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CO 2 exposure has been used to investigate the panicogenic response in patients with panic disorder. These patients are more sensitive to CO 2 , and more likely to experience the "false suffocation alarm" which triggers panic attacks. Imbalances in locus coeruleus noradrenergic (LC-NA) neurotransmission are responsible for psychiatric disorders, including panic disorder. These neurons are sensitive to changes in CO 2 /pH. Therefore, we investigated if LC-NA neurons are differentially activated after severe hypercapnia in mice. Further, we evaluated the participation of LC-NA neurons in ventilatory and panic-like escape responses induced by 20% CO 2 in male and female wild type mice and two mouse models of altered LC-NA synthesis. Hypercapnia activates the LC-NA neurons, with males presenting a heightened level of activation. Mutant males lacking or with reduced LC-NA synthesis showed hypoventilation, while animals lacking LC noradrenaline present an increased metabolic rate compared to wild type in normocapnia. When exposed to CO 2 , males lacking LC noradrenaline showed a lower respiratory frequency compared to control animals. On the other hand, females lacking LC noradrenaline presented a higher tidal volume. Nevertheless, no change in ventilation was observed in either sex. CO 2 evoked an active escape response. Mice lacking LC noradrenaline had a blunted jumping response and an increased freezing duration compared to the other groups. They also presented fewer racing episodes compared to wild type animals, but not different from mice with reduced LC noradrenaline. These findings suggest that LC-NA has an important role in ventilatory and panic-like escape responses elicited by CO 2 exposure in mice., Competing Interests: Declaration of competing interest The authors have no competing interests to declare and have no relevant financial or non- financial interests to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Rationale: The prelimbic division (PrL) of the medial prefrontal cortex (mPFC) is a key structure in panic., Objectives: To evaluate the role of nitric oxide (NO) in defensive behaviour and antinociception., Methods: Either Nω-propyl-L-arginine (NPLA) or Carboxy-PTIO was microinjected in the PrL cortex, followed by hypothalamic treatment with bicuculline. The exploratory behaviours, defensive reactions and defensive antinociception were recorded. Encephalic c-Fos protein was immunolabelled after escape behaviour., Results: NPLA (an inhibition of nNOs) decreased panic-like responses and innate fear-induced antinociception. The c-PTIO (a membrane-impermeable NO scavenger) decreased the escape behaviour. PrL cortex pre-treatment with c-PTIO at all doses decreased defensive antinociception. c-Fos protein was labelled in neocortical areas, limbic system, and mesencephalic structures., Conclusion: The NPLA and c-PTIO in the PrL/mPFC decreased the escape behaviour and defensive antinociception organised by medial hypothalamic nuclei. The oriented escape behaviour recruits neocortical areas, limbic system, and mesencephalic structures. These findings suggest that the organisation of defensive antinociception recruits NO-signalling mechanisms within the PrL cortex. Furthermore, the present findings also support the role of NO as a retrograde messenger in the PrL cortex during panic-like emotional reactions., (Copyright © 2024. Published by Elsevier B.V.)

Rationale: Although the study of emotions can look back to over 100 years of research, it is unclear which information the brain uses to construct the subjective experience of an emotion., Objective: In the current study, we assess the role of the peripheral and central adrenergic system in this respect., Methods: Healthy volunteers underwent a double inhalation of 35% CO 2 , which is a well-validated procedure to induce an intense emotion, namely panic. In a randomized, cross-over design, 34 participants received either a β 1 -blocker acting selectively in the peripheral nervous system (atenolol), a β 1 -blocker acting in the peripheral and central nervous system (metoprolol), or a placebo before the CO 2 inhalation., Results: Heart rate and systolic blood pressure were reduced in both β-blocker conditions compared to placebo, showing effective inhibition of the adrenergic tone. Nevertheless, the subjective experience of the induced panic was the same in all conditions, as measured by self-reported fear, discomfort, and panic symptom ratings., Conclusions: These results indicate that information from the peripheral and central adrenergic system does not play a major role in the construction of the subjective emotion., (© 2024. The Author(s).)

