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

Schreiber, Allyson L.; Lu, Yi-Ling; Baynes, Brittni B; Richardson, H. G.; Gilpin, Nicholas W.

doi:10.1016/j.neuropharm.2016.05.008

Cited by 40 publications

(41 citation statements)

References 41 publications

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“…Predator odor stress produces behavioral, molecular, and physiological alterations that recapitulate some PTSD symptoms [40,43]. In line with previous studies, bobcat urine exposure elicited significant avoidance in a subset of animals [35,44]. A similar proportion of alcohol-naïve male and female rats exposed to predator odor were classified as Avoiders (males: 42%; females: 37%), with similar magnitude of bobcat urine-paired context avoidance 24 hours post-stress.…”

Section: Discussionsupporting

confidence: 85%

Sex differences in traumatic stress reactivity of rats with a history of alcohol drinking

Albrechet‐Souza

Schratz

Gilpin

2019

Preprint

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Background: Alcohol misuse and post-traumatic stress disorder (PTSD) are highly comorbid and treatment outcomes are worse in individuals with both conditions. Although more men report experiencing traumatic events than women, the lifetime prevalence of PTSD is twice as high in females. Despite these data trends in humans, preclinical studies of traumatic stress reactivity have been performed almost exclusively in male animals. Methods:This study was designed to examine sex differences in traumatic stress reactivity in alcohol-naïve rats and rats given intermittent access to 20% ethanol in a 2-bottle choice paradigm for 5 weeks. Rats were exposed to predator odor (bobcat urine) and tested for avoidance of the odor-paired context 24 hours later; unstressed Controls were never exposed to odor. Two days after stress, we measured physiological arousal using the acoustic startle response (ASR) test. We also measured anxiety-like behavior using the elevated plus-maze (EPM) and circulating corticosterone levels before and immediately after odor exposure. Results:Male and female rats exposed to predator odor displayed blunted weight gain 24 hours post-stress, but only a subset of stressed animals exhibited avoidance behavior. Chronic intermittent alcohol drinking increased the proportion of Avoiders in males and predator odor exposure increased ASR in these animals. Predator odor stress reduced ASR in females relative to unstressed females and stressed males, regardless of alcohol drinking history. Bobcat urine exposure did not promote persistent anxiety-like behavior, but alcohol-experienced males exhibited reduced activity in the EPM in comparison to alcohol-experienced females.3 Furthermore, predator odor increased circulating corticosterone levels in females relative to males and baseline. Conclusions:We report robust sex differences in behavioral and endocrine responses to bobcat urine exposure in adult Wistar rats. Also, chronic moderate alcohol drinking increased traumatic stress reactivity in males but not females. Our findings emphasize the importance of considering sex as a biological variable in the investigation of traumatic stress effects on physiology and behavior. BackgroundPost-traumatic stress disorder (PTSD) is a chronic psychiatric disease that is seen in some but not all individuals after experiencing a life-threatening traumatic event. Major diagnostic criteria for PTSD include re-experiencing the traumatic event, negative affective state, exaggerated startle responses and persistent avoidance of trauma-related cues [1]. Women are twice as likely to develop PTSD after trauma [2, 3] and women with trauma exposure and/or PTSD exhibit more sensitivity to and less tolerance of negative emotions [4,5].Alcohol use disorder (AUD) is one of the most common co-occurring conditions among individuals diagnosed with PTSD [6,7]. Approximately one-third of individuals with lifetime PTSD also meet criteria for AUD [8]. Some populations, such as military personnel, are at high risk for AUD and PTSD comorbidities. For...

