Fear Stress Research Articles

Pharmacological evaluation of a novel corticotropin‐releasing factor 1 receptor antagonist T‐3047928 in stress‐induced animal models in a comparison with alosetron

The major symptoms of irritable bowel syndrome (IBS) are changes in bowel habits and abdominal pain. Psychological stress is the major pathophysiological components of IBS. Corticotropin-releasing factor (CRF) is a well-known integrator in response to psychological stress. In this study, a novel CRF1 receptor antagonist T-3047928 was evaluated in stress-induced IBS models of rats to explore its potency for IBS. Plasma adrenocorticotropic hormone (ACTH) levels after intravenous oCRH challenge were measured as a pharmacodynamic marker. Efficacies of oral T-3047928 were compared with oral alosetron, a 5-HT3 antagonist, on conditioning fear stress (CFS)-induced defecation, restraint stress (RS)-induced acute visceral pain, specific alteration of rhythm in temperature (SART) stress-induced chronic visceral pain, and normal defecation. T-3047928 (1-10mg/kg, p.o.) demonstrated a dose-dependent inhibition on oCRH-induced ACTH secretion. In disease models, T-3047928 suppressed fecal pellet output induced by CFS and improved both acute and chronic visceral hypersensitivity induced by RS and SART stress, respectively. Alosetron was also efficacious in stress-induced defecation and visceral pain models at 1 and 10mg/kg, respectively. Alosetron, however, also suppressed normal defecation at lower those. On the other hand, T-3047928 did not change normal defecation even at higher dose than those in disease models. T-3047928 is an orally active CRF1 antagonist that demonstrated potent inhibitory effects in stress-associated IBS models with no effect on normal defecation. Therefore, it is suggested that T-3047928 may have a potency as a novel option for IBS-D therapy with minimal constipation risk.

5-HT6 receptor antagonism reduces defecation in rat: A potential treatment strategy for irritable bowel syndrome with diarrhea

Whereas the potential role of serotonin for the pathophysiology of irritable bowel syndrome (IBS) has since long been discussed, the possibility that 5-hydroxytryptamine 6 (5-HT6) receptors may serve as targets for the treatment of this condition has as yet not been explored. The aim of the current study was to assess to what extent defecation in rats is influenced by manipulation of 5-HT6 receptors. Reduced defecation following SB-399885 was observed in non-stressed animals assessed for 7 h after drug administration. While not impacting context-conditioned freezing, three 5-HT6 receptor antagonists (SB-399885, SB-271046 and SB-258585) also markedly reduced the number of faecal boli produced by rats exposed to context-conditioned fear. In contrast, a 5-HT6 receptor agonist, WAY-208466, influenced defecation neither in unstressed animals nor in rats experiencing conditioned fear stress. A clinical study on the possible effect of a 5-HT6 receptor antagonist in IBS with diarrhea appears warranted.

Malnutrition screening in patients with pancreatic disorders

Cancer patients often experience multiple emotional distresses, particularly the fear of death. However, there are rare studies to assess the direct effect of the fear of death on disease progression.Xenograft pancreatic cancer animal models were established in nude mice. Fear stress was induced to tumor bearing mice by closely housing with a cat and depressive behaviors were measured using open field test, forced swimming test, and sucrose consumption test. Plasma adrenaline concentration was measured using ELISA.Fear stress induced depression-like behaviors in tumor bearing mice which were accompanied with increases in tumor growth, plasma adrenaline levels as well as the protein expression of alpha 2 adrenergic receptor (α2 AR) and beta 2 adrenergic receptor (β2-AR) in tumor tissues. The β-adrenergic antagonist propranolol (Pro) treatment blocked the effect of stress on tumor growth in pancreatic cancer xenograft animal model, but had no effects on the levels of plasma adrenaline level, and α2 AR and β2-AR expression in tumor tissues. Moreover, fear stress increased Frizzled-1, Wnt1, vimentin, but decreased E-cadherin protein expression in tumor tissues, while Pro reversed the effects of fear stress on the expression of these proteins.Fear of death impacted the growth of PDAC tumor though activation of epithelial-mesenchymal transition. Treating pancreatic cancer patients with β-adrenergic antagonist implicates an effective strategy to treat cancer including PDAC.