Environment enrichment (EE) is a well-known eustress model showing beneficial effects in different psychiatric diseases, but its positive properties in panic disorders are not yet established. The confrontation between prey and predator in complex arenas has been validated as a putative panic attack model. The principal aim of this work was to investigate the role of the EE on panic-like defensive responses elicited by mice threatened by venomous snakes. After 6 weeks of exposure either to an enriched or standard environments, 36 male mice were habituated in a complex polygonal arena for snakes containing an artificial burrow and elevated platforms for escape. The animals were confronted by Bothrops jararaca for 5 min, and the following antipredatory responses were recorded: defensive attention, stretched attend posture, flat back approach, prey versus predator interaction, oriented escape behavior, time spent in a safe place, and number of crossings. Mice threatened by snakes displayed several antipredatory reactions as compared to the exploratory behavior of those animals submitted to a nonthreatening situation (toy snake) in the same environment. Notably, EE causes anxiolytic- and panicolytic-like effects significantly decreasing the defensive attention and time spent in safe places and significantly increasing both prey versus predator interaction and exploratory behavior. In conclusion, our data demonstrate that EE can alter the processing of fear modulation regarding both anxiety- and panic-like responses in a dangerous condition, significantly modifying the decision-making defensive strategy., (© 2024 Wiley Periodicals LLC.)

The serotonin (5-HT) system is heavily implicated in the regulation of anxiety and trauma-related disorders such as panic disorder and post-traumatic stress disorder, respectively. However, the neural mechanisms of how serotonergic neurotransmission regulates innate panic and fear brain networks are poorly understood. Our earlier studies have identified that orexin (OX)/glutamate neurons within the perifornical hypothalamic area (PFA) play a critical role in adaptive and pathological panic and fear. While site-specific and electrophysiological studies have shown that intracranial injection and bath application of 5-HT inhibits PFA neurons via 5-HT 1a receptors, they largely ignore circuit-specific neurotransmission and its physiological properties that occur in vivo. Here, we investigate the role of raphe nuclei 5-HT inputs into the PFA in panic and fear behaviors. We initially confirmed that photostimulation of glutamatergic neurons in the PFA of rats produces robust cardioexcitation and flight/aversive behaviors resembling panic-like responses. Using the retrograde tracer cholera toxin B, we determined that the PFA receives discrete innervation of serotonergic neurons clustered in the lateral wings of the dorsal (lwDRN) and in the median (MRN) raphe nuclei. Selective lesions of these serotonergic projections with saporin toxin resulted in similar panic-like responses during the suffocation-related CO 2 challenge and increased freezing to fear-conditioning paradigm. Conversely, selective stimulation of serotonergic fibers in the PFA attenuated both flight/escape behaviors and cardioexcitation responses elicited by the CO 2 challenge and induced conditioned place preference. The data here support the hypothesis that PFA projecting 5-HT neurons in the lwDRN/MRN represents a panic/fear-off circuit and may also play a role in reward behavior., (© 2024. The Author(s).)

