Cell Physiology Lab, Department of Physiology, Seoul National University College of Medicine, Seoul, Republic of Korea.
Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea.
Biol Psychiatry. 2023 Sep 1;94(5):378-392. doi: 10.1016/j.biopsych.2022.12.024. Epub 2023 Jan 12.
Unbalanced activity of medium spiny neurons (MSNs) of the direct and indirect pathways mediates reward-related behaviors induced by addictive drugs. Prelimbic (PL) input to MSNs in the nucleus accumbens core (NAcC) plays a key role in cocaine-induced early locomotor sensitization (LS). However, the adaptive plastic changes at PL-to-NAcC synapses underlying early LS remain unclear.
Using transgenic mice and retrograde tracing, we identified NAcC-projecting pyramidal neurons (PNs) in the PL cortex based on the expression of dopamine receptor types (D1R or D2R). To examine cocaine-induced alterations in PL-to-NAcC synapses, we measured excitatory postsynaptic current amplitudes evoked by optostimulation of PL afferents to MSNs. Riluzole was chosen to test the effects of PL excitability on cocaine-induced changes of PL-to-NAcC synapses.
NAcC-projecting PNs were segregated into D1R- and D2R-expressing PNs (D1- and D2-PNs, respectively), and their excitability was opposingly regulated by respective dopamine agonists. Both D1- and D2-PNs exhibited balanced innervation of direct MSNs and indirect MSNs in naïve animals. Repeated cocaine injections resulted in biased synaptic strength toward direct MSNs through presynaptic mechanisms in both D1- and D2-PNs, although D2R activation reduced the D2-PN excitability. Under group 1 metabotropic glutamate receptors coactivation, however, D2R activation enhanced the D2-PN excitability. The cocaine-induced rewiring accompanied LS, and both rewiring and LS were precluded by PL infusion of riluzole, which reduced the intrinsic excitability of PL neurons.
These findings indicate that cocaine-induced rewiring of PL-to-NAcC synapses correlates well with early behavioral sensitization and that rewiring and LS can be prevented by riluzole-induced reduction of excitability of PL neurons.
直接和间接通路的中间神经元（MSNs）活性失衡介导了成瘾药物引起的与奖励相关的行为。扣带回皮层的边缘前皮质（PL）输入到伏隔核核心（NAcC）中的 MSNs 中在可卡因诱导的早期运动敏化（LS）中起着关键作用。然而，PL 到 NAcC 突触的适应性可塑性变化在早期 LS 中尚不清楚。
使用转基因小鼠和逆行追踪，我们根据多巴胺受体类型（D1R 或 D2R）的表达鉴定了 PL 皮层中的 NAcC 投射锥体神经元（PNs）。为了研究可卡因诱导的 PL 到 NAcC 突触的改变，我们测量了光刺激 PL 传入纤维到 MSNs 时诱发的兴奋性突触后电流幅度。选择利鲁唑来测试 PL 兴奋性对可卡因诱导的 PL 到 NAcC 突触变化的影响。
NAcC 投射 PNs 分为 D1R 和 D2R 表达的 PNs（分别为 D1-和 D2-PNs），它们的兴奋性分别受到各自多巴胺激动剂的反向调节。在未处理的动物中，D1-和 D2-PNs 对直接 MSNs 和间接 MSNs 均具有平衡的支配。重复可卡因注射通过直接 MSNs 的突触前机制导致两种 D1-和 D2-PNs 中的突触强度偏向，尽管 D2R 激活降低了 D2-PN 的兴奋性。然而，在组 1 代谢型谷氨酸受体共激活下，D2R 激活增强了 D2-PN 的兴奋性。可卡因诱导的重布线伴随着 LS，并且 PL 输注利鲁唑可防止重布线和 LS，利鲁唑降低了 PL 神经元的内在兴奋性。
这些发现表明，可卡因诱导的 PL 到 NAcC 突触的重布线与早期行为敏化密切相关，并且通过利鲁唑诱导的 PL 神经元兴奋性降低可以预防重布线和 LS。
