Estradiol Regulation of the Prelimbic Cortex and the Reinstatement of Cocaine Seeking in Female Rats. J Neurosci 2021 Jun 16;41(24):5303-5314
Date
04/22/2021Pubmed ID
33879537Pubmed Central ID
PMC8211550DOI
10.1523/JNEUROSCI.3086-20.2021Scopus ID
2-s2.0-85108385872 (requires institutional sign-in at Scopus site) 11 CitationsAbstract
Relapse susceptibility in women with substance use disorders (SUDs) has been linked to the estrogen, 17β-estradiol (E2). Our previous findings in female rats suggest that the influence of E2 on cocaine seeking can be localized to the prelimbic prefrontal cortex (PrL-PFC). Here, we investigated the receptor mechanisms through which E2 regulates the reinstatement of extinguished cocaine seeking. Sexually mature female rats underwent intravenous cocaine self-administration (0.5 mg/inf; 14 × 2 h daily) and extinction, and then were ovariectomized before reinstatement testing. E2 (10 µg/kg, i.p.) alone did not reinstate cocaine seeking, but it potentiated reinstatement when combined with an otherwise subthreshold priming dose of cocaine. A similar effect was observed following intra-PrL-PFC microinfusions of E2 and by systemic or intra-PrL-PFC administration of the estrogen receptor (ER)β agonist, DPN, but not agonists at ERα or the G-protein-coupled ER1 (GPER1). By contrast, E2-potentiated reinstatement was prevented by intra-PrL-PFC microinfusions of the ERβ antagonist, MPP, or the GPER1 antagonist, G15, but not an ERα antagonist. Whole-cell recordings in PrL-PFC layer (L)5/6 pyramidal neurons revealed that E2 decreases the frequency, but not amplitude, of GABAA-dependent miniature IPSCs (mIPSC). As was the case with E2-potentiated reinstatement, E2 reductions in mIPSC frequency were prevented by ERβ and GPER1, but not ERα, antagonists and mimicked by ERβ, but not GPER1, agonists. Altogether, the findings suggest that E2 activates ERβ and GPER1 in the PrL-PFC to attenuate the GABA-mediated constraint of key outputs that mediate cocaine seeking.
Author List
Doncheck EM, Anderson EM, Konrath CD, Liddiard GT, DeBaker MC, Urbanik LA, Hearing MC, Mantsch JRAuthor
John Mantsch PhD Chair, Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCocaine-Related Disorders
Drug-Seeking Behavior
Estradiol
Estrogen Receptor beta
Extinction, Psychological
Female
Prefrontal Cortex
Rats
Rats, Sprague-Dawley
Receptors, G-Protein-Coupled
