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Prazosin during fear conditioning facilitates subsequent extinction in male C57Bl/6N mice

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Abstract

Rationale

Recovery from a traumatic experience requires extinction of cue-based fear responses, a process that is impaired in post-traumatic stress disorder. While studies suggest a link between fear behavioral flexibility and noradrenaline signaling, the role of specific receptors and brain regions in these effects is unclear.

Objectives

Here, we examine the role of prazosin, an α1-adrenergic receptor (α1-AR) antagonist, in auditory fear conditioning and extinction.

Methods

C57Bl/6N mice were subjected to auditory fear conditioning and extinction in combination with systemic (0.1–2 mg/kg) or local microinjections (3 or 6 mM) of the α1-AR antagonist prazosin into the prelimbic division of medial prefrontal cortex or basolateral amygdala. Conditioned fear and anxiety-like behaviors were compared with vehicle-injected control animals.

Results

Mice that received systemic prazosin prior to fear conditioning exhibited similar initial levels of cue-elicited freezing compared to vehicle controls on the following day. However, at all doses tested, fear that was acquired during prazosin treatment was more readily extinguished, whereas anxiety-like behavior on the day of extinction was unaffected. A similar pattern of results was observed when prazosin was microinjected into the basolateral amygdala but not the prelimbic cortex. In contrast to pre-conditioning injections, prazosin administration prior to extinction had no effect on freezing.

Conclusions

Our results indicate that α1-AR activity during aversive conditioning is dispensable for memory acquisition but renders conditioned fear more impervious to extinction. This suggests that behavioral flexibility is constrained by noradrenaline at the time of initial learning via activation of a specific AR isoform.

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Acknowledgments

We would like to thank Stephen Salton, Matthew Shapiro, Paul Kenny, Anne Shaefer, Schahram Akbarian, Zhenyu Yue, and Glenn Cruse for the use of equipment, and Wei-Jye Lin, Kirstie Cummings, Molly Heyer, and Philip Avigan for technical advice and assistance.

Funding

This work was funded by NIH grant MH105414 (R.L.C.) and seed funds from NC State University (E.K.L).

Author information

Authors and Affiliations

  1. Fishberg Department of Neuroscience and the Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, Box 1065, New York, NY, 10029, USA

    Elizabeth K. Lucas, Wan-Chen Wu, Ciorana Roman-Ortiz & Roger L. Clem

  2. Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC, 27606, USA

    Elizabeth K. Lucas

  3. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Roger L. Clem

Authors
  1. Elizabeth K. Lucas
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  2. Wan-Chen Wu
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  3. Ciorana Roman-Ortiz
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  4. Roger L. Clem
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Corresponding author

Correspondence to Roger L. Clem.

Additional information

This article belongs to a Special Issue on Psychopharmacology of Extinction.

Electronic supplementary material

Figure S1

Fear acquired during α1-AR blockade is more readily extinguished in 8–12 week old male mice. A. Experimental timeline. B. Systemic injection of prazosin (1 mg/kg) prior to fear conditioning significantly reduced freezing behavior during extinction day 2 while having no effect on fear memory acquisition or retrieval (Extinction 1, CS 1–4). Two-way repeated-measures ANOVA, p < 0.05 for main effect of treatment. n/group indicated in parentheses in legend. CS, conditioned stimulus. (PNG 228 kb)

High Resolution image (TIF 2864 kb)

Figure S2

No effect of prazosin on cue-evoked freezing after low threshold training. A. Experimental timeline. B. Systemic injection of prazosin (2 mg/kg) prior to low-intensity fear conditioning (3 tone-shock pairings) did not affect fear memory retrieval. n/group indicated in parentheses in legend. (PNG 144 kb)

High Resolution image (TIF 2012 kb)

Figure S3

Map of cannula placement in Fig. 3. A. Prelimbic cortex cannula placements. B. Basolateral amygdala cannula placements. Taxonomy according to The Mouse Brain in Stereotaxic Coordinates, 3rd Edition, by Franklin & Paxinos (2007). (PNG 1144 kb)

High Resolution image (TIF 44853 kb)

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Lucas, E.K., Wu, WC., Roman-Ortiz, C. et al. Prazosin during fear conditioning facilitates subsequent extinction in male C57Bl/6N mice. Psychopharmacology 236, 273–279 (2019). https://doi.org/10.1007/s00213-018-5001-x

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  • DOI: https://doi.org/10.1007/s00213-018-5001-x

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