Fear stress enhanced xenograft pancreatic tumor growth through activating epithelial-mesenchymal transition

ObjectiveCancer patients often experience multiple emotional distresses, particularly the fear of death. However, there are rare studies to assess the direct effect of the fear of death on disease progression. MethodsXenograft pancreatic cancer animal models were established in nude mice. Fear stress was induced to tumor bearing mice by closely housing with a cat and depressive behaviors were measured using open field test, forced swimming test, and sucrose consumption test. Plasma adrenaline concentration was measured using ELISA. ResultsFear stress induced depression-like behaviors in tumor bearing mice which were accompanied with increases in tumor growth, plasma adrenaline levels as well as the protein expression of alpha 2 adrenergic receptor (α2 AR) and beta 2 adrenergic receptor (β2-AR) in tumor tissues. The β-adrenergic antagonist propranolol (Pro) treatment blocked the effect of stress on tumor growth in pancreatic cancer xenograft animal model, but had no effects on the levels of plasma adrenaline level, and α2 AR and β2-AR expression in tumor tissues. Moreover, fear stress increased Frizzled-1, Wnt1, vimentin, but decreased E-cadherin protein expression in tumor tissues, while Pro reversed the effects of fear stress on the expression of these proteins. ConclusionFear of death impacted the growth of PDAC tumor though activation of epithelial-mesenchymal transition. Treating pancreatic cancer patients with β-adrenergic antagonist implicates an effective strategy to treat cancer including PDAC.

The Dilemma of Guarding Self-Actualization from Fear Claws

My ultimate concern in this research is to investigate the culture of fear that we live in and how it impacts our vocational callings. Why the fear of failing can be immobilizing, or can paralyze us to do nothing, and therefore fall a prey to inner devastation between fulfilling our self-image belief and securing our daily responsibilities. This fear goes harshly against the inner psychological need that drives us to maximize our personal abilities and resources which may vary from one person to another. Ironically implementing the basics of organizational psychology aims to increase productivity and develop and train employees professionally. Instead there must be a huge consideration to the varied work stress that derives many to fall into deep depression. In this study I try to come closer to a clearer picture of what triggers this fear stress; is it work load or the way managers approach employees? Does a narcissist manager or any other person aggravate this stress by feeding an environment of fear that paralyzes others’ talents and capabilities? Is every individual responsible for fencing his own boundaries from any external fear threat that may attack him? Or the real threat comes from one’s own inner thoughts, supposing that we could easily block outer irritations.

Conditioned fear stress increases bone resorption in apical periodontitislesions in Wistar male rats

ObjectiveBecause the impact of conditioned fear stress on apical bone resorption is unknown, the aim of the current studywas to use a rat model to evaluate the impact of conditioned fear stress on the bone resorption of inflammatory apical periodontitis lesions. MethodsTwenty-five animals were divided into two groups. They underwent a surgical procedure in the first left lower molar tooth to expose the dental pulp and induce inflammatory apical periodontitis lesions through the retention of contamination (bacterial infection) during a 56-day period. The animals in the case group were stressed daily by using electrical stimuli (1.10 mA), whereas the animals in the control group were absent from the stressful stimuli (shocks). The open field test was performed to validate the stress methodology. The jaws were removed and collected for histological and radiographic analyses. ResultsStressed animals presented increased levels of bone loss and inflammatory cells in the root apex in comparison with the control group (P = 0.0001). However, no radiographic differences were observed between the groups (P > 0.05). ConclusionsOur results demonstrated that conditioned fear stress could modify a periapical lesion by increasing the size of bone loss there. Conditioned fear stress also increased the total number of inflammatory cells compared with the control group. Studies evaluating the impact of conditioned fear stress on human periapical inflammatory lesions should be encouraged.

