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Isoforms, Clocks, and Acetylcholine: Regulation of Cocaine’s Effects by Dopamine D2 Receptors

Creative Commons 'BY-NC' version 4.0 license

Cocaine is a highly addictive stimulant which immensely raises dopamine levels in brain areas controlling motor and reward functions. Dopamine signaling is controlled by the five dopamine receptors (D1-D5) which are part of the G-protein coupled receptor superfamily. The dopamine D2 receptor (D2R) plays a key role regulating cocaine’s effects. However, its study has been difficult due to its ubiquitous expression throughout the brain using pharmacological tools alone. Moreover, the presence of two D2R isoforms has further complicated the study of this receptor. Using a combination of pharmacological and genetic approaches, we investigated the isoform- and cell- specific roles of D2R in mediating the effects and consequences of cocaine in mouse models. Here, we show that while both isoforms of D2R are sufficient in the control of basal behaviors, under dopaminergic challenge the long D2R isoform (D2L) contributes largely to post-synaptic heteroreceptor functions while the short D2R isoform (D2S) has a predominant pre-synaptic autoreceptor function (Radl et al. 2018). Furthermore, we show that D2R signaling in indirect pathway medium spiny neurons (iMSNs) has a major control of the circadian transcriptome and metabolome in the nucleus accumbens through control of PPAR activation (Brami-Cherrier et al. 2020). Relatedly, we show that D2R signaling in iMSNs contributes to the synchrony of the liver metabolic clock (Cervantes et al. 2022). Lastly, by regulating the balance of dopamine and acetylcholine in the striatum, D2R signaling in cholinergic interneurons (ChIs), underlies cocaine’s psychostimulating and rewarding effects (Lewis et al. 2020).

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