Open access

CCKergic System, Hypothalamus-Pituitary-Adrenal (HPA) Axis, and Early-Life Stress (ELS)

Written By

Mingxi Tang, Anu Joseph, Qian Chen, Jianwei Jiao and Ya-Ping Tang

Submitted: March 15th, 2012 Published: November 28th, 2012

DOI: 10.5772/52042

Chapter metrics overview

2,137 Chapter Downloads

View Full Metrics

1. Introduction

Early-life exposure to adverse experience or stress, simply termed early-life stress (ELS), is a worldwide problem that has a significantly negative impact in human health [1, 2]. In the United States, about 50% of adults had experienced some kind of stress before age 18 [3], and up to 15-25% of adults had traumatic ELS such as sexual abuse [4]. Most ELS is parents-originated, such as neglect, maltreatment, and abuse [5, 6]. In addition to the immediate, dreadful, and destructive effects on a child’s life, ELS may produce a series of mental [7, 8], cardiovascular [9, 10], metabolic disorders [11, 12], and many other types of disease [13, 14], at a later life stage. For example, adults who were sexually abused during childhood have a 5.7-fold increase in risk for drug abuse over those without ELS [7], and the prevalence of posttraumatic stress disorder (PTSD), a predominant form of anxiety disorders (ADs), is highly associated with ELS, with a 4-5 fold difference between adults with ELS and those without ELS [15]. Moreover, cognitive dysfunctions [16-18] such as learning and memory impairment [19-21] are also highly associated with ELS. Given that children, especially early adolescents, have a higher possibility to expose to a traumatic insult [22], adolescent trauma (AT) is an important risk factor for these post-ELS disorders.

Over the past decades, considerable insights have been gained into the molecular/neuronal mechanisms regarding how ELS impacts brain function and behavior [23-26]. Generally, it is now accepted that ELS can produce changes, most permanently, at multiple levels [25, 27]. Following ELS, for example, the overall volume of the hippocampus [28-30], corpus callosum [31-33], and cortex [34-36] all becomes smaller, compared to that of those brain regions in age-matched subjects. Besides these neuroanatomical changes, the neuronal activity and the synaptic function in the brain in ELS-victims are impaired [37-39], and most neurotransmitter systems are significantly affected too. By using positron emission tomography or fMRI,, it has been found that a significantly increased release of dopamine in the ventral striatum is associated to ELS [40, 41]. The turnover rate of the serotonin (5-HT) metabolism or the 5-HT receptor density [42, 43] is altered following ELS. Similarly, the activity of the glutamatergic system [44, 45] and the cholinergic system [46, 47] are also altered in the brain of individuals following ELS. However, it should be emphasized that the changes in the hypothalamic-pituitary-adrenal (HPA) axis activity is of the most interest [48-52].

As the most important stress-related neuroendocrine system in the body, the HPA axis is anatomically and functionally composed of three major structures: the paraventricular nucleus of the hypothalamus (PVN), the anterior lobe of the pituitary gland, and the adrenal gland [53, 54]. The HPA contains magnocellular neurosecretory neurons that synthesize and release a corticotropin-releasing factor (CRF). CRF is a 41 amino acid peptide [55, 56], and can bind to three types of G-protein-coupled receptors: CRFR1, CRFR2, and CRFR3 [57-59]. In the mammalian brain, both CRF and CRFR1 are mainly distributed in the limbic system, while CRFR-2 is in the hypothalamus [60-62]. The essential role for the CRF system is to maintain the basal HPA axis activity as well as to trigger the HPA axis in response to stresses. After released from the PVN, the CRF binds to CRFR1 at the anterior pituitary and increase the release of adrenocorticotropic hormone (ACTH). The ACTH consequently stimulates the release of glucocorticoids from the adrenal gland [63]. Once released, glucocorticoids bind both high-affinity mineralocorticoid receptors and lower-affinity glucocorticoid receptors. The glucocorticoids, or cortisol in humans and corticosterone in rodents, play an essential role in energy metabolism, growth processes, immune function, and brain functions [63, 64].

In response to stress, CRF system plays an essential role in modifying peripheral physiological response to support “fight or flight” reactions, such as mobilizing energy stores, increasing blood sugar and heart rate, inhibiting digestive functions etc [65,66]. In addition, CRF itself may act on CRFR2 in the brain to directly regulate adaptive behavioral changes encountering stress [67-69]. Taken together, the CRF/HPA system plays a primary role in coordinating the endocrine, autonomic, immune, and behavioral response to stress. As stress, either real or imaged, is a necessary inducer for ADs, the CRF/HPA system must play a unique role in anxiety-related behaviors. Indeed, a huge body of evidence has documented this notion. For example, administration of CRF [70-72] or CRFR1 agonists [69,73,74] or overexpression of the CRF gene [75-77] produces ALBs in the animals. On the other hand, CRFR1 antagonists exert significantly anxiolytic effects [78-80]. Knockout of CRF or CRFR1 in mice significantly reduces ALBs to stress and dramatically blunts stress-induced HPA axis activity [61,81,82]. Remarkably, previous chronic stress is able to enhance HPA axis activity in response to a novel acute stress, despite the negative feedback effects of increased glucocorticoids produced by the chronic stress [83-85]. For example, CCK-4-induced panic status in healthy volunteers significantly increases HPA axis activities [86]. Even the effects of early-life stress on HPA axis function are found to be associated with CCK sensitivity 130. Most interestingly, interactions between the CCKergic system and the CRF/HPA system exist [88-90]. For example, the CCKergic system was found to be involved in this chronic stress-enhanced responsiveness, since chronic stress can specifically facilitate the release of CCK into the paraventricular nucleus of the hypothalamus (PVN), which directly projects to the pituitary, in response to acute stress 125. All these findings have not only established the role of the CRF/HPA system in initiating behavioral responses to stresses, but also indicate that a significant interaction may exist between CRF/HPA system and CCKergic system to regulate stress-related behaviors.

However, the vulnerability among different individuals to AT is different. This variability may at least partially attribute to a genetic variability [91]. A twin study of Vietnam veterans revealed that about 37.9% of vulnerability to PTSD was genetically related [92]. Further genetic evidence comes from clinical association studies, by which several candidate genes for ADs including PTSD have been associated, although a causative gene has not been yet established [91]. Among those candidate genes, cholecystokinin (CCK) receptor-2 (CCKR-2) has been linked to panic disorder, another major form of ADs [93,94].

