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

Liu, Xiaojie, Vickstrom, Casey R, Yu, Hao, Liu, Shuai, Snarrenberg, Shana Terai, Friedman, Vladislav, Mu, Lianwei, Chen, Bixuan, Kelly, Thomas J, Baker, David A, Liu, Qing-song·2022·eLife
DOI 10.7554/elife.80747PMC PMC9436413

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Abstract

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.

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Metadata

Authors
Liu, X., Vickstrom, C. R., Yu, H., Liu, S., Snarrenberg, S. T., Friedman, V., Mu, L., Chen, B., Kelly, T. J., Baker, D. A., & Liu, Q.-S.
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2022-08-22
Volume
11
ISSN
2050-084X
DOI
10.7554/elife.80747
PMC
PMC9436413
Cited by
16
References
4
Language
en
Licence
Funders
  • National Institute on Drug Abuse (R01DA035217, R01DA047269, R01DA050180, F31DA054759)
  • National Institute of Mental Health (F30MH115536, MH121454)

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