The Role of Central Amygdala Corticotropin-Releasing Factor in Predator Odor Stress-Induced Avoidance Behavior and Escalated Alcohol Drinking in Rats

Abstract

Post-traumatic stress disorder (PTSD) is characterized by avoidance of trauma-associated stimuli and amygdala hyperreactivity, and is highly co-morbid with alcohol use disorder (AUD). Our lab uses a predator odor (bobcat urine) stress model that produces conditioned avoidance of an odorpaired context in a subset of rats, mirroring avoidance symptoms that manifest in some but not all humans exposed to trauma. We previously showed that after predator odor stress, Avoiders exhibit escalated alcohol drinking, higher aversion-resistant operant alcohol responding, hyperalgesia, and greater anxiety-like behavior compared to unstressed Controls. We also showed that systemic antagonism of corticotropin-releasing factor-1 receptors (CRFR1) reduced escalation of alcohol drinking in rats not indexed for avoidance, that corticotropin-releasing factor (CRF) infusions into the central amygdala (CeA) produced conditioned place avoidance in stressnaïve rats, and that intra-CeA infusion of a CRFR1 antagonist reduced hyperalgesia in Avoiders.Here, we show that avoidance behavior is persistent after repeated predator odor exposure and is resistant to extinction. In addition, Avoiders showed lower weight gain than Controls after predator odor re-exposure. In the brain, higher avoidance was correlated with higher number of c-Fos+ cells and CRF immunoreactivity in the CeA. Finally, we show that intra-CeA CRFR1 antagonism reversed post-stress escalation of alcohol drinking and reduced avoidance behavior in Avoiders. Collectively, these findings suggest that elucidation of the mechanisms by which CRFR1-gated CeA circuits regulate avoidance behavior and alcohol drinking may lead to better understanding of the neural mechanisms underlying co-morbid PTSD and AUD.

Central Amygdala Projections to Lateral Hypothalamus Mediate Avoidance Behavior in Rats

“…The CeL contains a high density of CRFexpressing cells that release CRF both locally and distally (Pomrenze et al, 2015), whereas the CeM contains a high density of CRFR1-expressing cells that can be activated by CRF (Radulovic et al, 1998). This anatomic distribution, along with prior findings that predator odor stress increases CRF peptide content in CeA of Avoiders and CRFR1 antagonism in CeA reduces avoidance, escalated alcohol drinking (Weera et al, 2020), and hyperalgesia in Avoiders (Itoga et al, 2016), makes it reasonable to hypothesize that CRFR1 may be enriched on CeA-LH cells and may gate the activity of this circuit, especially because we show here that a subset of CeA-LH cells are CRFR11.…”

“…Our laboratory uses a model in which a subset of rats exposed to predator odor stress show persistent and stable avoidance of odor-paired stimuli (context with distinct tactile and visual cues), mirroring avoidance symptoms in some but not all humans exposed to stress (Breslau, 2009;Albrechet-Souza and Gilpin, 2019). After stress, rats classified as Avoiders exhibit hyperalgesia (Itoga et al, 2016), escalated alcohol drinking, more aversion-resistant alcohol responding (Edwards et al, 2013;Weera et al, 2020), higher anxiety-like behavior than unstressed controls (Whitaker and Gilpin, 2015), and blunted corticosterone response to predator odor relative to Non-Avoiders exposed to the same stress (Whitaker and Gilpin, 2015). These effects are not attributable to non-specific factors such as learning or animals' ability to detect the predator odor stimulus.…”

“…Previous findings in our lab suggest that CeA is an important node for mediating avoidance of aversive stimuli and other behaviors in Avoider rats. For example, male Avoider rats show escalated corticotropin-releasing factor (CRF) peptide content in CeA after stress compared with Non-Avoiders and unstressed Controls, intra-CeA infusions of CRF produce avoidance in stress-naive male rats (Itoga et al, 2016), and intra-CeA blockade of CRF1 receptors (CRFR1) attenuates stress-induced avoidance behavior, escalated alcohol drinking (Weera et al, 2020), and hyperalgesia in male Avoider rats (Itoga et al, 2016).…”