Repeated panic attacks are the core symptom of panic disorder and severely stressful for patients. Additional to the psychological response, the physiological symptoms are an important aspect of the experienced panic. However, data on the extent of hypothalamic-pituitary-adrenal (HPA)-axis activation during panic attacks is inconsistent. Therefore, in the present study, we aimed at investigating the stress-axis activity in more detail by including Copeptin (CoP) as a stable surrogate parameter for the vasopressinergic hypothalamic activity during experimentally induced panic attacks in healthy adults (N = 21). During a placebo-controlled panic challenge with 35% CO 2 compared to normal air inhalation, we measured CoP and the peripheral effector hormones Adrenocorticotropic Releasing Hormone (ACTH) and cortisol in plasma along with the psychological response to panic anxiety. We analyzed hormonal secretion patterns, their correlations and individual panic ratings over time and explored differences between female and male participants. We found a significant CO 2 -induced increase of CoP plasma levels and psychological panic symptoms after CO 2 -administration, while no positive correlations of CoP levels with the peripheral HPA-axis hormones and with panic symptoms were present. No differences between female and male participants concerning their psychological response nor their baseline CoP levels, the release of CoP or its increase during the experiment were found. CoP could be a sensitive indicator for an organism's physiologic acute hypothalamic response during stress and panic attacks., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Anxiety-related diseases are more than twice as common in women than in men, and in women, symptoms may be exacerbated during the late luteal phase of the menstrual cycle. Despite this, most research into the underlying mechanisms, which drives drug development, have been carried out using male animals. In an effort to redress this imbalance, we compared responses of male and female Wistar rats during exposure to two unconditioned threatening stimuli that evoke panic-related defensive behaviours: confrontation with a predator (Bothrops alternatus) and acute exposure to hypoxia (7% O 2 ). Threatened by venomous snake, male and female rats initially displayed defensive attention, risk assessment, and cautious interaction with the snake, progressing to defensive immobility to overt escape. Both males and females displayed higher levels of risk assessment but less interaction with the predator. They also spent more time in the burrow, displaying inhibitory avoidance, and more time engaged in defensive attention, and non-oriented escape behaviour. In females, anxiety-like behaviour was most pronounced in the oestrous and proestrus phases whereas panic-like behaviour was more pronounced during the dioestrus phase, particularly during late dioestrus. Acute hypoxia evoked panic-like behaviour (undirected jumping) in both sexes, but in females, responsiveness in late dioestrus was significantly greater than at other stages of the cycle. The results reveal that females respond in a qualitatively similar manner to males during exposure to naturally occurring threatening stimuli, but the responses of females is oestrous cycle dependent with a significant exacerbation of panic-like behaviour in the late dioestrus phase., (© 2021 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

The lateral hypothalamus (LH) sends neural pathways to structures involved on predator‑related defensive behaviours, escape and antinociception. The aim of this study was to investigate the role played by μ-opioid receptors located on LH neurons in defensive behaviour and unconditioned fear‑induced antinociception elicited by electric stimulation of LH. To achieve the goals, the μ1-opioid receptor selective antagonist naloxonazine was administered at different concentrations in the LH, and the defensive behaviour and fear‑induced antinociception elicited by electrical stimulation of LH were evaluated. The electrical stimulation of LH caused escape behaviour followed by defensive antinociception. Microinjections of naloxonazine in a concentration of 5.0 μg/0.2 μL in the LH decreased the aversive stimulus‑induced escape behaviour thresholds, but diminished defensive antinociception. These findings suggest that μ-opioid receptors of LH can be critical to panic attack‑related symptoms and facilitate the unconditioned fear‑induced antinociception produced by LH neurons activation.