As the most abundant neuropeptides, CCK distributes broadly in the brain and mainly in the limbic system [95,96]. CCK binds to CCK receptor-1 (CCKR-1) and CCKR-2, of which the CCKR-2 is predominantly found in the brain with the highest level in cortical area and the limbic system [97], a brain region that is critically involved in emotion response emotion and behavior. Virtually, the CCKergic system has long been recognized as an anxiogenic factor for the animals [98], and this effect has been well validated in human populations as well [89,99,100]. Our recent study also showed that overexpression of CCKR2 in neurons of the forebrain of mice significantly enhanced anxiety-like behavior [101]. At the same time, some candidate genes that are linked to ADs are also associated with HPA axis activity. For example, a common polymorphism at the serotonin transporter (5-HTT) gene, namely 5HTTLPR, is a strong candidate genetic variation for ADs and depression [102-103], and also is significantly implicated in HPA axis activity [104]. Similar to the CCKergic system, the HPA axis system has long been recognized as a stress hormone [105,106], and plays a critical role in the pathogenesis of ADs [107,108]. Indeed, following ELS, the activity of the HPA axis system is dysfunctional [109-111]. Moreover, given the overall role of both the HPA axis system [112-114] and the CCKergic system [115-117] in regulating neuronal, cardiovascular, and metabolic functions in the body, these two systems may play an integrative role in the pathogenesis of post-ELS disorders.

In this study, by using our previously engineered inducible forebrain-specific CCKR-2 transgenic (IF-CCKR-2 tg) mice [101], we demonstrated that the elevated CCKergic tone in the brain significantly facilitated the effect of AT on the impairment of the glucocorticoid negative feedback inhibition in response to a novel acute stressor during the adult stage in the mouse, providing direct evidence that reveals a molecular basis for this co-effect.


2. Materials and methods

2.1. Experimental animals

The procedures for the generation of IF-CCKR-2 tg (simply dtg) mice were described in our previous publication [101]. Briefly, we used the tTA/tetO-inducible gene expression system to produce these dtg mice. This system requires two independent transgenic mouse strains, tTA transgenic and tetO/CCKR-2 transgenic mice. Accordingly, two constructs were made. The first was for tTA transgenic mice, in which the expression of the tTA was under the control of an alpha-Ca2+ calmodulin kinase II (CaMKII) promoter. The tTA transgene cassette consists of 0.6 kb of exon-intron splicing signal (pNN265), 1.0 kb of tTA encoding sequence (pTet-Off, Clontech), and 0.5 kb of SV-40 poly-A signals (pTet-Off, CLONTECH). The other construct is for CCKR-2 transgenic mice, in which the expression of the CCKR-2 transgene was under the control of the tetO promoter. The CCKR-2 transgene cassette consisted of 1.3 kb of mouse CCKR-2 cDNA, an upstream 0.6 kb of splicing signal (pNN265), and a downstream 1.1 kb of b-globin poly-A signals. All these components were subcloned into the pTRE2 vector (CLONTECH). CCKR-2 cDNA was cloned by RT-PCR from total RNA extracted from the brain of a male B6/CBA F1 mouse (The Jackson Laboratory) with the primers of 5'-CGG GAT CCA TGG ATC TGC TCA AGC TG-3' and 5'-GCT CTA GAT CAG CCA GGT CCC AGC GT-3'. A commercial RNA extraction kit (Invitrogen) and a reverse transcription kit (Stratagene) were used. The cloned cDNA was confirmed by sequencing. The plasmid constructs were then linearized with suitable enzymes and separately injected into the pronucleoli of B6/CBA F1 zygotes, as described [118]. Transgenic founders and the transgene copy numbers were determined by Southern blot analyses of the tail DNA. Founder mice with suitable gene copy numbers were backcrossed into B6/CBA F1 mice first to produce hemizygous single transgenic mice and then to produce double hemizygous transgenic mice. We have totally generated nine CaMKII-tTA transgenic founders and seven tetO-CCKR-2 transgenic founders. Southern blot analyses indicated that the gene copy numbers were from 2 to 70 for tTA transgenic founders and 2-150 for CCKR-2 transgenic founders (data not shown). To map the tTA expression pattern in the brain, we crossed a tetO-Lac-Z reporter mouse line (SJL-TgN-tetoplacZ, the Jackson Laboratory) into different independent CaMKII-tTA mouse lines to produce different tTA-LacZ double transgenic mouse lines. For Lac-Z staining, a commercial X-Gal staining kit (Invitrogen) and the recommended staining protocol were used with sagittal brain sections (30 µm), by which we identified a tTA transgenic line that was of the capacity to drive tetO/gene expression in almost all the neurons in the forebrain region (data not shown) Genotyping was determined by PCR analyses of both tTA (5'-AGG CTT GAG ATC TGG CCA TAC-3' and 5'-AGG AAA AGT GAG TAT GGT G-3') and CCKR-2 (5'-ACG GTG GGA GGC CTA TAT AA-3' and 5'-GAG TGT GAA GGG CATG CAA-3') transgenes. Dtg mice used here were around 12-16 generations since they were generated, during which duration dtg mice were backcrossed into B6/CBA F1 mice in every 5-6 generations, in order to avoid an inbreed effect. Single transgenic (tTA or tetO-CCKR-2 only) and wild-type (wt) littermates of dtg mice were used as controls, and are collectively and simply called wt mice hereafter. Mice used here were kept in standard laboratory mouse cages under the standard condition (12 hours light/dark cycle, temperature at 22 ± 1 oC, humility at 75%) with food and water ad libitum. All experimental procedures for the use of animals were previously reviewed and approved by the institutional animal care and use committee at the Louisiana State University Heath Sciences Center at New Orleans, and all of the experiments were conducted in accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health.

2.2. In situ hybridization

The hybridization was used to detect the expression level and pattern of the CCKR-2 transgene in the brain. Brains from both wt and dtg mice were collected by decapitation, and were frozen with powered dry ice immediately. Sagittal sections (20 µm) were made with a Cryostat (Leica, CM 1900, Richmond, IL). An oligo probe for tTA and a cRNA probe for the total CCKR-2 mRNAs were labeled with 35S UTP (>1,000 Ci/mmol; NEN, Boston, MA) by a random labeling kit and in vitro transcription kit (Invitrogen, Carlsbad, CA), respectively. The hybridization was performed overnight at 55°C, and after washing, slides were exposed to Kodak BioMax film (NEN) for the same time.

2.3. Adolescent trauma (AT)

Both wt and dtg mice at the age of P25 were individually put into a small shock-box (4 X 4 X 10 inch in high) that was modified from the shock box from a fear-conditioning system (Coulbourn Instruments, Whitehall, PA), in order to ensure that the mice did not have much space for escaping during shocking. The current of the footshock was higher (1.0 mA) than it was commonly used in the fear-conditioning test (0.6-0.8 mA). The footshock was conducted for 5 times (trials), in total, during a period of 1 minute, and each trial lasted for 2 seconds, with an interval of 10 seconds between trials.

2.4. Acute stressor (AS)

Additional acute stressor (AS; 0.8 mA for 2 seconds for one trial) with a standard fear-conditioning paradigm as described previously [119], was used to trigger HPA axis reaction at the age of P60 (2 months).

2.5. ELISA

Commercially available kits for both the adrenocorticotropic hormone (ACTH) (MD Bioproducts, St. Paul, MN) and corticosteroid hormone (CORT) (R&D systems, Minneapolis, MN) were used to determine the serum level of these hormones. Experimental procedures followed the recommended steps. In order to have samples enough for triplicate measurements, blood was collected with a retroorbital eye bleeding method. In order to minimize non-specific effects, blood collection was conducted at 9:00 Am, and the procedure was completed within 30 seconds, by which time any possible change that might be produced by the sampling procedure was not yet measurable.

