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. 2019 Jul 31:13:168.
doi: 10.3389/fnbeh.2019.00168. eCollection 2019.

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

Hanna Yousuf  1 , Chad W Smies  1 , Madalyn Hafenbreidel  1 , Jennifer J Tuscher  1 , Ashley M Fortress  1 , Karyn M Frick  1 , Devin Mueller  1   2
Affiliations

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

Hanna Yousuf et al. Front Behav Neurosci. .

Abstract

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: brain-derived neurotrophic factor; cocaine abuse; conditioned place preference (CPP); electrophysiology; estrogens; extinction learning; intrinsic excitability; medial prefrontal cortex (mPFC).

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Figures

Figure 1
Figure 1
Infusions of E2 into infralimbic-medial prefrontal cortex (IL-mPFC) enhance extinction of a cocaine conditioned place preference (CPP). (A) Coronal drawings showing injector tip placements for IL-mPFC infusions. (B) IL-mPFC infusions (arrows) of E2 (n = 21) but not vehicle (n = 21) before each CPP trial promoted extinction of a CPP. **p < 0.01, and *p < 0.05. Error bars indicate SEM.
Figure 2
Figure 2
Bath-application of E2 potentiates IL-mPFC pyramidal neuron excitability. (A) Photomicrograph of a biocytin-filled IL-mPFC pyramidal neuron. Scale bar, 50 μm. (B) Individual traces of current-evoked action potentials (APs) from IL-mPFC pyramidal neurons before (top) and after (bottom) bath-application of E2 in slices from ovariectomized (OVX) female rats that were systemically injected with 2-hydroxypropyl-β-cyclodextrin (HBC)-vehicle (left) or with E2 (right). Scale bars, 10 mV (vertical) and 500 ms (horizontal). (C) Compared to artificial cerebral spinal fluid (aCSF) alone (n = 10), bath-application of E2 (n = 10) enhances intrinsic excitability in IL-mPFC neurons from OVX female rats that were systemically injected with HBC-vehicle prior to recordings. (D) Compared to aCSF alone (n = 9), bath-application of E2 (n = 9) does not enhance intrinsic excitability in IL-mPFC neurons from OVX female rats that were systemically injected with E2 prior to recordings. *p < 0.05. Error bars indicate SEM.
Figure 3
Figure 3
Blockade of tropomyosin-related kinase (Trk) receptors prevents E2-induced potentiation of IL-mPFC neuronal intrinsic excitability. (A) Individual traces of current-evoked APs from IL-mPFC neurons that were not incubated in K-252a (left) or were incubated in K-252a (right), before (top) and after (bottom) bath-application of E2. Scale bars, 10 mV (vertical) and 500 ms (horizontal). (B) IL-mPFC neurons treated with E2 (n = 10) have increased intrinsic excitability compared to aCSF alone (n = 10) or neurons that were incubated in K-252a prior to bath-application of E2 (n = 7). (C) Representative waveforms showing fast afterhyperpolarization (fAHP) in neurons that were not incubated in K-252a (left) or were incubated in K-252a (right), and after bath-application of E2. Scale bars, 10 mV (vertical) and 10 ms (horizontal). (D) E2 suppresses fAHP and this effect was blocked in the presence of Trk receptor antagonist, K-252a. *p < 0.05. Error bars indicate SEM.
Figure 4
Figure 4
Injections of selective TrkB receptor antagonist disrupted E2-induced facilitation of extinction of a cocaine CPP. Systemic injections (arrows) of E2 + ANA-12 (n = 9) but not E2 + vehicle (n = 10) before the first four CPP trials impaired extinction. ***p < 0.001, **p < 0.01, and *p < 0.05. Error bars indicate SEM.
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