Epac2 in midbrain dopamine neurons contributes to cocaine reinforcement via facilitation of dopamine release
- Medical College of Wisconsin, United States
- Marquette University, United States
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.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting file; Source Data files have been provided for figures 1-7. Custom code used for the analysis of the fiber photometry data is available at https://github.com/xiaojieliu17/Fiber-photometry.
Article and author information
Author details
Funding
National Institute on Drug Abuse (R01DA035217)
- Qing-song Liu
National Institute on Drug Abuse (R01DA047269)
- Qing-song Liu
National Institute of Mental Health (F30MH115536)
- Casey R Vickstrom
National Institute on Drug Abuse (R01DA050180)
- David A Baker
National Institute on Drug Abuse (F31DA054759)
- Vladislav Friedman
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal maintenance and use were in accordance with protocols (AUA #2420) approved by the Institutional Animal Care and Use Committee of Medical College of Wisconsin. All surgery was performed under ketamine and xylazine anesthesia, and every effort was made to minimize suffering.
Copyright
© 2022, Liu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,517
- views
-
- 308
- downloads
-
- 8
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Epac2 in midbrain dopamine neurons contributes to cocaine reinforcement via facilitation of dopamine release
eLife 11:e80747.
https://doi.org/10.7554/eLife.80747
Further reading
-
- Neuroscience
This study examines whether auditory cortex anatomy reflects multilingual experience, specifically individuals’ phonological repertoire. Using data from over 200 participants exposed to 1–7 languages across 36 languages, we analyzed the role of language experience and typological distances between languages they spoke in shaping neural signatures of multilingualism. Our findings reveal a negative relationship between the thickness of the left and right second transverse temporal gyrus (TTG) and participants’ degree of multilingualism. Models incorporating phoneme-level information in the language experience index explained the most variance in TTG thickness, suggesting that a more extensive and more phonologically diverse language experience is associated with thinner cortices in the second TTG. This pattern, consistent across two datasets, supports the idea of experience-driven pruning and neural efficiency. Our findings indicate that experience with typologically distant languages appear to impact the brain differently than those with similar languages. Moreover, they suggest that early auditory regions seem to represent phoneme-level cross-linguistic information, contrary to the most established models of language processing in the brain, which suggest that phonological processing happens in more lateral posterior superior temporal gyrus (STG) and superior temporal sulcus (STS).
-
- Neuroscience
The brain is organized into systems and networks of interacting components. The functional connections among these components give insight into the brain's organization and may underlie some cognitive effects of aging. Examining the relationship between individual differences in brain organization and cognitive function in older adults who have reached oldest old ages with healthy cognition can help us understand how these networks support healthy cognitive aging. We investigated functional network segregation in 146 cognitively healthy participants aged 85+ in the McKnight Brain Aging Registry. We found that the segregation of the association system and the individual networks within the association system [the fronto-parietal network (FPN), cingulo-opercular network (CON) and default mode network (DMN)], has strong associations with overall cognition and processing speed. We also provide a healthy oldest-old (85+) cortical parcellation that can be used in future work in this age group. This study shows that network segregation of the oldest-old brain is closely linked to cognitive performance. This work adds to the growing body of knowledge about differentiation in the aged brain by demonstrating that cognitive ability is associated with differentiated functional networks in very old individuals representing successful cognitive aging.