2.6. Statistical analysis

Both female and male mice were almost equally distributed in each group. Data were analyzed with one-way ANOVA, followed by post-hoc tests. The p value less than 0.05 is considered significant.


3. Results

3.1. Expression of the CCKR-2 transgene in the brain of dtg mice

As shown in Fig 1, in situ hybridization revealed that the expression of the tTA was forebrain-specific in dtg mice (Fig. 1B), but was not detectable in wt mice (Fig. 1A). The expression pattern of the CCKR-2 transgene (data not shown) was the same as both the pattern of the tTA expression and the CCKR-2 transgene expression reported in our previous study [101].

Figure 1.

Expression pattern of the tTA mRNA detected by in situ hybridization with saggital brain sections in wt (A) and dtg (B) mice.

3.2. Dtg mice with AT exhibit an increased HPA axis activity in response to AS

Either wt (n = 60) or dtg mice (n = 60) were subjected to AT, and then were divided into 5 groups (n = 12) for a time-course study, in which both ACTH and CORT were examined before the AS for the basal level, and 1, 2, 4, and 8 hours following the AS. As shown in Fig. 2, although the difference in the basal level of ACTH (Fig. 2A) or CORT (Fig. 2C) between these mice was not significant, a tendency of a lower level ACTH (p = 0.0741) and CORT (p = 0.0648) was observed in dtg groups, compared to wt groups. Following the AS, an one-way ANOVA revealed a significant effect of the AT and CCKR-2 transgene on ACTH [F(1,8) = 6.781, p < 0.01] and CORT [F(1,8) = 9.201, p < 0.01]. Detailed post-hoc tests revealed that both ACTH (Fig. 2B) and CORT (Fig. 2D) in either wt or dtg mice reached the peak level at 1 hr after the AS, while a significant difference was observed at 1 and 2 hr in ACTH between wt and dtg groups (p > 0.05), and at 1 and 2 hr in CORT between wt and dtg groups (p > 0.05). In both wt and dtg mice, ACTH returned to the basal level at 4 hr (Fig. 2B), while CORT returned to the basal level at 4 hr (Fig. 2D). All these results indicate that the interaction between the AT and CCKR-2 transgene does not only increase the activity of the HPA axis following a novel stressor, but also impairs the CORT negative feedback in response this stressor.

3.3. Disassociation of the CCKR2 transgene expression and AT largely diminishes the effect of AT on HPA axis activity in response to AS

In this study, both wt and dtg mice were treated with doxycycline (doxy, 2 mg/100 ml in drinking water) for 5 days prior to AT, so that the transgene expression in dtg mice was inhibited during the episode of AT, and this inhibition lasted for about 3-5 days after the doxy treatment. At 2 months old, these mice were subjected to AS, and 1 hr later, which is the peak time of HPA axis response, as described in Fig. 2, the HPA axis activity was measured. Surprisedly, the levels of both ACTH and CORT were indistinguishable between wt and dtg mice, indicating that the coupling of AT and the transgene expression is critical for the AT to produce impaired glucocorticoid negative feedback inhibition in the animals.

Figure 2.

Increased HPA axis activity in dtg mice with AT/AS. A. Basal serum level of ACTH in naïve wt mice and naïve dtg mice. A tendency of a difference is shown, but it is not significant. Data are expressed as mean ± SEM. B. Time-course of ACTH response following the AS. C. Basal serum level of CORT in naïve wt mice and naïve dtg mice. A tendency of a difference is shown, but it is not significant. Data are expressed as mean ± SEM. D. Time-course of CORT response following the AS. The same groups of mice above were examined.

Figure 3.

Level of ACTH (A) and CORT (B) in the mice after AT/AS. No significant difference was found between wt and dtg mice when the expression of the CCKR-2 transgene was suppressed during AT.


4. Discussion

We have for the first time demonstrated that a coupling of a higher CCKergic tone with an ELS event is a causative factor for the development of an impairment of glucocorticoid negative feedback inhibition in the animals in response to additional acute stressor at a later life stage.

This demonstration is achieved based on the technical merit in our transgenic mice, in which the transgene expression is inducible/reversible. The time resolution for this inducible/reversible feature is within 1 week, which is high enough for this time-coupling analysis. However, it is still not clear how this real-time coupling occurs, partially due to the fact that the functional significance of the CCKergic system is still not fully understood. As G protein-coupled receptors, CCKR are associated with Ca2+ release, PKC activation, PLA2 activity, and cAMP production [120]. In addition, there are robust interactions between the CCKergic system and other neurotransmitter systems including dopaminergic, serotonergic, and GABAergic systems at both the structural and functional levels [121,122], and therefore, the mechanism underlying this associative effect should be complicated, and need to be further studied.

An important finding in this study is the discovery of the change in the HPA axis activity, and these changes include (1) a slightly lower basal level of the HPA axis activity in dtg mice, compared to wt mice, (2) a synergistic effect of AT and the CCKR-2 transgene on the peak level of the HPA axis activity in response to the AS; (3) a prolonged decay time of the HPA axis activity following the AS in dtg mice with AT, and (4) a requirement of real-time coupling of the transgene expression and TA. It should be mentioned that it has been well established that a previous chronic stress in the animals down-regulates the HPA axis activity, but enhances their response to a novel acute stress, despite the negative feedback effects [83,123,124]. Because chronic stress can specifically facilitate the release of CCK into the paraventricular nucleus of the hypothalamus (PVN), which directly projects to the pituitary, in response to acute stress [88], the elevated CCKergic tone in our dtg mice may mimic the effect of a chronic stress by working as an “intrinsic stressor” for the animals. Therefore, this intrinsic stressor constitutes a basis for the higher vulnerability of dtg mice to AT. At the same time, the impaired AS-induced CORT negative feedback response may, in tern, significantly many other physiological functions, and eventually lead to a pathological condition.

Over the past decades, considerable insights have been gained into the molecular mechanisms regarding how ELS impacts human health, especially for brain function and behavior [23-26]. It is now generally accepted that ELS can produce changes, most permanently, at multiple levels [25, 27]. Following ELS, for example, the overall volume of the hippocampus [28, 29], corpus callosum [31, 32], and cortex [34, 35] all becomes smaller, and the neuronal activity or synaptic function in the brain is impaired [30, 38, 125]. Consistent to the current study, the activity of the HPA axis system in the subject who experienced RLS was dysregulated [48-52]. Moreover, many other neurotransmitter systems were also affected by RLS [40, 126-128]. Therefore, the finding from the current study has provided additional evidence regarding how the CCKergic system and the HPA axis system is involved in the pathogenesis of post-ELS disorders.

