The role of central amygdala corticotropin-releasing factor in predator odor stress-induced avoidance behavior and escalated alcohol drinking in rats

Weera, Marcus M.; Schreiber, Allyson L.; Avegno, Elizabeth M.; Gilpin, Nicholas W.

doi:10.1016/j.neuropharm.2020.107979

Cited by 43 publications

(43 citation statements)

References 38 publications

(35 reference statements)

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“…Second, these increases in alcohol self-administration began to emerge 24 days (12 sessions) after exposure to TMT, suggesting a delay in the escalation of alcohol drinking after stress exposure. This is in line with other studies that have shown increases and longterm (1-3 weeks) persistence in alcohol drinking after exposure to different models of predator odor stress [13,15,16], and other work from our lab showing changes in gene expression that emerge 4 weeks following TMT exposure [27]. Third, males in TMT-1 and 2 did not show changes in alcohol self-administration, suggesting that stress reactivity is a more efficient predictor of changes in self-administration in female rats.…”

Section: Discussionsupporting

confidence: 93%

Increased alcohol self-administration following exposure to the predator odor TMT in high stress-reactive female rats

Ornelas¹,

Tyler

Irukulapati³

et al. 2020

Preprint

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Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are highly comorbid. Additionally, individual differences in response to stress suggest resilient and susceptible populations. The current study exposed male and female Long Evans rats to the synthetically produced predator odor 2,5-dihydro-2,4,5-trimethylthiazoline (TMT) to examine individual differences in stress-reactive behaviors (digging and immobility) and whether these differences could predict lasting consequences of TMT and increases in alcohol drinking. Male and female Long Evans rats were trained on operant alcohol self-administration. After 9 sessions, rats underwent exposure to TMT or water (Control) in a distinct context. 6 days after TMT exposure, rats underwent re-exposure to the TMT-paired context (without TMT), and a series of behavioral assessments (acoustic startle, zero maze, light/dark box), after which rats resumed alcohol self-administration. Rats were divided into two TMT-subgroups using a ratio of digging and immobility behavior during TMT exposure: TMT-subgroup 1 (low digging/immobility ratio) and TMT-subgroup 2 (high digging/immobility ratio). Digging/immobility ratio scores predicted elevated corticosterone levels during TMT exposure and reactivity during context re-exposure in males and females (TMT-subgroup 2), as well as elevated corticosterone levels after context re-exposure and hyperarousal behavior in females (TMT-subgroup 1). Furthermore, TMT stress reactivity predicted increases in alcohol self-administration, specifically in females. These data show that stress-reactivity can predict lasting behavioral changes which may lead to a better understanding of increases in alcohol drinking following stress in females and that individual differences in stress-reactive behaviors using TMT may be helpful to understand resilience/susceptibility to the lasting consequences of stress.

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Section: Discussionsupporting

confidence: 93%

Increased alcohol self-administration following exposure to the predator odor TMT in high stress-reactive female rats

Ornelas¹,

Tyler

Irukulapati³

et al. 2020

Preprint

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“…In line with previous studies [27,37,38], bobcat urine exposure elicited significant avoidance in a subset of animals. A similar proportion of alcohol-naive male and female rats exposed to PO were classified as avoiders (males 42%; females 37%), with similar magnitude of bobcat urine-paired context avoidance 24 h post-stress.…”

Section: Discussionsupporting

confidence: 91%

“…Interestingly, a systematic review of the comorbidity between PTSD and alcohol misuse found associations between alcohol consumption and the avoidance/numbing and hyperarousal PTSD symptom clusters [39]. Moreover, our group demonstrated that male avoider rats exhibit persistent increases in alcohol self-administration, and avoidance behavior predicts post-stress escalation of alcohol drinking [27,38].…”

Section: Discussionmentioning

confidence: 67%

Sex differences in traumatic stress reactivity in rats with and without a history of alcohol drinking

