1] Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA [2] National Institute on Drug Dependence, Peking University, Beijing, People's Republic of China.
Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA.
Neuropsychopharmacology. 2014 Apr;39(5):1169-77. doi: 10.1038/npp.2013.318. Epub 2013 Nov 15.
Addictive drug use causes long-lasting changes in synaptic strength and dendritic spine morphology in the nucleus accumbens that might underlie the vulnerability to relapse. Although activity in mesocorticolimbic circuitry is required for reinstating cocaine seeking, its role in reinstatement-associated synaptic plasticity is not well characterized. Using rats extinguished from cocaine self-administration, we found potentiated synaptic strength (assessed as the AMPA/NMDA current amplitude ratio) and increased spine head diameter in medium spiny neurons in the accumbens core (NAcore). The basal changes in synaptic strength and morphology in cocaine-extinguished animals were further augmented during cocaine-induced reinstatement. Two NAcore afferents contributing to cocaine reinstatement are glutamatergic inputs from the prelimbic prefrontal cortex (PL) and dopamine from the ventral tegmental area (VTA). Pharmacological inhibition of either PL or VTA prevented cocaine-primed reinstatement. However, inhibiting the PL further potentiated AMPA/NMDA and spine head diameter, while inactivating the VTA or the combined systemic administration of dopamine D1 and D2 antagonists prevented the increase in AMPA/NMDA and spine diameter induced by cocaine priming. These data indicate that neuronal activity in the VTA and associated dopamine receptor stimulation is necessary for the synaptic potentiation in the NAcore during cocaine-induced reinstatement. Although activity in the PL was necessary for reinstatement, it inhibited synaptic potentiation initiated by an acute cocaine injection. Thus, although the PL and VTA differentially regulate the direction of synaptic plasticity induced by a cocaine-priming injection, coordinated synaptic potentiation by both NAcore afferents is necessary for cocaine-induced relapse.
药物成瘾会导致伏隔核中突触强度和树突棘形态的持久变化，这可能是导致易复发的基础。尽管中脑边缘奖赏回路的活动对于可卡因寻求的恢复是必需的，但它在恢复相关的突触可塑性中的作用尚未得到很好的描述。通过使可卡因自我给药的大鼠戒除药物，我们发现伏隔核核心（NAcore）中的中间神经元的突触强度（以 AMPA/NMDA 电流幅度比评估）增强，并且棘头直径增大。可卡因戒断动物的基础突触强度和形态变化在可卡因诱导的恢复过程中进一步增强。导致可卡因恢复的两个 NAcore 传入通路是来自前额叶皮层（PL）的谷氨酸能输入和来自腹侧被盖区（VTA）的多巴胺。PL 或 VTA 的药理学抑制均可防止可卡因引发的恢复。然而，抑制 PL 进一步增强了 AMPA/NMDA 和棘头直径，而 VTA 失活或联合给予多巴胺 D1 和 D2 拮抗剂则阻止了可卡因引发的 AMPA/NMDA 和棘头直径增加。这些数据表明，VTA 中的神经元活动和相关的多巴胺受体刺激对于可卡因诱导的恢复过程中 NAcore 中的突触增强是必需的。尽管 PL 中的活动对于恢复是必需的，但它抑制了急性可卡因注射引发的突触增强。因此，尽管 PL 和 VTA 以不同的方式调节可卡因引发的注射诱导的突触可塑性的方向，但 NAcore 传入神经的协调突触增强对于可卡因诱导的复发是必需的。