Escitalopram attenuates fear stress-induced increase in amygdalar dopamine following methamphetamine-induced sensitisation: Implications of fine-tuning action of selective serotonin reuptake inhibitors on emotional processing

Serotonin reuptake inhibitors modulate the serotonergic pathways of the nervous system and are widely used for treating psychiatric conditions such as anxiety and depression. The dopaminergic system is related to the development of these conditions. Previous studies on methamphetamine-sensitised rats (behavioural models of stress vulnerability) have shown increased release of dopamine in response to conditioned stress in the amygdala. This biochemical abnormality was proposed to underlie the pathophysiology of stress vulnerability. However, the effect of serotonin reuptake inhibitors on dopamine levels and its consequent impact on emotional processing is unclear. Here we examined the acute effect of escitalopram, a highly selective serotonin reuptake inhibitor, on fear-related behaviour, baseline dopamine release and dopamine release in response to conditioned fear stress in the amygdala of model rats. Male Sprague-Dawley rats received 2 mg/kg/day, s.c. of methamphetamine for 10 days to sensitise them to the drug, and a fear conditioning paradigm was instituted to model psychological stress. Dopamine changes in the amygdala in response to systemic administration of escitalopram followed by conditioned fear stress were measured using microdialysis and high-performance liquid chromatography. Baseline dopamine release in the amygdala was increased by escitalopram in non-sensitised rats but not in methamphetamine-sensitised rats. Escitalopram attenuated dopamine release in response to the fear-conditioned stimulus in both sensitised and non-sensitised rats. The extent of suppression in methamphetamine-sensitised rats (− 90%) was greater than that in non-sensitised rats (− 48%). These findings suggest that serotonin reuptake inhibitors indirectly stabilise the dopaminergic pathway and modulate emotional processing in the amygdala.

Docosahexaenoic Acid Helps to Lessen Extinction Memory in Rats.

Memory extinction is referred to as a learning process in which a conditioned response (CR) progressively reduces over time as an animal learns to uncouple a response from a stimulus. Extinction occurs when the rat is placed into a context without shock after training. Docosahexaenoic acid (DHA, C22:6, n-3) is implicated in memory formation in mammalian brains. In a two-way active shuttle-avoidance apparatus, we examined whether DHA affects the extinction memory and the expression of brain cognition-related proteins, including gastrin-releasing peptide receptor (GRPR), brain-derived neurotrophic factor receptor (BDNFR) tyrosine kinase receptor B (TrKB), and N-methyl-d-aspartate receptor (NMDAR) subunits NR2A and NR2B. Also, the protein levels of GRP, BDNF, postsynaptic density protein-95 (PSD-95), and vesicular acetylcholine transporter (VAChT), and the antioxidative potentials, in terms of lipid peroxide (LPO) and reactive oxygen species (ROS), were examined in the hippocampus. During the acquisition phase, the rats received a conditioned stimulus (CS-tone) paired with an unconditioned stimulus (UCS foot shock) for three consecutive days (Sessions S1, S2, and S3, each consisting of 30-trials) after 12 weeks of oral administration of DHA. After a three-day interval, the rats were re-subjected to two extinction sessions (S4, S5), each comprising 30 trials of CS alone. During the acquisition training in S1, the shock-related avoidance frequency (acquisition memory) was significantly higher in the DHA-administered rats compared with the control rats. The avoidance frequency, however, decreased with successive acquisition trainings in sessions S2 and S3. When the rats were subjected to the extinction sessions after a break for consolidation, the conditioned response (CR) was also significantly higher in the DHA-administered rats. Interestingly, the freezing responses (frequency and time) also significantly decreased in the DHA-administered rats, thus suggesting that a higher coping capacity was present during fear stress in the DHA-administered rats. DHA treatments increased the mRNA levels of GRPR, BDNF receptor TrKB, and NMDAR subunit NR2B. DHA also increased the protein levels of GRP, BDNF, PSD-95, and VAChT, and the antioxidative potentials in the hippocampus. These results suggest the usefulness of DHA for treating stress disorders.

