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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Behav. Neurosci. | doi: 10.3389/fnbeh.2019.00168

Infralimbic estradiol enhances neuronal excitability and facilitates extinction of cocaine seeking in female rats via a BDNF/TrkB mechanism

  • 1University of Wisconsin–Milwaukee, United States
  • 2Kent State University, United States

Women are more susceptible to developing cocaine dependence than men, but paradoxically, are more responsive to treatment. The potent estrogen, 17β-estradiol (E2), mediates these effects by augmenting cocaine seeking but also promoting extinction of cocaine seeking through E2’s memory-enhancing functions. Although we have previously shown that E2 facilitates extinction, the neuroanatomical locus of action and underlying mechanisms are unknown. Here we demonstrate that E2 infused directly into the infralimbic medial prefrontal cortex (IL-mPFC), a region critical for extinction consolidation, enhances extinction of cocaine seeking in ovariectomized (OVX) female rats. Using patch-clamp electrophysiology, we show that E2 may facilitate extinction by potentiating intrinsic excitability of IL-mPFC neurons. Because the mnemonic effects of E2 are known to be regulated by brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), we examined whether BDNF/TrkB signaling was necessary for E2-induced enhancement of excitability and extinction. We found that E2-mediated increases in excitability of IL-mPFC neurons were abolished by Trk receptor blockade. Moreover, blockade of TrkB signaling impaired E2-facilitated extinction of cocaine seeking in OVX female rats. Thus, E2 enhances IL-mPFC neuronal excitability in a TrkB-dependent manner to support extinction of cocaine seeking. Our findings suggest that pharmacological enhancement of E2 or BDNF/TrkB signaling during extinction-based therapies would improve therapeutic outcome in cocaine-addicted women.

Keywords: cocaine abuse, Conditioned place preference (CPP), Estrogens, Brain derived neurotrophic factor (BDNF), patch clamp electrophysiology, intrinsic excitability, Extinction learning, medial prefrontal cortex (mPFC)

Received: 09 May 2019; Accepted: 11 Jul 2019.

Edited by:

Jeansok J. Kim, University of Washington, United States

Reviewed by:

Hongjoo J. Lee, University of Texas at Austin, United States
Susan Sangha, Purdue University, United States  

Copyright: © 2019 Yousuf, Smies, Hafenbreidel, Tuscher, Frick and Mueller. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Devin Mueller, Kent State University, Kent, United States,