The striatum plays a critical role in regulating addiction-related behaviors. The conventional dichotomy model suggests that striatal D1/D2 medium spiny neurons (MSNs) positively/negatively regulate addiction-related behaviors. However, this model does not account for the neuronal heterogeneity and functional diversity of the striatum, and whether MSN subtypes beyond the pan-D1/D2 populations play distinct roles in drug addiction remains unknown. We characterized the role of a tachykinin 2 –expressing D1 MSN subtype ( Tac2 + ), present in both rodent and primate striatum, using cocaine addiction mouse models. We found that acute cocaine administration reduces Tac2 neuronal activity, and cocaine conditioning alters neuronal response related to cocaine reward contextual associations. In addition, activation/inhibition of Tac2 + neurons attenuates/promotes cocaine-induced conditioned place preference and cocaine intravenous self-administration. Furthermore, stimulation of the NAc-to-lateral hypothalamic projection of Tac2 + neurons suppresses cocaine reward behavior. Our study reveals an unconventional negative regulatory function of D1 MSNs in drug addiction that operates in a subtype- and projection-specific manner.

中文翻译：

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分子定义的 D1 中型多棘神经元亚型负调节可卡因成瘾


纹状体在调节成瘾相关行为中起着至关重要的作用。传统的二分法模型表明纹状体 D1/D2 中型多棘神经元 (MSN) 正向/负向调节成瘾相关行为。然而，该模型没有考虑纹状体的神经元异质性和功能多样性，并且泛 D1/D2 群体之外的 MSN 亚型是否在药物成瘾中发挥独特的作用仍然未知。我们描述了一个角色速激肽2 –表达 D1 MSN 亚型（塔克2 + ），存在于啮齿类动物和灵长类动物纹状体中，使用可卡因成瘾小鼠模型。我们发现急性可卡因给药可减少塔克2神经元活动和可卡因调节改变与可卡因奖励情境关联相关的神经元反应。此外，激活/抑制塔克2 +神经元减弱/促进可卡因诱导的条件性位置偏好和可卡因静脉自我给药。此外，刺激 NAc 到下丘脑外侧的投射塔克2 +神经元抑制可​​卡因奖赏行为。我们的研究揭示了 D1 MSN 在药物成瘾中的非常规负调节功能，该功能以亚型和投射特异性方式发挥作用。