Patient perspectives on engagement in decision-making in early management of non-ST elevation acute coronary syndrome: a qualitative study

BackgroundSurveys of patients suggest many want to be actively involved in treatment decisions for acute coronary syndromes. However, patient experiences of their engagement and participation in early phase decision-making have not been well described.MethodsWe performed a patient led qualitative study to explore patient experiences with decision-making processes when admitted to hospital with non-ST elevation acute coronary syndrome. Trained patient-researchers conducted the study via a three-phase approach using focus groups and semi-structured interviews and employing grounded theory methodology.ResultsTwenty patients discharged within one year of a non-ST elevation acute coronary syndrome participated in the study. Several common themes emerged. First, patients characterized the admission and early treatment of ACS as a rapidly unfolding process where they had little control. Participants felt they played a passive role in early phase decision-making. Furthermore, participants described feeling reduced capacity for decision-making owing to fear and mental stress from acute illness, and therefore most but not all participants were relieved that expert clinicians made decisions for them. Finally, once past the emergent phase of care, participants wanted to retake a more active role in their treatment and follow-up plans.ConclusionsPatients admitted with ACS often do not take an active role in initial clinical decisions, and are satisfied to allow the medical team to direct early phase care. These results provide important insight relevant to designing patient-centered interventions in ACS and other urgent care situations.

Impaired extinction of cued fear memory and abnormal dendritic morphology in the prelimbic and infralimbic cortices in VPAC2 receptor (VIPR2)-deficient mice

The structurally related neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) have been implicated in stress regulation and learning and memory. Several bodies of research have shown the impact of the PACAP specific receptor PAC1 on fear memory, but the roles of other PACAP receptors in regulating fear stress responses remain to be elucidated. Here we aimed to investigate the effects of genetic deletion of VIPR2 encoding the VPAC2 receptor, which binds both VIP and PACAP, on fear-related memory and on dendritic morphology in the brain regions of the fear circuitry. Male VPAC2 receptor knockout (VPAC2-KO) and littermate wild-type control mice were subjected to Pavlovian fear conditioning paradigm. VPAC2-KO mice displayed normal acquisition of fear conditioning, contextual and cued fear memory, but impaired extinction of cued fear memory. Morphological analyses revealed reductions in cell body size and total branch number and length of apical and basal dendrites of prelimbic cortex neurons in VPAC2-KO mice. In addition, Sholl analysis indicated that the amount of dendritic material distal to the soma was decreased, while proximal dendritic material was increased. In the infralimbic cortex, the amount of apical dendritic material proximal to the soma was increased in VPAC2-KO mice, while other indices of morphology did not differ. Finally, there were no differences in dendritic morphology in basolateral amygdala neurons between genotypes. These findings suggest that the VPAC2 receptor plays an important role in the fear extinction processes and the regulation of the dendritic morphology in the prelimbic and infralimbic cortices.

Stimulation of Anxiety-Like Behavior via ERK Pathway by Competitive Serotonin Receptors 2A and 1A in Post-Traumatic Stress Disordered Mice

Background/Aims: Serotonin 5HT2A and 5HT1A receptors (5HT2AR, 5HT1AR) have the closest connection to anxiety-like behavior in post-traumatic stress disorder (PTSD). However, the underlying mechanism remains unclear. In this study, we explored the connection between 5HT2A and 5HT1A receptors and anxiety-like behavior. Methods: In the PTSD animal model, mice were exposed to conditioned fear stress coupled with single-prolonged stress (CF+SPS). Post stress infliction and behavioral tests, of which include open field, freezing behavior and elevated plus maze tests were carried out to examine establishment of the proposed model. Both Western blot analysis and immunofluorescence labeling were used to evaluate protein expressions of 5HT2AR, 5HT1AR, ERK1, ERK2 and c-Myc in the hippocampi of the mice and RT Q-PCR was employed for evaluation of the relative mRNA expressions. Results: Based on the model established utilizing the CF+SPS procedure, we found 5HT2AR to play a positive role on anxiety-like behavior by inhibiting the expression of 5HT1AR. In addition, the ERK-c-Myc pathway elicited the effect of 5HT2AR and 5HT1AR on anxiety-like behavior in PTSD, 5-HT enhanced the anxiety-like behavior through both 5HT2AR and 5HT1AR. Conclusion: These findings suggest competive interaction between 5HT2AR and 5HT1AR actively affects anxiety-like behavior in the hippocampi of PTSD mice via the ERK pathway.

