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A molecularly defined D1 medium spiny neuron subtype negatively regulates cocaine addiction

A molecularly defined D1 medium spiny neuron

Authors: Zheng-dong Zhao, Xiao Han, Renchao Chen, Yiqiong Liu, Aritra Bhattacherjee, Wenqiang Chen, Yi Zhang
Publication: Science Advances
Date: August 12, 2022
Link to article: https://doi.org/10.1126/sciadv.abn3552


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 adminis-tration 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 re-veals an unconventional negative regulatory function of D1 MSNs in drug addiction that operates in a subtype- and projection-specific manner.

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