The most important finding in this study is the demonstration of that if the transgene was temporally suppressed during the time of AT exposure, this impaired HPA axis inhibition in response to another acute stressor was largely diminished, indicating that the temporal association of the elevated CCKergic tone with AT is critically pathogenic. This finding has a potential translational significance. It is well know that the endogenous CCKergic activity, or the CCKR-2 level in the brain, play a dominant role in the expression of anxiety. For example, the expression of anxiety was correlated with the increased CCKergic tone, which was evidenced by a higher CCK receptor-binding capacity in the brain of anxious animals, in comparison with non-anxious animals [129-131]. Different fear responses among different strains of the same animal species were attributed to different expression levels of CCKR-2 [132-134]. On the other hand, evidence also indicates that the CCKergic tone in the brain is dynamically regulated by stress. Following stress, for example, both CCK peptide immunoreactivity and CCK receptor density in the brain were significantly increased [135-139]. Social isolation, an anxiogenic stress, increased the CCK mRNA expression in the brain [140]. Especially, the effect of ELS on the HPA axis activity was associated with CCK activity [87]. Chronic stress could specifically facilitate the release of CCK into the paraventricular nucleus of the hypothalamus in response to acute stress [84,141]. Consistently, CCKR-2 agonists could only produce, or produce more pronounced, anxiogenic effect in stressed animals, but not in un-stressed animals [88, 142-144]. Patients with ADs were more sensitive to CCKR-2 agonists than normal controls [145-148]. Together with all these findings, it seems conclusive that the CCKergic system is dynamically involved in ELS-triggered mental disorders, and thus, an inhibition of the CCKergic tone timely associated with an ELS event might be useful to prevent the development of post-ELS disorder, especially ADs.

In summary, our study has revealed a novel underpinning for the development of post-ESL disorders, especially for mental disorders, and provide insightful information regarding how can we develop a preventive strategy for these post-ESL disorders in the humans.


This work was partially conducted in the University of Chicago. This study was partially supported by grants from National Institute of Mental Health (MH066243), Alzheimer’s Association (NIRG-02-4368), National Science Foundation (0213112), and NARSAD, all to YPT.


