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Women are more susceptible to developing cocaine dependence than men, but paradoxically, are more responsive to treatment. The potent estrogen, 17β-estradiol (E 2 ), mediates these effects by augmenting cocaine seeking but also promoting extinction of cocaine seeking through E 2 ’s memory-enhancing functions. Although we have previously shown that E 2  facilitates extinction, the neuroanatomical locus of action and underlying mechanisms are unknown. Here we demonstrate that E 2  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 E 2  may facilitate extinction by potentiating intrinsic excitability of IL-mPFC neurons. Because the mnemonic effects of E 2  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 E 2 -induced enhancement of excitability and extinction. We found that E 2 -mediated increases in excitability of IL-mPFC neurons were abolished by Trk receptor blockade. Moreover, blockade of TrkB signaling impaired E 2 -facilitated extinction of cocaine seeking in OVX female rats. Thus, E 2  enhances IL-mPFC neuronal excitability in a TrkB-dependent manner to support extinction of cocaine seeking. Our findings suggest that pharmacological enhancement of E 2  or BDNF/TrkB signaling during extinction-based therapies would improve therapeutic outcome in cocaine-addicted women.

Infralimbic Estradiol Enhances Neuronal Excitability and Facilitates Extinction of Cocaine Seeking in Female Rats via a BDNF/TrkB Mechanism