Tyrosine receptor kinase B receptor activation reverses the impairing effects of acute nicotine on contextual fear extinction

Abstract

Anxiety and stress disorders have been linked to deficits in fear extinction. Our laboratory and others have demonstrated that acute nicotine impairs contextual fear extinction, suggesting that nicotine exposure may have negative effects on anxiety and stress disorder symptomatology. However, the neurobiological mechanisms underlying the acute nicotine-induced impairment of contextual fear extinction are unknown. Therefore, based on the previous studies showing that brain-derived neurotrophic factor is central for fear extinction learning and acute nicotine dysregulates brain-derived neurotrophic factor signaling, we hypothesized that the nicotine-induced impairment of contextual fear extinction may involve changes in tyrosine receptor kinase B signaling. To test this hypothesis, we systemically, intraperitoneally, injected C57BL/6J mice sub-threshold doses (2.5 and 4.0 mg/kg) of 7,8-dihydroxyflavone, a small-molecule tyrosine receptor kinase B agonist that fully mimics the effects of brain-derived neurotrophic factor, or vehicle an hour before each contextual fear extinction session. Mice also received injections, intraperitoneally, of acute nicotine (0.18 mg/kg) or saline 2-4 min before extinction sessions. While the animals that received only 7,8-dihydroxyflavone did not show any changes in contextual fear extinction, 4.0 mg/kg of 7,8-dihydroxyflavone ameliorated the extinction deficits in mice administered acute nicotine. Overall, these results suggest that acute nicotine-induced impairment of context extinction may be related to a disrupted brain-derived neurotrophic factor signaling.

Keywords: Nicotine; brain-derived neurotrophic factor; extinction; post-traumatic stress disorder; tyrosine receptor kinase B receptors.

Figure 1

The schematic of experimental designs. While each box represents a phase of the experiment, the syringe represents 7,8-dihydroxyflavone (7,8-DHF), vehicle, nicotine, or saline injections and the lightning bolt symbol indicates the presentations of the footshocks. FC=Fear Conditioning

Figure 2

7,8-Dihydroxyflavone (7,8-DHF) reverses acute nicotine-induced impairment of contextual fear extinction. Acute nicotine (0.18 mg/kg) impairs contextual fear extinction and 7,8-DHF at the 4.0 mg/kg dose reverses the impairment (n=9–10 per group), (a) Normalized percentage freezing responses during testing and extinction phases, (b) Raw percentage freezing responses during testing and extinction phases, (c) Average number of freezing responses during the first (Binl), second (Bin2), and third (Bin3) hundred of seconds of testing and five extinction sessions. *p<0.05 on Bonferroni-corrected t-tests comparing the nicotine 0.18 mg/kg (Nic 0.18 mg/kg)-7,8-DHF 4.0 mg/kg and Nic 0.18 mg/kg-vehicle groups.