2020

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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-naive rats (experiment 1) and rats given intermittent access to 20% ethanol in a 2-bottle choice paradigm for 5 weeks (experiment 2). Animals were exposed to predator odor (bobcat urine) and tested for contextual avoidance 24 h later; unstressed controls were never exposed to predator odor. We evaluated changes in physiological arousal using the acoustic startle response (ASR) test at day 2 post-stress and anxiety-like behavior measured in the elevated plus-maze (EPM) at day 17 post-stress. In experiment 3, time course of corticosterone response was examined in male and female rats following exposure to predator odor stress. Results: Alcohol-naive males and females exposed to predator odor displayed blunted weight gain 24 h post-stress, but only a subset of stressed animals exhibited avoidance behavior. In alcohol-drinking animals, the proportion of avoiders was higher in males than females, and predator odor exposure increased ASR in males only. Stressed females exhibited blunted ASR relative to unstressed females and stressed males, regardless of alcohol drinking history. Alcohol-experienced females presented lower anxiety-like behavior and higher general activity in the EPM in comparison with alcohol-experienced males. Plasma corticosterone levels were higher in females immediately after predator odor exposure until 60 min post-stress relative to males. Conclusions: We report robust sex differences in behavioral and endocrine responses to bobcat urine exposure in adult Wistar rats. Also, males with a history of chronic moderate alcohol drinking exhibited increased traumatic stress reactivity relative to alcohol-drinking females. Our findings emphasize the importance of considering sex as a biological variable in the investigation of traumatic stress effects on physiology and behavior.

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“…Since the odor of rats is known to evoke fear in mice [ 35 , 36 , 38 , 39 , 68 – 70 ], and that predator odors evoke an increase in c-Fos expression levels in different amygdala nuclei (as demonstrated by increased number of c-Fos-positive cells [ 40 – 42 ], we assumed that a higher amygdala activation may become apparent after the presentation of the odor of rat soiled bedding as an aversive stimulus, even if the mice were under anesthetic. Previous work has shown the capability of several aversive odors including predator urine volatiles to evoke responses in the brain of anesthetized mice [ 71 – 74 ].…”

Section: Discussionmentioning

confidence: 99%

“…Mice that are exposed to rat predator scents exhibit innate defensive behaviors including flight and freezing as well as an increase in stress hormone levels [ 35 – 39 ]. Furthermore, predator odors were shown to evoke an increase in the immediate early gene (IEG) product c-Fos in the BL, Ce and medial nucleus in rodents [ 40 – 42 ]. Increase in c-Fos protein expression occurs in response to direct stimulation of neurons and serves as marker for neuronal activation [ 43 – 45 ].…”

Section: Introductionmentioning

confidence: 99%

Serotonin transporter genotype modulates resting state and predator stress-induced amygdala perfusion in mice in a sex-dependent manner

Kolter

Hildenbrand²,

Popp³

et al. 2021

PLoS ONE

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The serotonin transporter (5-HTT) is a key molecule of serotoninergic neurotransmission and target of many anxiolytics and antidepressants. In humans, 5-HTT gene variants resulting in lower expression levels are associated with behavioral traits of anxiety. Furthermore, functional magnetic resonance imaging (fMRI) studies reported increased cerebral blood flow (CBF) during resting state (RS) and amygdala hyperreactivity. 5-HTT deficient mice as an established animal model for anxiety disorders seem to be well suited for investigating amygdala (re-)activity in an fMRI study. We investigated wildtype (5-HTT+/+), heterozygous (5-HTT+/-), and homozygous 5-HTT-knockout mice (5-HTT-/-) of both sexes in an ultra-high-field 17.6 Tesla magnetic resonance scanner. CBF was measured with continuous arterial spin labeling during RS, stimulation state (SS; with odor of rats as aversive stimulus), and post-stimulation state (PS). Subsequently, post mortem c-Fos immunohistochemistry elucidated neural activation on cellular level. The results showed that in reaction to the aversive odor CBF in total brain and amygdala of all mice significantly increased. In male 5-HTT+/+ mice amygdala RS CBF levels were found to be significantly lower than in 5-HTT+/- mice. From RS to SS 5-HTT+/+ amygdala perfusion significantly increased compared to both 5-HTT+/- and 5-HTT-/- mice. Perfusion level changes of male mice correlated with the density of c-Fos-immunoreactive cells in the amygdaloid nuclei. In female mice the perfusion was not modulated by the 5-Htt-genotype, but by estrous cycle stages. We conclude that amygdala reactivity is modulated by the 5-Htt genotype in males. In females, gonadal hormones have an impact which might have obscured genotype effects. Furthermore, our results demonstrate experimental support for the tonic model of 5-HTTLPR function.

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The role of central amygdala corticotropin-releasing factor in predator odor stress-induced avoidance behavior and escalated alcohol drinking in rats

Cited by 43 publications

References 38 publications

Increased alcohol self-administration following exposure to the predator odor TMT in high stress-reactive female rats

Increased alcohol self-administration following exposure to the predator odor TMT in high stress-reactive female rats

Sex differences in traumatic stress reactivity in rats with and without a history of alcohol drinking

Serotonin transporter genotype modulates resting state and predator stress-induced amygdala perfusion in mice in a sex-dependent manner

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