CCK‐antagonists in a rat exposed to acute stress: Implication for anxiety associated with post‐traumatic stress disorder

Cohen, Hagit; Kaplan, Zeev; Kotler, Moshe

doi:10.1002/(sici)1520-6394(1999)10:1<8::aid-da2>3.0.co;2-#

Cited by 56 publications

(24 citation statements)

References 36 publications

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“…Several lines of evidence have indirectly indicated that a basal CCKergic tone in the brain may play a determinative role in shaping effects associated with anxiogenic factors. For example, many studies have found that CCKR-2 agonists can produce more pronounced anxiogenic effects only in stressed but not unstressed animals (41,42), and that patients with generalized anxiety or panic disorder are more sensitive to CCKR-2 agonists (43)(44)(45). In addition, after stressors, both CCK-like immunoreactivity and CCK receptor density in the brain are increased, indicating that elevated CCKergic tone is associated with these stressors (46,47).…”

Section: Discussionsupporting

confidence: 73%

Elevated cholecystokininergic tone constitutes an important molecular/neuronal mechanism for the expression of anxiety in the mouse

Chen

Nakajima

Meacham

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Cholecystokinin (CCK), one of the most abundant neuropeptides in the brain, plays an important role in anxiogenesis through the activation of CCK receptor-2 (CCKR-2). Accumulating evidence, however, has suggested this role depends on endogenous CCKergic ''tone,'' which is largely determined by the expression level of the CCKR-2. Using the tTA͞tetO-inducible transgenic (tg) approach, we show here that overexpression of the CCKR-2 in neurons of the forebrain significantly increases CCKR-2 binding capacity in tg mice compared with their littermate controls. Interestingly, these tg mice consistently exhibit increased fear responses, which are generally interpreted as anxiety-like behaviors in the rodent, in a battery of behavioral tests, which represented conflict situations or delivered stress to the subjects. The inhibition of transgene expression with doxycycline treatment completely diminished both increased receptor-binding activity and all behavioral phenotypes. Furthermore, treatment of tg mice with diazepam significantly attenuated these anxiety-like behaviors. Our results directly demonstrate that the elevated CCKergic tone via overexpression of the CCKR-2 in the brain may constitute an underlying molecular͞ neuronal mechanism for the expression of anxiety. In addition, our study has validated a robust genetic anxiety model in the mouse in terms of their face, constructive, and predictive validity.behaviors ͉ transgenic mouse

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Section: Discussionsupporting

confidence: 73%

Elevated cholecystokininergic tone constitutes an important molecular/neuronal mechanism for the expression of anxiety in the mouse

Chen

Nakajima

Meacham

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…Over the past decades, a variety of animal models have been put forward as being valid for the study of stress and anxiety, and of their chronic or long-term effects, such as inescapable electric (foot) shock (Pynoos et al, 1996;Servatius et al, 1995), social confrontations (Stam et al, 2000), underwater trauma (Richter-Levin, 1998;Wang et al, 2000), and exposure to a predator (Adamec, 1997;Adamec R et al, 1998;Adamec RE et al, 1999;Adamec and Shallow 1993;Adamec RE et al, 1997;Cohen et al, 2000;Cohen et al, 1996;Cohen et al, 2003;Cohen et al, 1999). Various behavioral tests and biophysiologic measures have been performed ensuing the exposure.…”

Section: Introductionsupporting

confidence: 84%

“…Predatory stimuli are ecologically relevant for an animal's survival and, consequently, induce responses quite similar to those shown in natural contexts. In our model, we exposed rats to a cat for 10 min as previously described by Adamec et al (1999Adamec et al ( , 1997, Adamec and Shallow (1993), and Cohen et al (2000Cohen et al ( , 1996Cohen et al ( , 1999.…”

