Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, USA.
Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA.
Neuropsychopharmacology. 2021 Oct;46(11):1969-1980. doi: 10.1038/s41386-021-01067-6. Epub 2021 Jun 23.
Persistent susceptibility to cue-induced relapse is a cardinal feature of addiction. Discriminative stimuli (DSs) are one type of drug-associated cue that signal drug availability (DS+) or unavailability (DS-) and control drug seeking prior to relapse. We previously established a trial-based procedure in rats to isolate DSs from context, conditioned stimuli, and other drug-associated cues during cocaine self-administration and demonstrated DS-controlled cocaine seeking up to 300 abstinence days. The behavioral and neural mechanisms underlying trial-based DS-control of drug seeking have rarely been investigated. Here we show that following discrimination training in our trial-based procedure, the DS+ and DS- independently control the expression and suppression of cocaine seeking during abstinence. Using microinjections of GABA + GABA receptor agonists (muscimol + baclofen) in medial prefrontal cortex, we report that infralimbic, but not prelimbic, subregion of medial prefrontal cortex is critical to persistent DS-controlled relapse to cocaine seeking after prolonged abstinence, but not DS-guided discriminated cocaine seeking or DS-controlled cocaine self-admininstration. Finally, using ex vivo whole-cell recordings from pyramidal neurons in the medial prefrontal cortex, we demonstrate that the disruption of DS-controlled cocaine seeking following infralimbic cortex microinjections of muscimol+baclofen is likely a result of suppression of synaptic transmission in the region via a presynaptic mechanism of action.
持续易感性导致线索诱发的复吸是成瘾的一个主要特征。辨别刺激（DS）是与药物相关的线索之一，它可以预示药物的可用性（DS+）或不可用性（DS-），并在复吸前控制药物寻求。我们之前在大鼠中建立了一种基于试验的程序，用于在可卡因自我给药期间从环境、条件刺激和其他与药物相关的线索中分离 DS，并证明了 DS 控制的可卡因寻求行为可达 300 天的戒断期。基于试验的 DS 控制药物寻求的行为和神经机制很少被研究。在这里，我们表明，在我们的基于试验的程序的辨别训练之后，DS+和 DS-独立控制着可卡因寻求在戒断期间的表达和抑制。通过在内侧前额叶皮层中注射 GABA+GABA 受体激动剂（muscimol+baclofen），我们报告说，在长时间的戒断后，内侧前额叶皮层的眶额回，但不是额前回，亚区对于持续的 DS 控制可卡因寻求复吸至关重要，但对于 DS 引导的辨别可卡因寻求或 DS 控制的可卡因自我给药则不是。最后，通过对内侧前额叶皮层中的锥体神经元进行离体全细胞记录，我们证明了内侧前额叶皮层 infralimbic 皮质微注射 muscimol+baclofen 后，DS 控制的可卡因寻求行为的中断很可能是由于该区域的突触传递被抑制，这是通过一种突触前作用机制导致的。
