Sex-Specific Role for Egr3 in Nucleus Accumbens D2-Medium Spiny Neurons Following Long-Term Abstinence From Cocaine Self-administration
Biological Psychiatry. 2020-06-01; 87(11): 992-1000
DOI: 10.1016/j.biopsych.2019.10.019
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Engeln M(1), Mitra S(2), Chandra R(1), Gyawali U(1), Fox ME(1), Dietz DM(3), Lobo MK(4).
Author information:
(1)Department of Anatomy and Neurobiology, University of Maryland School of
Medicine, Baltimore, Maryland.
(2)Department of Pharmacology and Toxicology, Program in Neuroscience, Research
Institute on Addictions, The State University of New York at Buffalo, Buffalo,
New York.
(3)Department of Pharmacology and Toxicology, Program in Neuroscience, Research
Institute on Addictions, The State University of New York at Buffalo, Buffalo,
New York; Department of Psychology, The State University of New York at Buffalo,
Buffalo, New York.
(4)Department of Anatomy and Neurobiology, University of Maryland School of
Medicine, Baltimore, Maryland. Electronic address: .
BACKGROUND: We previously showed that the transcription factor Egr3 (early growth
response 3) is oppositely regulated in nucleus accumbens (NAc) cell subtypes 24
hours following cocaine exposure and bidirectionally mediates cocaine-related
behaviors in male rodents. Overexpressing Egr3 in D2 receptor-containing medium
spiny neurons (D2-MSNs) before drug exposure reduces the rewarding and
psychomotor sensitization effects of cocaine. However, it is unknown if Egr3
plays a role in long-term neuroadaptations in the NAc and relapse to cocaine
seeking.
METHODS: We measured EGR3 protein levels in the NAc following 20 days of forced
abstinence from intravenous cocaine self-administration in 10-week-old Sprague
Dawley rats and C57BL/6 mice. In 8- to 10-week-old A2A-Cre mice, we used virally
mediated Egr3 overexpression in NAc D2-MSNs to test the role of Egr3 on operant
responding during seeking, extinction, and drug-induced reinstatement of cocaine
self-administration. To evaluate if Egr3 contributed to sex differences to
cocaine relapse, we conducted these procedures in both male and female rodents.
RESULTS: We found that EGR3 expression was reduced only in female rodents after
20 days of forced abstinence. Additionally, we showed that our
self-administration paradigm in mice recapitulated the sex differences in cocaine
intake and relapse demonstrated in humans and rats. Finally, whereas Egr3
overexpression in D2-MSNs during forced abstinence facilitated extinction and
blunted drug-induced reinstatement in female mice, it had the opposite effect in
male mice.
CONCLUSIONS: We showed that the immediate early gene Egr3 has long-term effects
on drug-related behaviors. Our work suggests that changes in Egr3 expression in
D2-MSNs contributes to sex differences in cocaine relapse.
Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All
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