Abstract
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.