Section: Methodsmentioning

confidence: 99%

“…In keeping with the work of Blanchard et al (1990Blanchard et al ( , 1998Blanchard et al ( , 1993, Shalev (2000), Adamec (1997), Adamec R et al (1998), Adamec RE et al (1999, 1997, and our own previous studies (Cohen et al (2000(Cohen et al ( , 1996(Cohen et al ( , 2003(Cohen et al ( , 1999, the observed behaviours at this time point are considered to reflect relatively long-term and persistent changes. Since it has as yet not been possible to design an animal model for the intrusive cluster of symptoms, changes such as these, which persist over the space of a week or more, are considered a fair representation of PTSDlike symptoms in terms of animal models.…”

Section: Behavioral Assessments For Determination Of Cbcmentioning

confidence: 99%

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Setting Apart the Affected: The Use of Behavioral Criteria in Animal Models of Post Traumatic Stress Disorder

Cohen

Zohar

Matar

et al. 2004

Neuropsychopharmacol

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235

142

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Post-traumatic stress disorder (PTSD) affects about 20-30% of exposed individuals. Clinical studies of PTSD generally employ stringent criteria for inclusion in study populations, and yet in animal studies the data collection and analysis are generally expressed as a function of exposed vs nonexposed populations, regardless of individual variation in response. Prior data support an approach to animal models analogous to inclusion criteria in clinical studies. This series of studies sought to assess prevalence rates of maladaptive vs adaptive responses determined according to a more stringent approach to the concept of inclusion/exclusion criteria (cutoff behavioral criteriaFCBC), consisting of two successive behavioral tests (elevated plus maze and acoustic startle response tests). The rats were exposed to stressors in two different paradigms; exposure to a predator and underwater trauma. The prevalence rates of maladaptive responses to stress in these two distinct models dropped over time from 90% in the acute phase to 25% enduring/maladaptive response at 7 days, to remain constant over 30 days. As setting the affected individuals apart from the unaffected approximates clinical studies, it might also help to clarify some of the pending issues in PTSD research.

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“…The application of direct physical stressors, such as electric shock, [6][7][8][9] underwater trauma 10 and restraint stress, 11,12 are the most widely used methods of applying a stressor to laboratory animals. Nevertheless, the use of exogenous stimuli that closely mimic those seen in nature, such as exposure to a live predator, [13][14][15] a predatory cue [16][17][18][19] or psychological stress, 20,21 might have greater etiological relevance, thereby leading to improved modeling and analysis of fear and anxiety states.…”

Section: Introductionmentioning

confidence: 99%

WFS1 gene as a putative biomarker for development of post-traumatic syndrome in an animal model

et al. 2007

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Post-traumatic stress disorder (PTSD) is an anxiety disorder that may develop after the experiencing or witnessing of a life-threatening event. PTSD is defined by the coexistence of three clusters of symptoms: re-experiencing, avoidance and hyperarousal, which persist for at least 1 month in survivors of the event (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition). Using an established model of PTSD, we addressed the well-accepted clinical finding that only a minority (about 20%) of the individuals exposed to a traumatic event develop PTSD. Moreover, we followed individual rat behavior for up to a month, and then treated the PTSD-like animals with citalopram. Our data demonstrate high face (20% of rats exposed to a reminder of the stressor develop symptoms characteristic of PTSD) and predictive (response to citalopram) validities. Based on these validities we identified alterations in the Wolframin gene in the CA1 and amygdala regions, specifically in exposed PTSD-like rats, which were normalized after treatment with citalopram. We suggest the Wolframin gene as a putative biomarker for PTSD. Since Wolframin gene undergoes alternative splicing and has polymorphism in the population, it may serve a future marker for identification of the vulnerable population exposed to a traumatic event.

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CCK‐antagonists in a rat exposed to acute stress: Implication for anxiety associated with post‐traumatic stress disorder

Cited by 56 publications

References 36 publications

Elevated cholecystokininergic tone constitutes an important molecular/neuronal mechanism for the expression of anxiety in the mouse

Elevated cholecystokininergic tone constitutes an important molecular/neuronal mechanism for the expression of anxiety in the mouse

Setting Apart the Affected: The Use of Behavioral Criteria in Animal Models of Post Traumatic Stress Disorder

WFS1 gene as a putative biomarker for development of post-traumatic syndrome in an animal model

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