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Section: Discussionsupporting

confidence: 85%

Sex differences in traumatic stress reactivity of rats with a history of alcohol drinking

Albrechet‐Souza

Schratz

Gilpin

2019

Preprint

Self Cite

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“…It is likely that our observed intracellular signaling changes interact with specific stress-related neurotransmitter systems to mediate pain avoidance behavior. For example, using a conditioned place avoidance model of post-traumatic stress disorder, Schreiber and colleagues discovered a higher density of corticotropin-releasing factor (CRF) cells in the vmPFC to be positively correlated with avoidance-like behavior (Schreiber et al, 2017). In the same study, CRF1 receptor antagonism in the vmPFC reduced avoidance of the stress-paired context.…”

Section: Discussionmentioning

confidence: 99%

Neurobiological Correlates of Pain Avoidance-Like Behavior in Morphine-Dependent and Non-Dependent Rats

et al. 2017

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Repeated use of opioids can lead to the development of analgesic tolerance and dependence. Additionally, chronic opioid exposure can cause a paradoxical emergence of heightened pain sensitivity to noxious stimuli, termed hyperalgesia, which may drive continued or escalated use of opioids to manage worsening pain symptoms. Opioid-induced hyperalgesia has traditionally been measured in rodents via reflex-based assays, including the von Frey method. To better model the cognitive/motivational dimension of pain in a state of opioid dependence and withdrawal, we employed a recently developed non-reflex-based method for measuring pain avoidance-like behavior in animals (mechanical conflict avoidance test). Adult male Wistar rats were administered an escalating dose regimen of morphine (opioid-dependent group) or repeated saline (control group). Morphine-dependent rats exhibited significantly greater avoidance of noxious stimuli during withdrawal. We next investigated individual relationships between pain avoidance-like behavior and alterations in protein phosphorylation in central motivation-related brain areas. We discovered that pain avoidance-like behavior was significantly correlated with alterations in phosphorylation status of protein kinases (ERK, CaMKII), transcription factors (CREB), presynaptic markers of neurotransmitter release (Synapsin), and the rate-limiting enzyme for dopamine synthesis (TH) across specific brain regions. Our findings suggest that alterations in phosphorylation events in specific brain centers may support cognitive/motivational responses to avoid pain.

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“…Avoider rats) consume more alcohol than Non‐Avoiders and unstressed Controls, and that these rats exhibit increases in extracellular signal‐regulated kinases phosphorylation in vmPFC after re‐exposure to the stress‐paired context relative to Non‐Avoiders (Edwards et al ). Nine days after stress, these Avoider rats have more corticotropin‐releasing factor (CRF)‐positive cells in vmPFC (but not in dmPFC) than Non‐Avoider rats and unstressed controls, the distribution of cell counts suggest that this effect is driven by the stress event, and antagonism of CRF‐1 receptors in vmPFC reduces avoidance but not escalated alcohol drinking in Avoider rats (Schreiber et al ).…”

Section: Anatomy and Circuitry Of Comorbid Ptsd And Audmentioning

confidence: 99%

Neurobiology of comorbid post‐traumatic stress disorder and alcohol‐use disorder

Gilpin

Weiner

2016

Genes Brain and Behavior

123

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Post-traumatic stress disorder (PTSD) and alcohol-use disorder (AUD) are highly comorbid in humans. Although we have some understanding of the structural and functional brain changes that define each of these disorders, and how those changes contribute to the behavioral symptoms that define them, little is known about the neurobiology of comorbid PTSD and AUD, which may be due in part to a scarcity of adequate animal models for examining this research question. The goal of this review is to summarize the current state-of-the-science on comorbid PTSD and AUD. We summarize epidemiological data documenting the prevalence of this comorbidity, review what is known about the potential neurobiological basis for the frequent co-occurrence of PTSD and AUD and discuss successes and failures of past and current treatment strategies. We also review animal models that aim to examine comorbid PTSD and AUD, highlighting where the models parallel the human condition, and we discuss the strengths and weaknesses of each model. We conclude by discussing key gaps in our knowledge and strategies for addressing them: in particular, we (1) highlight the need for better animal models of the comorbid condition and better clinical trial design, (2) emphasize the need for examination of subpopulation effects and individual differences and (3) urge cross-talk between basic and clinical researchers that is reflected in collaborative work with forward and reverse translational impact.

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

Cited by 40 publications

References 41 publications

Sex differences in traumatic stress reactivity of rats with a history of alcohol drinking

Sex differences in traumatic stress reactivity of rats with a history of alcohol drinking

Neurobiological Correlates of Pain Avoidance-Like Behavior in Morphine-Dependent and Non-Dependent Rats

Neurobiology of comorbid post‐traumatic stress disorder and alcohol‐use disorder

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