Xie Qiaowei, Namba Mark D, Dasari Rohan, Buck Lauren A, Side Christine M, Goldberg Samuel L, Park Kyewon, Jackson Joshua G, Giacometti Laura, Barker Jacqueline M
Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, 245 N 15th Street, PA, 19102, USA.
Graduate Program in Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, USA.
Psychopharmacology (Berl). 2025 Jul 16. doi: 10.1007/s00213-025-06849-0.
HIV is highly comorbid with cocaine use disorder (CUD). Relapse is a major challenge in the treatment of CUD, and people living with HIV (PLWH) exhibit shorter time to relapse. One driver of relapse may be re-exposure to cocaine, which can be modeled in rodents using cocaine-primed reinstatement. This process involves neuroadaptations within the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) shell, regions that mediate cocaine reward learning and relapse-related behavior. HIV infection interacts with cocaine to alter corticostriatal circuits, which may further dysregulate cocaine seeking. To investigate the impact of HIV infection on cocaine reward learning and reinstatement and the role of mPFC-NAc circuits, we utilized the EcoHIV mouse model, a chimeric form of HIV-1 which can infect wild-type mice. Our findings demonstrate that EcoHIV infection enhances cocaine-primed reinstatement. We also observed increased cocaine-induced expression of the cellular activation marker cFos in the NAshell in EcoHIV-infected mice. Given the role of the mPFC-NAshell circuit in cocaine-seeking behaviors, we further demonstrated that chemogenetic activation of this circuit could reverse the behavioral deficits induced by EcoHIV. We propose that HIV infection contributes to neuroadaptations in the mPFC-NAshell circuit, and enhancing its activity may inhibit relapse-related behavior. These findings indicate that key neuronal circuits underlying cocaine reinstatement are similarly implicated in HIV infection and suggest potential strategies for managing relapse in PLWH.
人类免疫缺陷病毒（HIV）与可卡因使用障碍（CUD）高度共病。复发是CUD治疗中的一项重大挑战，而感染HIV的人（PLWH）复发时间更短。复发的一个驱动因素可能是再次接触可卡因，这可以在啮齿动物中通过可卡因激发的复吸模型来模拟。这个过程涉及内侧前额叶皮质（mPFC）和伏隔核（NAc）壳内的神经适应性变化，这些区域介导可卡因奖赏学习和与复发相关的行为。HIV感染与可卡因相互作用，改变皮质纹状体回路，这可能会进一步失调对可卡因的寻求行为。为了研究HIV感染对可卡因奖赏学习和复吸的影响以及mPFC-NAc回路的作用，我们利用了EcoHIV小鼠模型，这是一种可感染野生型小鼠的嵌合形式的HIV-1。我们的研究结果表明，EcoHIV感染增强了可卡因激发的复吸。我们还观察到，在感染EcoHIV的小鼠的NA壳中，可卡因诱导的细胞激活标记物cFos的表达增加。鉴于mPFC-NA壳回路在寻求可卡因行为中的作用，我们进一步证明，对该回路进行化学遗传激活可以逆转EcoHIV诱导的行为缺陷。我们提出，HIV感染促成了mPFC-NA壳回路中的神经适应性变化，增强其活性可能会抑制与复发相关的行为。这些发现表明，可卡因复吸背后的关键神经回路在HIV感染中也有类似的牵连，并为管理PLWH的复发提出了潜在策略。
