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

Abstract

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 <i>tachykinin 2</i>-expressing D1 MSN subtype (<i>Tac2⁺</i>), present in both rodent and primate striatum, using cocaine addiction mouse models. We found that acute cocaine administration reduces <i>Tac2</i> neuronal activity, and cocaine conditioning alters neuronal response related to cocaine reward contextual associations. In addition, activation/inhibition of <i>Tac2⁺</i> neurons attenuates/promotes cocaine-induced conditioned place preference and cocaine intravenous self-administration. Furthermore, stimulation of the NAc-to-lateral hypothalamic projection of <i>Tac2⁺</i> 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.