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Neuropharmacology. 2017 Feb;113(Pt A):323-330. doi: 10.1016/j.neuropharm.2016.05.008. Epub 2016 May 24.

Corticotropin-releasing factor in ventromedial prefrontal cortex mediates avoidance of a traumatic stress-paired context.

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Department of Physiology, Louisiana State University Health Science Center, New Orleans, LA 70112, USA.
Neuroscience and Behavior Program, University of Massachusetts, Amherst, MA, 01003, USA.
Department of Psychological and Brain Sciences, University of Massachusetts, Amherst, MA, 01003, USA.
Department of Physiology, Louisiana State University Health Science Center, New Orleans, LA 70112, USA; Neuroscience Center of Excellence, Louisiana State University Health Science Center, New Orleans, LA, 70112, USA. Electronic address:


Post-traumatic stress disorder (PTSD) affects 7.7 million Americans. One diagnostic criterion for PTSD is avoidance of stimuli that are related to the traumatic stress. Using a predator odor stress conditioned place aversion (CPA) model, rats can be divided into groups based on stress reactivity, as measured by avoidance of the odor-paired context. Avoider rats, which show high stress reactivity, exhibit persistent avoidance of stress-paired context and escalated alcohol drinking. Here, we examined the potential role of corticotropin-releasing factor (CRF), a neuropeptide that promotes anxiety-like behavior in mediating avoidance and escalated alcohol drinking after stress. CRF is expressed in the medial prefrontal cortex (mPFC). The dorsal and ventral sub-regions of the mPFC (dmPFC and vmPFC) have opposing roles in stress reactivity and alcohol drinking. We hypothesized that vmPFC CRF-CRFR1 signaling contributes functionally to stress-induced avoidance and escalated alcohol self-administration. In Experiment 1, adult male Wistar rats were exposed to predator odor stress in a CPA paradigm, indexed for avoidance of odor-paired context, and brains processed for CRF-immunoreactive cell density in vmPFC and dmPFC. Post-stress, Avoiders exhibited higher CRF cell density in vmPFC, but not the dmPFC. In Experiment 2, rats were tested for avoidance of a context repeatedly paired with intra-vmPFC CRF infusions. In Experiment 3, rats were stressed and indexed, then tested for the effects of intra-vmPFC CRFR1 antagonism on avoidance and alcohol self-administration. Intra-vmPFC CRF infusion produced avoidance of a paired context, and intra-vmPFC CRFR1 antagonism reversed avoidance of a stress-paired context, but did not alter post-stress alcohol self-administration. These findings suggest that vmPFC CRF-CRFR1 signaling mediates avoidance of stimuli paired with traumatic stress.


Alcohol self-administration; Anxiety; Avoidance; Corticotropin-releasing factor (CRF); Medial prefrontal cortex (mPFC); Post-traumatic stress disorder (PTSD)

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