronal level for the concept that the increased excitability of mPFC pyramidal neurons following cocaine self-administration drives drug-seeking and augments the neuropathophysiology caused by HIV-1 Tat.