Brailoiu G Cristina, Deliu Elena, Barr Jeffrey L, Console-Bram Linda M, Ciuciu Alexandra M, Abood Mary E, Unterwald Ellen M, Brailoiu Eugen
Department of Pharmaceutical Sciences, Jefferson College of Pharmacy, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Center for Substance Abuse Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
Drug Alcohol Depend. 2017 Sep 1;178:7-14. doi: 10.1016/j.drugalcdep.2017.04.015. Epub 2017 Jun 8.
HIV-1 infection and drug abuse are frequently co-morbid and their association greatly increases the severity of HIV-1-induced neuropathology. While nucleus accumbens (NAcc) function is severely perturbed by drugs of abuse, little is known about how HIV-1 infection affects NAcc.
We used calcium and voltage imaging to investigate the effect of HIV-1 trans-activator of transcription (Tat) on rat NAcc. Based on previous neuronal studies, we hypothesized that Tat modulates intracellular Ca homeostasis of NAcc neurons.
We provide evidence that Tat triggers a Ca signaling cascade in NAcc medium spiny neurons (MSN) expressing D1-like dopamine receptors leading to neuronal depolarization. Firstly, Tat induced inositol 1,4,5-trisphsophate (IP) receptor-mediated Ca release from endoplasmic reticulum, followed by Ca and Na influx via transient receptor potential canonical channels. The influx of cations depolarizes the membrane promoting additional Ca entry through voltage-gated P/Q-type Ca channels and opening of tetrodotoxin-sensitive Na channels. By activating this mechanism, Tat elicits a feed-forward depolarization increasing the excitability of D1-phosphatidylinositol-linked NAcc MSN. We previously found that cocaine targets NAcc neurons directly (independent of the inhibition of dopamine transporter) only when IP-generating mechanisms are concomitantly initiated. When tested here, cocaine produced a dose-dependent potentiation of the effect of Tat on cytosolic Ca.
We describe for the first time a HIV-1 Tat-triggered Ca signaling in MSN of NAcc involving TRPC and depolarization and a potentiation of the effect of Tat by cocaine, which may be relevant for the reward axis in cocaine-abusing HIV-1-positive patients.
HIV-1感染与药物滥用常合并存在，二者的关联极大地增加了HIV-1所致神经病理学的严重程度。虽然伏隔核（NAcc）功能会受到滥用药物的严重干扰，但关于HIV-1感染如何影响伏隔核却知之甚少。
我们利用钙成像和电压成像技术研究HIV-1转录激活因子（Tat）对大鼠伏隔核的影响。基于先前的神经元研究，我们假设Tat可调节伏隔核神经元的细胞内钙稳态。
我们提供的证据表明，Tat在表达D1样多巴胺受体的伏隔核中等棘状神经元（MSN）中触发钙信号级联反应，导致神经元去极化。首先，Tat诱导内质网中肌醇1,4,5-三磷酸（IP）受体介导的钙释放，随后钙和钠通过瞬时受体电位经典通道内流。阳离子的内流使膜去极化，促进更多钙通过电压门控P/Q型钙通道进入，并打开河豚毒素敏感的钠通道。通过激活这一机制，Tat引发前馈去极化，增加D1-磷脂酰肌醇连接的伏隔核MSN的兴奋性。我们之前发现，只有当产生IP的机制同时启动时，可卡因才直接作用于伏隔核神经元（独立于对多巴胺转运体的抑制）。在此处进行测试时，可卡因对Tat对胞质钙的影响产生剂量依赖性增强作用。
我们首次描述了HIV-1 Tat在伏隔核MSN中触发的涉及瞬时受体电位经典通道（TRPC）和去极化的钙信号，以及可卡因对Tat作用的增强作用，这可能与滥用可卡因的HIV-1阳性患者的奖赏轴有关。
