Department of Neurobiology & Behavior, University of California, Irvine, 1203 McGaugh Hall, Irvine, CA, 92697, USA.
Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
Neuropsychopharmacology. 2019 Dec;44(13):2174-2185. doi: 10.1038/s41386-019-0507-4. Epub 2019 Sep 2.
Addiction is a chronic relapsing disorder, and during recovery many people experience several relapse events as they attempt to voluntarily abstain from drug. New preclinical relapse models have emerged that capture this common human experience, and mounting evidence indicates that resumption of drug seeking after voluntary abstinence recruits neural circuits distinct from those recruited during reinstatement after experimenter-imposed abstinence, or abstinence due to extinction training. Ventral pallidum (VP), a key limbic node involved in drug seeking, has well-established roles in conventional reinstatement models tested following extinction training, but it is unclear whether this region also participates in more translationally relevant models of relapse. Here we show that chemogenetic inhibition of VP neurons decreased cocaine-, context-, and cue-induced relapse tested after voluntary, punishment-induced abstinence. This effect was strongest in the most compulsive, punishment-resistant rats, and reinstatement was associated with neural activity in anatomically defined VP subregions. VP inhibition also attenuated the propensity of rats to display "abortive lever pressing," a species-typical risk assessment behavior seen here during punished drug taking, likely resulting from concurrent approach and avoidance motivations. These results indicate that VP, unlike other connected limbic brain regions, is essential for resumption of drug seeking after voluntary abstinence. Since VP inhibition effects were strongest in the most compulsively cocaine-seeking individuals, this may also indicate that VP plays a particularly important role in the most pathological, addiction-like behavior, making it an attractive target for future therapeutic interventions.
成瘾是一种慢性复发性疾病，在康复过程中，许多人在试图自愿戒除药物时会经历多次复发事件。新的临床前复发模型已经出现，这些模型捕捉到了这种常见的人类体验，越来越多的证据表明，在自愿戒断后，药物寻求的恢复会招募到与实验者强制戒断或因消退训练而戒断时不同的神经回路。腹侧苍白球（VP）是参与药物寻求的关键边缘节点，在经过消退训练后的传统再巩固模型测试中具有明确的作用，但尚不清楚该区域是否也参与了更具转化相关性的复发模型。在这里，我们表明，化学遗传抑制 VP 神经元可减少自愿、惩罚诱导的戒断后可卡因、环境和线索诱导的复吸。在最强迫、最能抵抗惩罚的大鼠中，这种效果最强，而再巩固与解剖定义的 VP 亚区中的神经活动有关。VP 抑制还减弱了大鼠表现出“中止压杆”的倾向，这是一种在受惩罚的药物摄入期间在此处观察到的物种典型风险评估行为，可能是由于同时存在接近和回避动机。这些结果表明，VP 与其他连接的边缘脑区不同，是自愿戒断后药物寻求恢复所必需的。由于 VP 抑制作用在最强迫性地寻求可卡因的个体中最强，这也可能表明 VP 在最病态、最类似成瘾的行为中起着特别重要的作用，使其成为未来治疗干预的有吸引力的目标。