Vasovagal Response After Pain Procedures

Vasovagal syncope (VVS) is a specific type of syncope associated with hypotension, bradycardia, and peripheral vasodilation usually lasting 20 seconds and rarely longer than several minutes. It is caused by emotional stress, fear, pain, instrumentation, blood phobia, heat, and orthostatic stress. When a triggering event is present, VVS is usually preceded by autonomic symptoms of pallor, sweating, nausea, and abdominal discomfort. It is a frequently cited immediate adverse event during pain procedures, with rates ranging between 0 and 8.7%. The use of moderate sedation has been shown to reduce the risk of first-time and repeat episodes of vasovagal reactions. However, early detection, simple conservative management, and a willingness to terminate the procedure have resulted in no serious adverse outcomes.

Asenapine reduces anxiety-related behaviours in rat conditioned fear stress model.

Asenapine is an atypical antipsychotic that is currently available for the treatment of schizophrenia and bipolar I disorder. Although the atypical antipsychotics clozapine and olanzapine are effective for depression and anxiety in schizophrenia, as demonstrated by animal model studies, this has not been clarified for asenapine. Therefore, we compared the effects of asenapine in the conditioned fear stress model with those of clozapine and olanzapine. Rats were individually fear conditioned using electrical foot shock in a Skinner box. Approximately 24 h later, individual animals were returned to the same Skinner box (without electrical shock) and their freezing behaviour was observed for 5 min. Animals were treated with asenapine, clozapine, olanzapine, the 5-HT1A receptor partial agonist buspirone, or the 5-HT2C receptor antagonist SB242084 at 30 min before freezing behaviour assessment. The 5-HT1A receptor antagonist WAY100635 or the 5-HT2C receptor agonist Ro60-0175 was also used concomitantly with asenapine. The effects of asenapine, clozapine, and olanzapine on serotonin release in the rat hippocampus were also measured using in vivo microdialysis. Asenapine reduced freezing behaviour, while neither clozapine nor olanzapine reduced freezing behaviour. Buspirone and SB242084 also reduced freezing behaviour. The effect of asenapine in reducing freezing behaviour was not altered by the concomitant administration of WAY100635 or Ro60-0175. Both asenapine and clozapine, but not olanzapine, increased serotonin release in the rat hippocampus. Asenapine may have superior therapeutic effect on anxiety symptoms than other agents, although the underlying mechanism of its anxiolytic activity remains unknown.

How Farm Animals React and Perceive Stressful Situations Such As Handling, Restraint, and Transport.

Simple SummaryA common animal welfare question is: how stressful is handling and restraining farm animals for veterinary procedures even when no surgical or invasive procedures are done? It depends on how a particular animal perceives it. For one animal, restraint for an injection may be a positive experience associated with food treats and a different animal may be highly fearful and actively resist being restrained. The animal’s response is highly dependent on both its previous experiences and inherited traits such as temperament.An animal that has been carefully acclimated to handling may willingly re-enter a restrainer. Another animal may have an intense agitated behavioral reaction or refuse to re-enter the handling facility. Physiological measures of stress such as cortisol may be very low in the animal that re-enters willingly and higher in animals that actively resist restraint. Carefully acclimating young animals to handling and restraint can help improve both productivity and welfare by reducing fear stress. Some of the topics covered in this review are: How an animal perceives handling and restraint, the detrimental effects of a sudden novel event, descriptions of temperament and aversion tests and the importance of good stockmanship.

