SRI-32743, a novel allosteric modulator, attenuates HIV-1 Tat protein-induced inhibition of the dopamine transporter and alleviates the potentiation of cocaine reward in HIV-1 Tat transgenic mice.
SRI-32743, a novel allosteric modulator, attenuates HIV-1 Tat protein-induced inhibition of the dopamine transporter and alleviates the potentiation of cocaine reward in HIV-1 Tat transgenic mice.
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SRI-32743 是一种新型变构调节剂，可减弱 HIV-1 Tat 蛋白诱导的多巴胺转运蛋白抑制，并减轻 HIV-1 Tat 转基因小鼠中可卡因奖赏的增强。
DOI：
10.1016/j.neuropharm.2022.109239
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发表时间：
2022
影响因子：
4.7
通讯作者：
Vekari
中科院分区：
文献类型：
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作者：
Zhu,Jun;Quizon,PamelaM;Wang,Yingying;Adeniran,CharlesA;Strauss,MatthewJ;Jiménez-Torres,AnaC;Patel,Palak;Cirino,ThomasJ;Eans,ShainnelO;Hammond,HayleeR;Deliscar,LaureS;O'Hara,Priscilla;Saini,SurendraK;Ofori,Edward;Vekari
可卡因滥用会增加hiv -1相关神经认知障碍的发病率。我们已经证明HIV-1转录反激活子（Tat）通过人类DA转运体（hDAT）变构调节多巴胺（DA）的再摄取，可能导致多巴胺诱导的认知障碍和可卡因条件位置偏好（CPP）的增强。本研究确定了一种新的DAT变构调节剂SRI-32743对HIV-1 Tat、DA、可卡因和[3H]WIN35,428与hDATin体外相互作用的影响。在表达hDAT的CHO细胞中，SRI-32743（50 nM）减弱了tat诱导的对[3H]DA摄取的抑制，并降低了可卡因介导的[3H]WIN35,428结合的解离，表明asri -32743介导的Tat-DAT相互作用的变构调节。在使用多西环素诱导Tat转基因（iTat-tg）小鼠的进一步体内研究中，与对照iTat-tg小鼠相比，Tat表达14天显著降低了新物体识别（NOR）最后阶段的识别指数31.7%，增强了可卡因- cpp 2.7倍。在盐水处理的iTat-tg或强力霉素处理的G-tg （Tat-null）小鼠中未观察到tat诱导的NOR缺陷和可卡因- cpp增强。在行为测试之前，全身给药sri -32743改善了tat诱导的NOR损伤（剂量为10mg /kg）和tat诱导的可卡因- cpp增强（剂量为1或10mg /kg）。这些发现表明，Tat和可卡因与DAT的相互作用可能受到DAT变构调节位点上相互作用的化合物的调节，这表明对并发可卡因滥用的hiv感染患者有潜在的治疗干预。
Cocaine abuse increases the incidence of HIV-1-associated neurocognitive disorders. We have demonstrated that HIV-1 transactivator of transcription (Tat) allosterically modulates dopamine (DA) reuptake through the human DA transporter (hDAT), potentially contributing to Tat-induced cognitive impairment and potentiation of cocaine conditioned place preference (CPP). This study determined the effects of a novel allosteric modulator of DAT,SRI-32743, on the interactions of HIV-1 Tat, DA, cocaine, and [3H]WIN35,428 with hDATin vitro.SRI-32743(50 nM) attenuated Tat-induced inhibition of [3H]DA uptake and decreased the cocaine-mediated dissociation of [3H]WIN35,428 binding in CHO cells expressing hDAT, suggesting aSRI-32743-mediated allosteric modulation of the Tat-DAT interaction. In furtherin vivostudies utilizing doxycycline-inducible Tat transgenic (iTat-tg) mice, 14 days of Tat expression significantly reduced the recognition index by 31.7% in the final phase of novel object recognition (NOR) and potentiated cocaine-CPP 2.7-fold compared to responses of vehicle-treated control iTat-tg mice. The Tat-induced NOR deficits and potentiation of cocaine-CPP were not observed in saline-treated iTat-tg or doxycycline-treated G-tg (Tat-null) mice. Systemic administration (i.p.) ofSRI-32743prior to behavioral testing ameliorated Tat-induced impairment of NOR (at a dose of 10 mg/kg) and the Tat-induced potentiation of cocaine-CPP (at doses of 1 or 10 mg/kg). These findings demonstrate that Tat and cocaine interactions with DAT may be regulated by compounds interacting at the DAT allosteric modulatory sites, suggesting a potential therapeutic intervention for HIV-infected patients with concurrent cocaine abuse.