  1. 1. TureckiG.ErnstC.JollantF.LabonteB.MechawarN.2012The neurodevelopmental origins of suicidal behavior. Trends Neurosci 3511423
  2. 2. Mc GowanP. O.SzyfM.2110The epigenetics of social adversity in early life: implications for mental health outcomes. Neurobiol Dis 3916672
  3. 3. Green JG, et al.2010Childhood adversities and adult psychiatric disorders in the national comorbidity survey replication I: associations with first onset of DSM-IV disorders. Arch Gen Psychiatry 672113123
  4. 4. Vogeltanz ND, et al.1999Prevalence and risk factors for childhood sexual abuse in women: national survey findings. Child Abuse Negl 236579592
  5. 5. Luecken LJ & Lemery KS2004Early caregiving and physiological stress responses. Clin Psychol Rev 242171191
  6. 6. WeichS.PattersonJ.ShawR.Stewart-BrownS.2009Family relationships in childhood and common psychiatric disorders in later life: systematic review of prospective studies. Br J Psychiatry 1945392398
  7. 7. Kendler KS, et al.2000Childhood sexual abuse and adult psychiatric and substance use disorders in women: an epidemiological and cotwin control analysis. Arch Gen Psychiatry 5710953959
  8. 8. Howell BR & Sanchez MM2011Understanding behavioral effects of early life stress using the reactive scope and allostatic load models. Dev Psychopathol 23410011016
  9. 9. Schooling CM, et al.2011Parental death during childhood and adult cardiovascular risk in a developing country: the Guangzhou Biobank Cohort Study. PLoS One 6(5):e19675.
  10. 10. Nuyt AM & Alexander BT2009Developmental programming and hypertension. Curr Opin Nephrol Hypertens 182144152
  11. 11. Tarry-Adkins JL & Ozanne SE2011Mechanisms of early life programming: current knowledge and future directions. Am J Clin Nutr 94(6):1765S-1771S
  12. 12. PorthaB.ChaveyA.MovassatJ.2011Early-life origins of type 2 diabetes: fetal programming of the beta-cell mass. Exp Diabetes Res 2011:105076
  13. 13. RooksC.VeledarE.GoldbergJ.JDBremnerVaccarinoV.2012Early trauma and inflammation: role of familial factors in a study of twins. Psychosom Med 742146152
  14. 14. al.2011Stress exposure in intrauterine life is associated with shorter telomere length in young adulthood. Proc Natl Acad Sci U S A 108(33):E513518
  15. 15. BreslauN.DavisG. C.SchultzL. R.2003Posttraumatic stress disorder and the incidence of nicotine, alcohol, and other drug disorders in persons who have experienced trauma. Arch Gen Psychiatry 603289294
  16. 16. PechtelP.PizzagalliD. A.2010Effects of early life stress on cognitive and affective function: an integrated review of human literature. Psychopharmacology (Berl).
  17. 17. MajerM.NaterU. M.LinJ. M.CapuronL.ReevesW. C.2010Association of childhood trauma with cognitive function in healthy adults: a pilot study. BMC Neurol 10:61.
  18. 18. Hedges DW & Woon FL2010Early-life stress and cognitive outcome. (Translated from Eng) Psychopharmacology (Berl)
  19. 19. Chu JA, Frey LM, Ganzel BL, & Matthews JA1999Memories of childhood abuse: dissociation, amnesia, and corroboration. Am J Psychiatry 1565749755
  20. 20. Goodman GS, Quas JA, & Ogle CM2010Child maltreatment and memory. Annu Rev Psychol 61325351
  21. 21. McCormick CM & Mathews IZ2010Adolescent development, hypothalamic-pituitary-adrenal function, and programming of adult learning and memory. (Translated from eng) Prog Neuropsychopharmacol Biol Psychiatry 34(5):756-765 (in eng).
  22. 22. CostelloE. J.ErkanliA.FairbankJ. A.AngoldA.2002The prevalence of potentially traumatic events in childhood and adolescence. (Translated from eng) J Trauma Stress 15(2):99-112 (in eng).
  23. 23. Loman MM & Gunnar MR2010Early experience and the development of stress reactivity and regulation in children. (Translated from eng) Neurosci Biobehav Rev 34(6):867-876 (in eng).
  24. 24. Fenoglio KA, Brunson KL, & Baram TZ2006Hippocampal neuroplasticity induced by early-life stress: functional and molecular aspects. (Translated from eng) Front Neuroendocrinol 27(2):180-192 (in eng).
  25. 25. GunnarM.QuevedoK.2007The neurobiology of stress and development. (Translated from eng) Annu Rev Psychol 58:145-173 (in eng).
  26. 26. GlaserR.Kiecolt-GlaserJ.2005How stress damages immune system and health. (Translated from eng) Discov Med 5(26):165-169 (in eng).
  27. 27. Kiecolt-Glaser JK, et al.2011Childhood adversity heightens the impact of later-life caregiving stress on telomere length and inflammation. (Translated from eng) Psychosom Med 73(1):16-22 (in eng).
  28. 28. al.2010Hippocampal changes associated with early-life adversity and vulnerability to depression. (Translated from eng) Biol Psychiatry 67(4):357-364 (in eng).
  29. 29. Cohen RA, et al.2006Early life stress and morphometry of the adult anterior cingulate cortex and caudate nuclei. (Translated from eng) Biol Psychiatry 59(10):975-982 (in eng).
  30. 30. al.2010Early parental care is important for hippocampal maturation: evidence from brain morphology in humans. (Translated from eng) Neuroimage 49(1):1144-1150 (in eng).
  31. 31. al.2007Morphologic alterations in the corpus callosum in abuse-related posttraumatic stress disorder: a preliminary study. (Translated from eng) J Nerv Ment Dis 195(12):1027-1029 (in eng).
  32. 32. Teicher MH, et al.2004Childhood neglect is associated with reduced corpus callosum area. (Translated from eng) Biol Psychiatry 56(2):80-85 (in eng).
  33. 33. al.2011Early-life stress, corpus callosum development, hippocampal volumetrics, and anxious behavior in male nonhuman primates. (Translated from eng) Psychiatry Res 192(1):37-44 (in eng).
  34. 34. van Harmelen AL, et al.2010Reduced medial prefrontal cortex volume in adults reporting childhood emotional maltreatment. (Translated from eng) Biol Psychiatry 68(9):832-838 (in eng).
  35. 35. al.2009Reduced prefrontal cortical gray matter volume in young adults exposed to harsh corporal punishment. (Translated from eng) Neuroimage 47 Suppl 2:T66-71 (in eng).
  36. 36. HohmannC. F.BeardN. A.Kari-KariP.JarvisN.SimmonsQ.2012Effects of brief stress exposure during early postnatal development in Balb/CByJ mice: II. Altered cortical morphology. (Translated from Eng) Dev Psychobiol (in Eng).
  37. 37. al.2010Early stress exposure impairs synaptic potentiation in the rat medial prefrontal cortex underlying contextual fear extinction. (Translated from eng) Neuroscience 169(4):1705-1714 (in eng).
  38. 38. CarrionV. G.HaasB. W.GarrettA.SongS.ReissA. L.2010Reduced hippocampal activity in youth with posttraumatic stress symptoms: an FMRI study. (Translated from eng) J Pediatr Psychol 35(5):559-569 (in eng).
  39. 39. al.2010Early-life experience reduces excitation to stress-responsive hypothalamic neurons and reprograms the expression of corticotropin-releasing hormone. (Translated from eng) J Neurosci 30(2):703-713 (in eng).
  40. 40. PruessnerJ. C.ChampagneF.MJMeaneyDagherA.2004Dopamine release in response to a psychological stress in humans and its relationship to early life maternal care: a positron emission tomography study using [11C]raclopride. (Translated from eng) J Neurosci 24(11):2825-2831 (in eng).
  41. 41. al.2011Limbic response to psychosocial stress in schizotypy: a functional magnetic resonance imaging study. (Translated from eng) Schizophr Res 131(1-3):184-191 (in eng).