Fear conditioning, social groups and stress

Fear conditioning, social groups and stress

Behavioral impairments and serotonin reductions in rats after chronic L-dopa

L-dopa, the main therapeutic for Parkinson's disease (PD), has been shown to increase brain dopamine concentrations that are necessary for proper motor control; however, PD patients experience non-motor symptoms that are not improved or could be exacerbated by L-dopa. The purpose of this study is to determine the effects of L-dopa treatment on cognitive and affective behavioral responses of rats, as well as their corresponding monoamine brain concentrations. Rats were treated with L-dopa (6 mg/kg; twice daily) for 10 consecutive days. Sodium ascorbate (400 mg/kg) was co-administered with L-dopa to investigate the effects of antioxidant co-treatment on behavior and monoamine concentrations. Rats underwent cognitive and affective behavioral testing. Monoamine concentrations of several brain regions were analyzed. L-dopa treatment resulted in significant impairment in the performance in the Barnes maze and improvement in conditioned fear stress paradigms. Specifically, L-dopa caused an increase in latency to find the goal box during Barnes maze testing and increased freezing behavior in context-induced conditioned fear testing. Furthermore, the rats in the conditioned fear stress experiments showed corresponding depletions in serotonin (5-HT) and its metabolite, 5-HIAA, in the dorsal raphe nucleus (DRN) and the mPFC. The behavioral impairments as well as monoamine depletions were blocked by ascorbate co-treatment. Chronic L-dopa may contribute to non-motor symptoms related to spatial memory and fear. These effects may be attributable to a dysregulation of brain 5-HT caused by L-dopa treatment. The results presented here provide further rationale for investigating adjunctive therapeutics to L-dopa for PD, such as antioxidants.

Factors associated with psychological and physiological stress reactions to blood donation: a systematic review of the literature.

Blood donation is generally seen as a safe, voluntary and socially useful activity, based on the altruism of donors1. A number of positive effects of blood donation are described in scientific literature, such as feelings of satisfaction, feelings of being more alert and feeling better in general2. However, the majority of the literature concerning blood donation describes adverse events, such as fatigue, vasovagal symptoms, fainting and bruises2–5. In addition to the discomfort experienced by the donor, these might also impede blood donation in the future. Studies report that up to 10 to 20% of donors experience such adverse events6,7. For a blood supply organisation, it is crucial to maintain the donor pool in order to be able to deliver an optimal supply of blood. This can be achieved by recruiting new donors and retaining existing ones. Either way, negative donor experiences should be kept to a minimum. In blood donor research, several studies have investigated the occurrence of adverse events, retention, or the interaction between adverse events and retention. For instance, Bravo et al. investigated factors associated with fainting and donating blood and showed that vasovagal reactions are more common during or after phlebotomy than during registration8. Newman et al. showed that donors who experienced an adverse event were less likely to return to the blood centre9. In line with this, Veldhuizen et al. showed a strong association between reporting a vasovagal reaction and stopping donating, especially among men6. Adverse events may upset the donors, causing increased anxiety. However, despite some indications that anxiety is increased before and during donating blood10, it remains largely unclear what factors are associated with such a stress reaction. Stress reactions are quite common phenomena11,12. Various factors, known as stressors or stress stimuli, can induce a stress reaction. Although any situation and any object may elicit a stress reaction, the resulting stress experience may differ between individuals and circumstances12. After being confronted with a stressor, a psychological stress reaction occurs, which can consist of higher levels of anxiety, irritation, fear, worry, tension or anger13. At the same time, physiological stress reactions take place, such as increases in the levels of cortisol and (nor-)adrenaline14, a decrease in heart rate variability15, and negative changes in blood coagulation parameters16. As mentioned earlier, blood donation does not always elicit positive feelings, but can be accompanied by anxiety-eliciting factors as well8–17. These factors (stressors) may induce a stress reaction. The relation between blood donation on the one hand, and anxiety and stress reactions on the other remains largely unclear. Although stress reactions (e.g. anxiety) do seem to be present, the factors capable of inducing or enhancing these reactions (i.e. stressors) are largely unidentified. The aim of this study was, therefore, to perform a systematic review of the literature in order to evaluate existing knowledge on the following research question: what factors are associated with psychological and physiological stress reactions in blood donors in a blood donation setting? We hypothesised that both physiological (e.g. increased levels of adrenaline or cortisol) and psychological (e.g. increased levels of anxiety or fear) stress reactions take place in a blood donation setting. We also hypothesised that a greater stress reaction would be associated with factors such as donation-related adverse events, e.g. bruises or fainting, as opposed to not experiencing such an event. Knowing and identifying potential stressors could help to optimise the donation experience for the donor.