Changes in 5-HT 1A receptor (5-HT 1A R)-mediated neurotransmission in the hippocampus have been associated with anxiety, depression and in the mode of action of antidepressant drugs. It has been commonly accepted that whereas the dorsal pole of the hippocampus (DH) is involved in cognitive processing, the ventral pole (VH) is associated with emotional regulation. However, to date, only a few studies have directly addressed the role played by VH 5-HT 1A Rs in anxiety and panic processing, and their results are conflicting. Here we report that intra-VH administration of the 5-HT 1A receptor agonist 8-OH-DPAT, the endogenous agonist serotonin (5-HT), or the standard anxiolytic benzodiazepine midazolam impaired the acquisition of inhibitory avoidance in the elevated T-maze (ETM) of male Wistar rats, indicating an anxiolytic effect. Conversely, local injection of the 5-HT 1A R antagonist WAY-100635 caused the opposite effect. These results were equally found in the Vogel conflict test. None of these drugs interfered with locomotor activity in the open-field test, nor did they alter the expression of the escape response in the ETM, a defensive behavior associated with panic. Pre-injection of a sub-effective dose of WAY-100635 in the VH blocked the anxiolytic effect of 5-HT or 8-OH-DPAT in the Vogel test, confirming the involvement of 5-HT 1A R for this behavioral effect. The effect in this test was anxiety-selective as none of the drugs affected water consumption or nociception. In conclusion, our results suggest that 5-HT 1A Rs in the VH play a tonic inhibitory role in anxiety processing. These receptors, however, are not involved in the regulation of panic-related escape behavior., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Cannabinoid receptor type 1 (CB 1 R) is widely distributed in the substantia nigra pars reticulata (SNpr). However, the role of CB 1 R at the SNpr level in threatening situations is poorly understood. We investigated the role of CB 1 R in the SNpr on the expression of fear responses in mice confronted with urutu-cruzeiro pit vipers. First, a bidirectional neurotracer was injected into the SNpr; then, immunostaining of the vesicular GABA transporter was conducted at the levels of the striatum (CPu) and deep layers of the superior colliculus (dlSC). In addition, CB 1 R immunostaining and GABA labelling were performed in the SNpr. Using a prey-versus-snake paradigm, mice were pretreated with the CB 1 R antagonist AM251 (100 pmol) and treated with the endocannabinoid anandamide (AEA, 5 pmol) in the SNpr, followed by bicuculline (40 ng) in the dlSC, and were then confronted with a snake. Bidirectional neural tract tracers associated with immunofluorescence showed the GABAergic striatonigral disinhibitory and nigrotectal inhibitory pathways. Furthermore, we showed that CB 1 R labelling was restricted to axonal fibres surrounding SNpr GABAergic cells. We also demonstrated a decrease in the defensive behaviours of mice treated with AEA in the SNpr, but this effect was blocked by pre-treatment with AM251 in this structure. Taken together, our results show that the panicolytic consequences of the AEA enhancement in the SNpr are signalled by CB 1 R, suggesting that CB 1 R localised in axon terminals of CPu GABAergic neurons in the SNpr modulates the activity of the nigrotectal GABAergic pathway during the expression of defensive behaviours in threatening situations., (Copyright © 2020. Published by Elsevier B.V.)

The over-purchasing and hoarding of necessities is a common response to crises, especially in developed economies where there is normally an expectation of plentiful supply. This behaviour was observed internationally during the early stages of the Covid-19 pandemic. In the absence of actual scarcity, this behaviour can be described as 'panic buying' and can lead to temporary shortages. However, there have been few psychological studies of this phenomenon. Here we propose a psychological model of over-purchasing informed by animal foraging theory and make predictions about variables that predict over-purchasing by either exacerbating or mitigating the anticipation of future scarcity. These variables include additional scarcity cues (e.g. loss of income), distress (e.g. depression), psychological factors that draw attention to these cues (e.g. neuroticism) or to reassuring messages (eg. analytical reasoning) or which facilitate over-purchasing (e.g. income). We tested our model in parallel nationally representative internet surveys of the adult general population conducted in the United Kingdom (UK: N = 2025) and the Republic of Ireland (RoI: N = 1041) 52 and 31 days after the first confirmed cases of COVID-19 were detected in the UK and RoI, respectively. About three quarters of participants reported minimal over-purchasing. There was more over-purchasing in RoI vs UK and in urban vs rural areas. When over-purchasing occurred, in both countries it was observed across a wide range of product categories and was accounted for by a single latent factor. It was positively predicted by household income, the presence of children at home, psychological distress (depression, death anxiety), threat sensitivity (right wing authoritarianism) and mistrust of others (paranoia). Analytic reasoning ability had an inhibitory effect. Predictor variables accounted for 36% and 34% of the variance in over-purchasing in the UK and RoI respectively. With some caveats, the data supported our model and points to strategies to mitigate over-purchasing in future crises., Competing Interests: The authors have declared that no competing interests exist.