  42. 42. Huggins KN, et al.2012Effects of early life stress on drinking and serotonin system activity in rhesus macaques: 5hydroxyindoleacetic acid in cerebrospinal fluid predicts brain tissue levels. (Translated from Eng) Alcohol (in Eng).
  43. 43. al.2011Juvenile stress attenuates the dorsal hippocampal postsynaptic 5HT1A receptor function in adult rats. (Translated from eng) Psychopharmacology (Berl) 214(1):329-337 (in eng).
  44. 44. al.2012Long lasting effects of early-life stress on glutamatergic/GABAergic circuitry in the rat hippocampus. (Translated from eng) Neuropharmacology 62(5-6):1944-1953 (in eng).
  45. 45. Alexander GM, et al.2012Disruptions in serotonergic regulation of cortical glutamate release in primate insular cortex in response to chronic ethanol and nursery rearing. (Translated from eng) Neuroscience 207:167-181 (in eng).
  46. 46. al.2009Neonatal stress affects vulnerability of cholinergic neurons and cognition in the rat: involvement of the HPA axis. (Translated from eng) Psychoneuroendocrinology 34(10):1495-1505 (in eng).
  47. 47. Lapiz MD, et al.2003Influence of postweaning social isolation in the rat on brain development, conditioned behavior, and neurotransmission. (Translated from eng) Neurosci Behav Physiol 33(1):13-29 (in eng).
  48. 48. Carpenter LL, Shattuck TT, Tyrka AR, Geracioti TD, & Price LH2010Effect of childhood physical abuse on cortisol stress response. (Translated from Eng) Psychopharmacology (Berl) (in Eng).
  49. 49. GillespieC. F.PhiferJ.BradleyB.ResslerK. J.2009Risk and resilience: genetic and environmental influences on development of the stress response. (Translated from eng) Depress Anxiety 26(11):984-992 (in eng).
  50. 50. MirescuC.JDPetersGouldE.2004Early life experience alters response of adult neurogenesis to stress. (Translated from eng) Nat Neurosci 7(8):841-846 (in eng).
  51. 51. CicchettiD.RogoschF. A.GunnarM. R.TothS. L.2010The differential impacts of early physical and sexual abuse and internalizing problems on daytime cortisol rhythm in school-aged children. (Translated from eng) Child Dev 81(1):252-269 (in eng).
  52. 52. GunnarM. R.FrennK.WewerkaS. S.MJVan Ryzin2009Moderate versus severe early life stress: associations with stress reactivity and regulation in 10-12-year-old children. (Translated from eng) Psychoneuroendocrinology 34(1):62-75 (in eng).
  53. 53. Smith SM & Vale WW2006The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. (Translated from eng) Dialogues Clin Neurosci 8(4):383-395 (in eng).
  54. 54. Koob GF2010The role of CRF and CRF-related peptides in the dark side of addiction. (Translated from eng) Brain Res 1314:3-14 (in eng).
  55. 55. ValeW.SpiessJ.RivierC.RivierJ.1981Characterization of a 41residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. (Translated from eng) Science 213(4514):1394-1397 (in eng).
  56. 56. al.2004Corticotropin-releasing factor and Urocortin I modulate excitatory glutamatergic synaptic transmission. (Translated from eng) J Neurosci 24(16):4020-4029 (in eng).
  57. 57. Dautzenberg FM & Hauger RL2002The CRF peptide family and their receptors: yet more partners discovered. (Translated from eng) Trends Pharmacol Sci 23(2):71-77 (in eng).
  58. 58. al.2001Identification of urocortin III, an additional member of the corticotropin-releasing factor (CRF) family with high affinity for the CRF2 receptor. (Translated from eng) Proc Natl Acad Sci U S A 98(13):7570-7575 (in eng).
  59. 59. Perrin MH & Vale WW1999Corticotropin releasing factor receptors and their ligand family. (Translated from eng) Ann N Y Acad Sci 885:312-328 (in eng).
  60. 60. KostichW. A.GrzannaR.LuN. Z.LargentB. L.2004Immunohistochemical visualization of corticotropin-releasing factor type 1 (CRF1) receptors in monkey brain. (Translated from eng) J Comp Neurol 478(2):111-125 (in eng).
  61. 61. al.1994Distribution of corticotropin-releasing factor receptor mRNA expression in the rat brain and pituitary. (Translated from eng) Proc Natl Acad Sci U S A 91(19):8777-8781 (in eng).
  62. 62. Van al.2000Distribution of mRNAs encoding CRF receptors in brain and pituitary of rat and mouse. (Translated from eng) J Comp Neurol 428(2):191-212 (in eng).
  63. 63. Dallman MF, Akana SF, Strack AM, Hanson ES, & Sebastian RJ1995The neural network that regulates energy balance is responsive to glucocorticoids and insulin and also regulates HPA axis responsivity at a site proximal to CRF neurons. (Translated from eng) Ann N Y Acad Sci 771:730-742 (in eng).
  64. 64. Feek CM, Marante DJ, & Edwards CR1983The hypothalamic-pituitary-adrenal axis. (Translated from eng) Clin Endocrinol Metab 12(3):597-618 (in eng).
  65. 65. PecoraroN.GomezF.DallmanM. F.2005Glucocorticoids dose-dependently remodel energy stores and amplify incentive relativity effects. (Translated from eng) Psychoneuroendocrinology 30(9):815-825 (in eng).
  66. 66. Dunn AJ & Berridge CW1990Physiological and behavioral responses to corticotropin-releasing factor administration: is CRF a mediator of anxiety or stress responses? (Translated from eng) Brain Res Brain Res Rev 15(2):71-100 (in eng).
  67. 67. al.2000Deletion of crhr2 reveals an anxiolytic role for corticotropin-releasing hormone receptor-2. (Translated from eng) Nat Genet 24(4):415-419 (in eng).
  68. 68. al.2004Tissue plasminogen activator promotes the effects of corticotropin-releasing factor on the amygdala and anxiety-like behavior. (Translated from eng) Proc Natl Acad Sci U S A 101(46):16345-16350 (in eng).
  69. 69. Rainnie DG, et al.2004Corticotrophin releasing factor-induced synaptic plasticity in the amygdala translates stress into emotional disorders. (Translated from eng) J Neurosci 24(14):3471-3479 (in eng).
  70. 70. Butler PD, Weiss JM, Stout JC, & Nemeroff CB1990Corticotropin-releasing factor produces fear-enhancing and behavioral activating effects following infusion into the locus coeruleus. (Translated from eng) J Neurosci 10(1):176-183 (in eng).
  71. 71. SuttonR. E.KoobG. F.Le MoalM.RivierJ.ValeW.1982Corticotropin releasing factor produces behavioural activation in rats. (Translated from eng) Nature 297(5864):331-333 (in eng).
  72. 72. Salak-Johnson JL, Anderson DL, & McGlone JJ2004Differential dose effects of central CRF and effects of CRF astressin on pig behavior. (Translated from eng) Physiol Behav 83(1):143-150 (in eng).
  73. 73. ValdezG. R.ZorrillaE. P.RivierJ.ValeW. W.KoobG. F.2003Locomotor suppressive and anxiolytic-like effects of urocortin 3, a highly selective type 2 corticotropin-releasing factor agonist. (Translated from eng) Brain Res 980(2):206-212 (in eng).
  74. 74. Bale TL2005Sensitivity to stress: dysregulation of CRF pathways and disease development. (Translated from eng) Horm Behav 48(1):1-10 (in eng).
  75. 75. Heinrichs SC, et al.1997Anti-sexual and anxiogenic behavioral consequences of corticotropin-releasing factor overexpression are centrally mediated. (Translated from eng) Psychoneuroendocrinology 22(4):215-224 (in eng).
  76. 76. MMvan Gaalen-PooreStenzel.HolsboerM. P.F.StecklerT.2002Effects of transgenic overproduction of CRH on anxiety-like behaviour. (Translated from eng) Eur J Neurosci 15(12):2007-2015 (in eng).
  77. 77. KasaharaM.GroeninkL.BreuerM.OlivierB.SarnyaiZ.2007Altered behavioural adaptation in mice with neural corticotrophin-releasing factor overexpression. (Translated from eng) Genes Brain Behav 6(7):598-607 (in eng).
