The fronto-striatal circuitry, involving the nucleus accumbens, ventral tegmental area, and prefrontal cortex, mediates goal-directed behavior and is targeted by both drugs of abuse and HIV-1 infection. Acutely, both drugs and HIV-1 provoke increased dopamine activity within the circuit. However, chronic exposure to drugs or HIV-1 leads to dysregulation of the dopamine system as a result of fronto-striatal adaptations to oppose the effects of repeated instances of transiently increased dopamine. Specifically, chronic drug use leads to reduced dopaminergic tone, upregulation of dopamine transporters, and altered circuit connectivity, sending users into an allosteric state in which goal-directed behaviors are dysregulated (i.e., addiction). Similarly, chronic exposure to HIV-1, even with combination antiretroviral therapy (cART), dysregulates dopamine and dopamine transporter function and alters connectivity of the fronto-striatal circuit, contributing to apathy and clinical symptoms of HIV-1 associated neurocognitive disorders (HAND). Thus, in a drug user also exposed to HIV-1, dysregulation of the fronto-striatal dopamine circuit advances at an exacerbated rate and appears to be driven by mechanisms unique from those seen with chronic drug use or HIV-1 exposure alone. We posit that the effects of drug use and HIV-1 infection on microglia interact to drive the progression of motivational dysfunction at an accelerated rate. The current review will therefore explore how the fronto-striatal circuit adapts to drug use (using cocaine as an example), HIV-1 infection, and both together; emphasizing proper methods and providing future directions to develop treatments for pathologies disrupting goal-directed behaviors and improve clinical outcomes for affected patients.

Drug use and HIV-1 in the fronto-striatal circuit. Drugs of abuse and HIV-1 infection both target the fronto-striatal circuit which mediates goal-directed behavior. Acutely, drugs and HIV-1 increase dopamine activity; in contrast chronic exposure produces circuit adaptions leading to dysregulation, addiction and/or apathy. Comorbid drug use and HIV-1 infection may interact with microglia to exacerbate motivational dysregulation.

涉及伏隔核、腹侧被盖区和前额叶皮层的额纹状体回路介导目标导向的行为，是滥用药物和 HIV-1 感染的目标。严重的是，药物和 HIV-1 都会引起回路内的多巴胺活性增加。然而，长期接触药物或 HIV-1 会导致多巴胺系统失调，这是由于额纹状体适应以抵抗反复短暂增加的多巴胺的影响。具体而言，长期吸毒会导致多巴胺能基调降低、多巴胺转运蛋白上调和电路连通性改变，使用户进入变构状态，其中目标导向的行为失调（即成瘾）。同样，长期暴露于 HIV-1，即使联合抗逆转录病毒疗法 (cART)，失调多巴胺和多巴胺转运蛋白功能并改变额纹状体回路的连通性，导致 HIV-1 相关神经认知障碍 (HAND) 的冷漠和临床症状。因此，在也暴露于 HIV-1 的吸毒者中，额纹状体多巴胺回路的失调以加剧的速度发展，并且似乎是由与长期吸毒或单独暴露于 HIV-1 所见的机制不同的机制驱动的。我们假设药物使用和 HIV-1 感染对小胶质细胞的影响相互作用，以加速动机功能障碍的进展。因此，当前的审查将探讨额纹状体回路如何适应吸毒（以可卡因为例）、HIV-1 感染，以及两者兼而有之；

药物使用和额纹状体回路中的 HIV-1。滥用药物和 HIV-1 感染均针对介导目标导向行为的额纹状体回路。药物和 HIV-1 会急剧增加多巴胺活性；相比之下，长期暴露会产生导致失调、成瘾和/或冷漠的回路适应。共病药物使用和 HIV-1 感染可能与小胶质细胞相互作用，从而加剧动机失调。