The effects of AP521, a novel anxiolytic drug, in three anxiety models and on serotonergic neural transmission in rats

We investigated the anxiolytic effects and mechanism of action of a new anxiolytic drug, (R)-piperonyl-1,2,3,4-tetrahydro[1]benzothieno[2,3-c]pyridine-3- carboxamide hydrochloride (AP521). AP521 showed equal or more potent anxiolytic-like effects compared with diazepam, a benzodiazepine receptor agonist, or tandospirone, a partial 5-hydroxytryptamine (5-HT)1A receptor agonist, in three rat anxiety models; the Vogel-type conflict test, elevated plus maze test, and conditioned fear stress test. Although AP521 did not bind to the benzodiazepine receptor, it did bind to 5-HT1A, 5-HT1B, 5-HT1D, 5-HT5A and 5-HT7 receptors, and showed agonist activity for the human 5-HT1A receptor expressed in HEK293 cells. Tandospirone, which can stimulate the presynaptic 5-HT1A receptors in the raphe, tended to decrease extracellular 5-HT concentration in the medial prefrontal cortex (mPFC) in rats. In contrast, AP521 increased extracellular 5-HT concentration. In addition, AP521 enhanced the anti-freezing effect of citalopram, a selective serotonin reuptake inhibitor, in the fear conditioning model in rats and enhanced the citalopram-caused increase of the extracellular 5-HT concentration in the mPFC. These results suggest that AP521 exhibits potent anxiolytic effects by acting as a postsynaptic 5-HT1A receptor agonist and by enhancing serotonergic neural transmission in the mPFC by a novel mechanism of action.

Repeated exposure to conditioned fear stress increases anxiety and delays sleep recovery following exposure to an acute traumatic stressor.

Repeated stressor exposure can sensitize physiological responses to novel stressors and facilitate the development of stress-related psychiatric disorders including anxiety. Disruptions in diurnal rhythms of sleep–wake behavior accompany stress-related psychiatric disorders and could contribute to their development. Complex stressors that include fear-eliciting stimuli can be a component of repeated stress experienced by human beings, but whether exposure to repeated fear can prime the development of anxiety and sleep disturbances is unknown. In the current study, adult male F344 rats were exposed to either control conditions or repeated contextual fear conditioning for 22 days followed by exposure to no, mild (10), or severe (100) acute uncontrollable tail shock stress. Exposure to acute stress produced anxiety-like behavior as measured by a reduction in juvenile social exploration and exaggerated shock-elicited freezing in a novel context. Prior exposure to repeated fear enhanced anxiety-like behavior as measured by shock-elicited freezing, but did not alter social exploratory behavior. The potentiation of anxiety produced by prior repeated fear was temporary; exaggerated fear was present 1 day but not 4 days following acute stress. Interestingly, exposure to acute stress reduced rapid eye movement (REM) and non-REM (NREM) sleep during the hours immediately following acute stress. This initial reduction in sleep was followed by robust REM rebound and diurnal rhythm flattening of sleep/wake behavior. Prior repeated fear extended the acute stress-induced REM and NREM sleep loss, impaired REM rebound, and prolonged the flattening of the diurnal rhythm of NREM sleep following acute stressor exposure. These data suggest that impaired recovery of sleep/wake behavior following acute stress could contribute to the mechanisms by which a history of prior repeated stress increases vulnerability to subsequent novel stressors and stress-related disorders.

Local infusion of citalopram into the basolateral amygdala decreased conditioned fear of rats through increasing extracellular serotonin levels.

Selective serotonin reuptake inhibitors (SSRIs) are widely used for the treatment of depressive disorders and anxiety disorders. The anxiolytic mechanism of SSRIs is currently unclear. To investigate the anxiolytic effects of SSRIs, we measured both freezing behavior and extracellular serotonin and dopamine levels in the basolateral amygdala when rats were given conditioned fear stress under local reverse-dialysis of citalopram, an SSRI, into the basolateral amygdala. Local administration of citalopram into the basolateral amygdala significantly decreased freezing behavior induced by conditioned fear stress, and serotonin levels were simultaneously found to be significantly higher. Furthermore, repeated conditioned fear stress under local infusion of citalopram into the basolateral amygdala induced further increases in extracellular dopamine levels. Further studies investigating the role of dopamine in the amygdala for conditioned fear stress will be necessary. These results suggest that the basolateral amygdala is one of the target areas of the anxiolytic effects of citalopram and the increases of extracellular serotonin levels in the basolateral amygdala may be related to the anxiolytic effects.