  78. 78. RassnickS.HeinrichsS. C.BrittonK. T.KoobG. F.1993Microinjection of a corticotropin-releasing factor antagonist into the central nucleus of the amygdala reverses anxiogenic-like effects of ethanol withdrawal. (Translated from eng) Brain Res 605(1):25-32 (in eng).
  79. 79. Takahashi LK2001Role of CRF(1) and CRF(2) receptors in fear and anxiety. (Translated from eng) Neurosci Biobehav Rev 25(7-8):627-636 (in eng).
  80. 80. KehneJ.De LombaertS.2002Non-peptidic CRF1 receptor antagonists for the treatment of anxiety, depression and stress disorders. (Translated from eng) Curr Drug Targets CNS Neurol Disord 1(5):467-493 (in eng).
  81. 81. al.1998Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1. (Translated from eng) Nat Genet 19(2):162-166 (in eng).
  82. 82. Nguyen NK, et al.2006Conditional CRF receptor 1 knockout mice show altered neuronal activation pattern to mild anxiogenic challenge. (Translated from eng) Psychopharmacology (Berl) 188(3):374-385 (in eng).
  83. 83. Akana SF, et al.1996Clamped Corticosterone (B) Reveals the Effect of Endogenous B on Both Facilitated Responsivity to Acute Restraint and Metabolic Responses to Chronic Stress. (Translated from Eng) Stress 1(1):33-49 (in Eng).
  84. 84. al.2000A cholecystokinin-mediated pathway to the paraventricular thalamus is recruited in chronically stressed rats and regulates hypothalamic-pituitary-adrenal function. (Translated from eng) J Neurosci 20(14):5564-5573 (in eng).
  85. 85. YoungE. A.AkanaS.DallmanM. F.1990Decreased sensitivity to glucocorticoid fast feedback in chronically stressed rats. (Translated from eng) Neuroendocrinology 51(5):536-542 (in eng).
  86. 86. al.2005Panic induction with cholecystokinin-tetrapeptide (CCK-4) Increases plasma concentrations of the neuroactive steroid 3alpha, 5alpha tetrahydrodeoxycorticosterone (3alpha, 5alpha-THDOC) in healthy volunteers. (Translated from eng) Neuropsychopharmacology 30(1):192-195 (in eng).
  87. 87. GreisenM. H.BolwigT. G.WortweinG.2005Cholecystokinin tetrapeptide effects on HPA axis function and elevated plus maze behaviour in maternally separated and handled rats. (Translated from eng) Behav Brain Res 161(2):204-212 (in eng).
  88. 88. AbelsonJ. L.KhanS.LiberzonI.YoungE. A.2007HPA axis activity in patients with panic disorder: review and synthesis of four studies. (Translated from eng) Depress Anxiety 24(1):66-76 (in eng).
  89. 89. Raedler TJ, et al.2006Megestrol attenuates the hormonal response to CCK-4induced panic attacks. (Translated from eng) Depress Anxiety 23(3):139-144 (in eng).
  90. 90. Abelson JL & Young EA2003Hypothalamic-pituitary adrenal response to cholecystokinin-B receptor agonism is resistant to cortisol feedback inhibition. (Translated from eng) Psychoneuroendocrinology 28(2):169-180 (in eng).
  91. 91. Cornelis MC, Nugent NR, Amstadter AB, & Koenen KC2010Genetics of post-traumatic stress disorder: review and recommendations for genome-wide association studies. (Translated from eng) Curr Psychiatry Rep 12(4):313-326 (in eng).
  92. 92. Chantarujikapong SI, et al.2001A twin study of generalized anxiety disorder symptoms, panic disorder symptoms and post-traumatic stress disorder in men. (Translated from eng) Psychiatry Res 103(2-3):133-145 (in eng).
  93. 93. Kennedy JL, et al.1999Investigation of cholecystokinin system genes in panic disorder. (Translated from eng) Mol Psychiatry 4(3):284-285 (in eng).
  94. 94. al.2005Association study of 90 candidate gene polymorphisms in panic disorder. (Translated from eng) Psychiatr Genet 15(1):17-24 (in eng).
  95. 95. Dockray GJ1976Immunochemical evidence of cholecystokinin-like peptides in brain. (Translated from eng) Nature 264(5586):568-570 (in eng).
  96. 96. LotstraF.VanderhaeghenJ. J.1987Distribution of immunoreactive cholecystokinin in the human hippocampus. (Translated from eng) Peptides 8(5):911-920 (in eng).
  97. 97. Hill DR, Campbell NJ, Shaw TM, & Woodruff GN1987Autoradiographic localization and biochemical characterization of peripheral type CCK receptors in rat CNS using highly selective nonpeptide CCK antagonists. (Translated from eng) J Neurosci 7(9):2967-2976 (in eng).
  98. 98. Della-Fera MA & Baile CA1979Cholecystokinin octapeptide: continuous picomole injections into the cerebral ventricles of sheep suppress feeding. (Translated from eng) Science 206(4417):471-473 (in eng).
  99. 99. MAKatzmanKoszycki. D.BradwejnJ.2004Effects of CCK-tetrapeptide in patients with social phobia and obsessive-compulsive disorder. (Translated from eng) Depress Anxiety 20(2):51-58 (in eng).
  100. 100. HebbA. L.PoulinJ. F.RoachS. P.ZacharkoR. M.DroletG.2005Cholecystokinin and endogenous opioid peptides: interactive influence on pain, cognition, and emotion. (Translated from eng) Prog Neuropsychopharmacol Biol Psychiatry 29(8):1225-1238 (in eng).
  101. 101. ChenQ.NakajimaA.MeachamC.TangY. P.2006Elevated cholecystokininergic tone constitutes an important molecular/neuronal mechanism for the expression of anxiety in the mouse. Proc Natl Acad Sci U S A 1031038813886
  102. 102. GondaX.RihmerZ.JuhaszG.ZsombokT.BagdyG.2007High anxiety and migraine are associated with the s allele of the 5HTTLPR gene polymorphism. (Translated from eng) Psychiatry Res 149(1-3):261-266 (in eng).
  103. 103. al.2002Association between serotonin transporter gene promoter polymorphism (5HTTLPR) and behavioral responses to tryptophan depletion in healthy women with and without family history of depression. (Translated from eng) Arch Gen Psychiatry 59(7):613-620 (in eng).
  104. 104. al.2009Sex-specific association between the 5HTT gene-linked polymorphic region and basal cortisol secretion. (Translated from eng) Psychoneuroendocrinology 34(7):972-982 (in eng).
  105. 105. UdelsmanR.ChrousosG. P.1988Hormonal responses to surgical stress. (Translated from eng) Adv Exp Med Biol 245:265-272 (in eng).
  106. 106. al.2012What can We Know from Pituitary-Adrenal Hormones About the Nature and Consequences of Exposure to Emotional Stressors? (Translated from Eng) Cell Mol Neurobiol (in Eng).
  107. 107. al.1999Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety. (Translated from eng) Nat Genet 23(1):99-103 (in eng).
  108. 108. van al.2010Psychological traits and the cortisol awakening response: results from the Netherlands Study of Depression and Anxiety. (Translated from eng) Psychoneuroendocrinology 36(2):240-248 (in eng).
  109. 109. Essex MJ, et al.2011Influence of early life stress on later hypothalamic-pituitary-adrenal axis functioning and its covariation with mental health symptoms: a study of the allostatic process from childhood into adolescence. (Translated from eng) Dev Psychopathol 23(4):1039-1058 (in eng).
  110. 110. Wilkinson PO & Goodyer IM2011Childhood adversity and allostatic overload of the hypothalamic-pituitary-adrenal axis: a vulnerability model for depressive disorders. (Translated from eng) Dev Psychopathol 23(4):1017-1037 (in eng).
  111. 111. MurgatroydC.SpenglerD.2011Epigenetic programming of the HPA axis: early life decides. (Translated from eng) Stress 14(6):581-589 (in eng).
  112. 112. BMKudielkaWustS.2011Human models in acute and chronic stress: assessing determinants of individual hypothalamus-pituitary-adrenal axis activity and reactivity. (Translated from eng) Stress 13(1):1-14 (in eng).
