Department of Medical Neurobiology, Faculty of Medicine, The Institute for Medical Research Israel-Canada, The Hebrew University of Jerusalem, Israel 9112102.
Department of Medical Neurobiology, Faculty of Medicine, The Institute for Medical Research Israel-Canada, The Hebrew University of Jerusalem, Israel 9112102
J Neurosci. 2020 Feb 5;40(6):1321-1331. doi: 10.1523/JNEUROSCI.1262-19.2019. Epub 2019 Dec 13.
Cocaine-driven changes in the modulation of neurotransmission by neuromodulators are poorly understood. The ventral pallidum (VP) is a key structure in the reward system, in which GABA neurotransmission is regulated by opioid neuropeptides, including dynorphin. However, it is not known whether dynorphin acts differently on different cell types in the VP and whether its effects are altered by withdrawal from cocaine. Here, we trained wild-type, D1-Cre, A2A-Cre, or vGluT2-Cre:Ai9 male and female mice in a cocaine conditioned place preference protocol followed by 2 weeks of abstinence, and then recorded GABAergic synaptic input evoked either electrically or optogenetically onto identified VP neurons before and after applying dynorphin. We found that after cocaine CPP and abstinence dynorphin attenuated inhibitory input to VP neurons through a postsynaptic mechanism. This effect was absent in saline mice. Furthermore, this effect was seen specifically on the inputs from nucleus accumbens medium spiny neurons expressing either the D1 or the D2 dopamine receptor. Unlike its effect on VP neurons, dynorphin surprisingly potentiated the inhibitory input on VP neurons, but this effect was abolished after cocaine CPP and abstinence. Thus, dynorphin has contrasting influences on GABA input to VP and VP neurons and these influences are affected differentially by cocaine CPP and abstinence. Collectively, our data suggest a role for dynorphin in withdrawal through its actions in the VP. As VP and VP neurons have contrasting effects on drug-seeking behavior, our data may indicate a complex role for dynorphin in withdrawal from cocaine. The ventral pallidum consists mainly of GABAergic reward-promoting neurons, but it also encloses a subgroup of aversion-promoting glutamatergic neurons. Dynorphin, an opioid neuropeptide abundant in the ventral pallidum, shows differential modulation of GABA input to GABAergic and glutamatergic pallidal neurons and may therefore affect both the rewarding and aversive aspects of withdrawal. Indeed, abstinence after repeated exposure to cocaine alters dynorphin actions in a cell-type-specific manner; after abstinence dynorphin suppresses the inhibitory drive on the "rewarding" GABAergic neurons but ceases to modulate the inhibitory drive on the "aversive" glutamatergic neurons. This reflects a complex role for dynorphin in cocaine reward and abstinence.
可卡因驱动的神经调质对神经传递的调制变化知之甚少。腹侧苍白球（VP）是奖励系统的关键结构，其中 GABA 神经传递受包括强啡肽在内的阿片神经肽调节。然而，目前尚不清楚强啡肽是否对 VP 中的不同细胞类型有不同的作用，以及其作用是否因可卡因戒断而改变。在这里，我们在可卡因条件性位置偏好方案中训练了野生型、D1-Cre、A2A-Cre 或 vGluT2-Cre：Ai9 雄性和雌性小鼠，然后在应用强啡肽前后，通过电或光遗传学记录到鉴定的 VP 神经元上的 GABA 能突触输入。我们发现，在可卡因 CPP 和戒断后，强啡肽通过突触后机制减弱了对 VP 神经元的抑制性输入。在盐水组小鼠中没有这种作用。此外，这种作用仅见于表达 D1 或 D2 多巴胺受体的伏隔核中间神经元的输入。与对 VP 神经元的作用不同，强啡肽出人意料地增强了对 VP 神经元的抑制性输入，但这种作用在可卡因 CPP 和戒断后被消除。因此，强啡肽对 VP 和 VP 神经元的 GABA 输入有相反的影响，这些影响受可卡因 CPP 和戒断的影响不同。总的来说，我们的数据表明强啡肽在 VP 中的作用与其在戒断中的作用有关。由于 VP 和 VP 神经元对觅药行为有相反的影响，我们的数据可能表明强啡肽在可卡因戒断中的作用复杂。腹侧苍白球主要由促进奖赏的 GABA 能神经元组成，但它也包含一组促进厌恶的谷氨酸能神经元。强啡肽是一种丰富的阿片神经肽，对 GABA 能和谷氨酸能苍白球神经元的 GABA 输入有不同的调节作用，因此可能影响戒断的奖赏和厌恶方面。事实上，反复接触可卡因后戒断会以细胞类型特异性的方式改变强啡肽的作用；戒断后，强啡肽抑制了“奖赏”GABA 能神经元的抑制性驱动，但不再调节“厌恶”谷氨酸能神经元的抑制性驱动。这反映了强啡肽在可卡因奖赏和戒断中的复杂作用。
