Elizabeth K Lucas1,2, Wan-Chen Wu1, Ciorana Roman-Ortiz1, Roger L Clem3,4. 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. 2. Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC, 27606, USA. 3. 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. roger.clem@mssm.edu. 4. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. roger.clem@mssm.edu.
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.
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.