  113. 113. NieuwenhuizenA. G.RuttersF.2008The hypothalamic-pituitary-adrenal-axis in the regulation of energy balance. (Translated from eng) Physiol Behav 94(2):169-177 (in eng).
  114. 114. Walker BR2007Glucocorticoids and cardiovascular disease. (Translated from eng) Eur J Endocrinol 157(5):545-559 (in eng).
  115. 115. BenedettiF.AmanzioM.VighettiS.AsteggianoG.2006The biochemical and neuroendocrine bases of the hyperalgesic nocebo effect. (Translated from eng) J Neurosci 26(46):12014-12022 (in eng).
  116. 116. Lovick TA2009CCK as a modulator of cardiovascular function. (Translated from eng) J Chem Neuroanat 38(3):176-184 (in eng).
  117. 117. LeeS. Y.SolteszI.2011Cholecystokinin: a multi-functional molecular switch of neuronal circuits. (Translated from eng) Dev Neurobiol 71(1):83-91 (in eng).
  118. 118. HoganB.BeddingtonR.CostantiniF.LacyE.1994Manipulating the mouse embryo, a laboratory manual. (in eng).
  119. 119. Im HI, et al.2009Post-training dephosphorylation of eEF-2 promotes protein synthesis for memory consolidation. (Translated from eng) PLoS One 4(10):e7424 (in eng).
  120. 120. Wank SA1995Cholecystokinin receptors. (Translated from eng) Am J Physiol 269(5 Pt 1):G628-646 (in eng).
  121. 121. MontignyC.1984Benzodiazepines antagonize cholecystokinin-induced activation of rat hippocampal neurones. (Translated from eng) Nature 312(5992):363-364 (in eng).
  122. 122. RasmussenK.HeltonD. R.BergerJ. E.ScearceE.1993The CCK-B antagonist LY288513 blocks effects of diazepam withdrawal on auditory startle. (Translated from eng) Neuroreport 5(2):154-156 (in eng).
  123. 123. HaugerR. L.LorangM.IrwinM.AguileraG.1990CRF receptor regulation and sensitization of ACTH responses to acute ether stress during chronic intermittent immobilization stress. (Translated from eng) Brain Res 532(1-2):34-40 (in eng).
  124. 124. MaS.MorilakD. A.2005Chronic intermittent cold stress sensitises the hypothalamic-pituitary-adrenal response to a novel acute stress by enhancing noradrenergic influence in the rat paraventricular nucleus. (Translated from eng) J Neuroendocrinol 17(11):761-769 (in eng).
  125. 125. Mueller SC, et al.2010Early-life stress is associated with impairment in cognitive control in adolescence: an fMRI study. (Translated from eng) Neuropsychologia 48(10):3037-3044 (in eng).
  126. 126. al.2009Remodelling by early-life stress of NMDA receptor-dependent synaptic plasticity in a gene-environment rat model of depression. (Translated from eng) Int J Neuropsychopharmacol 12(4):553-559 (in eng).
  127. 127. Coplan JD, et al.2010Early-life stress and neurometabolites of the hippocampus. (Translated from eng) Brain Res 1358:191-199 (in eng).
  128. 128. Gatt JM, et al.2010Early Life Stress Combined with Serotonin 3A Receptor and Brain-Derived Neurotrophic Factor Valine 66 to Methionine Genotypes Impacts Emotional Brain and Arousal Correlates of Risk for Depression. (Translated from Eng) Biol Psychiatry (in Eng).
  129. 129. HarroJ.KiivetR. A.LangA.VasarE.1990Rats with anxious or non-anxious type of exploratory behaviour differ in their brain CCK-8 and benzodiazepine receptor characteristics. (Translated from eng) Behav Brain Res 39(1):63-71 (in eng).
  130. 130. MacNeil. G.SelaY.Mc IntoshJ.ZacharkoR. M.1997Anxiogenic behavior in the light-dark paradigm follwoing intraventricular administration of cholecystokinin-8S, restraint stress, or uncontrollable footshock in the CD-1 mouse. (Translated from eng) Pharmacol Biochem Behav 58(3):737-746 (in eng).
  131. 131. PavlasevicS.BednarI.QureshiG. A.SoderstenP.1993Brain cholecystokinin tetrapeptide levels are increased in a rat model of anxiety. (Translated from eng) Neuroreport 5(3):225-228 (in eng).
  132. 132. Farook JM, et al.2004The CCK2 agonist BC264 reverses freezing behavior habituation in PVG hooded rats on repeated exposures to a cat. (Translated from eng) Neurosci Lett 355(3):205-208 (in eng).
  133. 133. Farook JM, et al.2001Strain differences in freezing behavior of PVG hooded and Sprague-Dawley rats: differential cortical expression of cholecystokinin2 receptors. (Translated from eng) Neuroreport 12(12):2717-2720 (in eng).
  134. 134. al.2003Genetic variations in CCK2 receptor in PVG hooded and Sprague-Dawley rats and its mRNA expression on cat exposure. (Translated from eng) Behav Neurosci 117(2):385-390 (in eng).
  135. 135. HarroJ.LofbergC.RehfeldJ. F.OrelandL.1996Cholecystokinin peptides and receptors in the rat brain during stress. (Translated from eng) Naunyn Schmiedebergs Arch Pharmacol 354(1):59-66 (in eng).
  136. 136. HarroJ.MarcussonJ.OrelandL.1992Alterations in brain cholecystokinin receptors in suicide victims. (Translated from eng) Eur Neuropsychopharmacol 2(1):57-63 (in eng).
  137. 137. NevoI.BeckerC.HamonM.BenolielJ. J.1996Stress- and yohimbine-induced release of cholecystokinin in the frontal cortex of the freely moving rat: prevention by diazepam but not ondansetron. (Translated from eng) J Neurochem 66(5):2041-2049 (in eng).
  138. 138. SiegelR. A.DukerE. M.PahnkeU.WuttkeW.1987Stress-induced changes in cholecystokinin and substance P concentrations in discrete regions of the rat hypothalamus. (Translated from eng) Neuroendocrinology 46(1):75-81 (in eng).
  139. 139. Zhang LX, et al.1996Changes in cholecystokinin mRNA expression after amygdala kindled seizures: an in situ hybridization study. (Translated from eng) Brain Res Mol Brain Res 35(1-2):278-284 (in eng).
  140. 140. Del Bel EA & Guimaraes FS1997Social isolation increases cholecystokinin mRNA in the central nervous system of rats. (Translated from eng) Neuroreport 8(16):3597-3600 (in eng).
  141. 141. HermanJ. P.FlakJ.JankordR.2008Chronic stress plasticity in the hypothalamic paraventricular nucleus. (Translated from eng) Prog Brain Res 170:353-364 (in eng).
  142. 142. Widom CS1999Posttraumatic stress disorder in abused and neglected children grown up. (Translated from eng) Am J Psychiatry 156(8):1223-1229 (in eng).
  143. 143. CohenH.KaplanZ.KotlerM.1999CCK-antagonists in a rat exposed to acute stress: implication for anxiety associated with post-traumatic stress disorder. (Translated from eng) Depress Anxiety 10(1):8-17 (in eng).
  144. 144. al.2000Cholecystokinin-induced anxiety in rats: relevance of pre-experimental stress and seasonal variations. (Translated from eng) J Psychiatry Neurosci 25(1):33-42 (in eng).
  145. 145. BradwejnJ.KoszyckiD.ShriquiC.1991Enhanced sensitivity to cholecystokinin tetrapeptide in panic disorder. Clinical and behavioral findings. (Translated from eng) Arch Gen Psychiatry 48(7):603-610 (in eng).
  146. 146. al.1997Effects of the cholecystokinin agonist pentagastrin in patients with generalized anxiety disorder. (Translated from eng) Am J Psychiatry 154(5):700-702 (in eng).
  147. 147. al.2000Behavioral and endocrine response to cholecystokinin tetrapeptide in patients with posttraumatic stress disorder. (Translated from eng) Biol Psychiatry 47(2):107-111 (in eng).
  148. 148. van Vliet IM, Westenberg HG, Slaap BR, den Boer JA, & Ho Pian KL1997Anxiogenic effects of pentagastrin in patients with social phobia and healthy controls. (Translated from eng) Biol Psychiatry 42(1):76-78 (in eng).

Written By

Mingxi Tang, Anu Joseph, Qian Chen, Jianwei Jiao and Ya-Ping Tang

Submitted: March 15th, 2012 Published: November 28th, 2012