Sex-Specific Role for Egr3 in Nucleus Accumbens D2-Medium Spiny Neurons Following Long-Term Abstinence From Cocaine Self-administration

Michel Engeln, Swarup Mitra, Ramesh Chandra, Utsav Gyawali, Megan E. Fox, David M. Dietz, Mary Kay Lobo

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


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.

Original languageEnglish
Pages (from-to)992-1000
Number of pages9
JournalBiological Psychiatry
Issue number11
StatePublished - 1 Jun 2020
Externally publishedYes


  • Female mice
  • Immediate early gene
  • Relapse
  • Sex differences
  • Transcription factor
  • Withdrawal


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