Epac2 in midbrain dopamine neurons contributes to cocaine reinforcement via enhancement of dopamine release.

Xiaojie Liu, Casey R Vickstrom, Hao Yu, Shuai Liu, Shana Terai Snarrenberg, Vladislav Friedman, Lianwei Mu, Bixuan Chen, Thomas J Kelly, David A Baker, Qing-Song Liu

eLife 2022 Aug 22

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Repeated exposure to drugs of abuse results in an upregulation of cAMP signaling in the mesolimbic dopamine system, a molecular adaptation thought to be critically involved in the development of drug dependence. Exchange protein directly activated by cAMP (Epac2) is a major cAMP effector abundantly expressed in the brain. However, it remains unknown whether Epac2 contributes to cocaine reinforcement. Here, we report that Epac2 in the mesolimbic dopamine system promotes cocaine reinforcement via enhancement of dopamine release. Conditional knockout of Epac2 from midbrain dopamine neurons (Epac2-cKO) and the selective Epac2 inhibitor ESI-05 decreased cocaine self-administration in mice under both fixed-ratio and progressive-ratio reinforcement schedules and across a broad range of cocaine doses. In addition, Epac2-cKO led to reduced evoked dopamine release, whereas Epac2 agonism robustly enhanced dopamine release in the nucleus accumbens in vitro. This mechanism is central to the behavioral effects of Epac2 disruption, as chemogenetic stimulation of ventral tegmental area (VTA) dopamine neurons via deschloroclozapine (DCZ)-induced activation of Gs-DREADD increased dopamine release and reversed the impairment of cocaine self-administration in Epac2-cKO mice. Conversely, chemogenetic inhibition of VTA dopamine neurons with Gi-DREADD reduced dopamine release and cocaine self-administration in wild-type mice. Epac2-mediated enhancement of dopamine release may therefore represent a novel and powerful mechanism that contributes to cocaine reinforcement. © 2022, Liu et al.

Citation

Xiaojie Liu, Casey R Vickstrom, Hao Yu, Shuai Liu, Shana Terai Snarrenberg, Vladislav Friedman, Lianwei Mu, Bixuan Chen, Thomas J Kelly, David A Baker, Qing-Song Liu. Epac2 in midbrain dopamine neurons contributes to cocaine reinforcement via enhancement of dopamine release. eLife. 2022 Aug 22;11