可卡因驱动的神经调节剂对神经传递的调节变化知之甚少。腹侧苍白球(VP)是奖励系统中的关键结构,其中GABA神经传递受阿片类神经肽调节,包括强啡肽.然而,目前尚不清楚强啡肽对VP中不同细胞类型的作用是否不同,以及从可卡因中撤出是否会改变其作用。这里,我们训练了野生型,D1-Cre,A2A-Cre,或vGluT2-Cre:Ai9雄性和雌性小鼠在可卡因条件下的位置偏爱方案中,然后禁欲2周,然后记录GABA能突触输入在应用强啡肽之前或之后电或光遗传学地诱发到鉴定的VP神经元上。我们发现,可卡因CPP和禁欲强啡肽通过突触后机制减弱了对VPGABA神经元的抑制性输入。这种作用在盐水小鼠中不存在。此外,这种作用特别是在表达D1或D2多巴胺受体的伏隔核中等多刺神经元的输入上观察到。与它对VPGABA神经元的影响不同,强啡肽令人惊讶地增强了对VPvGluT2神经元的抑制性输入,但这种影响在可卡因CPP和禁欲后被废除。因此,强啡肽对GABA输入到VPGABA和VPvGluT2神经元具有相反的影响,这些影响受可卡因CPP和禁欲的不同影响。总的来说,我们的数据表明强啡肽通过其在VP中的作用在戒断中发挥作用.由于VPGABA和VPvGluT2神经元对药物寻求行为有对比作用,我们的数据可能表明强啡肽在可卡因戒断中的复杂作用.腹侧苍白球主要由GABA能奖励促进神经元组成,但它也包含一个促进厌恶的谷氨酸能神经元的亚组。Dynorphin,腹侧苍白球中丰富的阿片类神经肽,显示了GABA输入对GABA能和谷氨酸能苍白球神经元的差异调节,因此可能会影响戒断的有益和厌恶方面。的确,反复暴露于可卡因后的禁欲以细胞类型特异性的方式改变了强啡肽的作用;禁欲后,强啡肽抑制了对“奖励”GABA能神经元的抑制驱动,但停止了对“厌恶”谷氨酸能神经元的抑制驱动。这反映了强啡肽在可卡因奖励和禁欲中的复杂作用。
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 VPGABA 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 VPGABA neurons, dynorphin surprisingly potentiated the inhibitory input on VPvGluT2 neurons, but this effect was abolished after cocaine CPP and abstinence. Thus, dynorphin has contrasting influences on GABA input to VPGABA and VPvGluT2 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 VPGABA and VPvGluT2 neurons have contrasting effects on drug-seeking behavior, our data may indicate a complex role for dynorphin in withdrawal from cocaine.SIGNIFICANCE STATEMENT 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.