Clinical and pre-clinical evidence demonstrates divergent psychotropic effects of THC vs. CBD. While THC can induce perceptual distortions and anxiogenic effects, CBD displays antipsychotic and anxiolytic properties. A key brain region responsible for regulation of cognition and affect, the medial prefrontal cortex (PFC), is strongly modulated by cannabinoids, suggesting that these dissociable THC/CBD-dependent effects may involve functional and molecular interplay within the PFC. The primary aim of this study was to investigate potential interactions and molecular substrates involved in PFC-mediated effects of THC and CBD on differential cognitive and affective behavioural processing. Male Sprague Dawley rats received intra-PFC microinfusions of THC, CBD or their combination, and tested in the latent inhibition paradigm, spontaneous oddity discrimination test, elevated T-maze and open field. To identify local, drug-induced molecular modulation in the PFC, PFC samples were collected and processed with Western Blotting. Intra-PFC THC induced strong panic-like responses that were counteracted with CBD. In contrast, CBD did not affect panic-like behaviours but blocked formation of associative fear memories and impaired latent inhibition and oddity discrimination performance. Interestingly, these CBD effects were dependent upon 5-HT 1A receptor transmission but not influenced by THC co-administration. Moreover, THC induced robust phosphorylation of ERK1/2 that was prevented by CBD, while CBD decreased phosphorylation of p70S6K, independently of THC. These results suggest that intra-PFC infusion of THC promotes panic-like behaviour associated with increased ERK1/2 phosphorylation. In contrast, CBD impairs perceptive functions and latent inhibition via activation of 5-HT 1A receptors and reduced phosphorylation of p70S6K., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Anxiety disorders and symptoms disproportionately impact women relative to men, but it is unclear what mechanism(s) contribute to this phenomenon. The present study examined sensitivity to unpredictable threat as a potential mechanism of gender differences in panic symptoms. The sample included 67 participants (35 women) who completed the no, predictable, and unpredictable threat (NPU-threat) startle paradigm with electric shocks as the aversive stimulus. Participants also completed the self-report Inventory of Depression and Anxiety Symptoms to assess current panic and depression symptoms. Results indicated that women, relative to men, reported greater panic symptoms and demonstrated increased startle potentiation in anticipation of predictable and unpredictable threat. Furthermore, across all participants increased startle potentiation in anticipation of unpredictable (but not predictable) threat was associated with greater panic symptoms, but there was no relationship with depression symptoms. Finally, the gender difference in panic symptoms was mediated by startle potentiation in anticipation of unpredictable (but not predictable) threat. The present study suggests that a heightened sensitivity to unpredictable threat might be a mechanism that contributes to increased anxiety in women., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to report., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Orexin has been implicated in a number of physiological functions, including arousal, regulation of sleep, energy metabolism, appetitive behaviors, stress, anxiety, fear, panic, and cardiovascular control. In this review, we will highlight research focused on orexin system in the medial hypothalamic regions of perifornical (PeF) and dorsomedial hypothalamus (DMH), and describe the role of this hypothalamic neuropeptide in the behavioral expression of panic and consequent fear and avoidance responses, as well as sympathetic regulation and possible development of chronic hypertension. We will also outline recent data highlighting the clinical potential of single and dual orexin receptor antagonists for neuropsychiatric conditions including panic, phobia, and cardiovascular conditions, such as in hypertension., (Copyright © 2018. Published by Elsevier B.V.)

Recurrent panic attacks (PAs) are a common feature of panic disorder (PD) and post-traumatic stress disorder (PTSD). Several distinct brain regions are involved in the regulation of panic responses, such as perifornical hypothalamus (PeF), periaqueductal gray, amygdala and frontal cortex. We have previously shown that inhibition of GABA synthesis in the PeF produces panic-vulnerable rats. Here, we investigate the mechanisms by which a panic-vulnerable state could lead to persistent fear. We first show that optogenetic activation of glutamatergic terminals from the PeF to the basolateral amygdala (BLA) enhanced the acquisition, delayed the extinction and induced the persistence of fear responses 3 weeks later, confirming a functional PeF-amygdala pathway involved in fear learning. Similar to optogenetic activation of PeF, panic-prone rats also exhibited delayed extinction. Next, we demonstrate that panic-prone rats had altered inhibitory and enhanced excitatory synaptic transmission of the principal neurons, and reduced protein levels of metabotropic glutamate type 2 receptor (mGluR2) in the BLA. Application of an mGluR2-positive allosteric modulator (PAM) reduced glutamate neurotransmission in the BLA slices from panic-prone rats. Treating panic-prone rats with mGluR2 PAM blocked sodium lactate (NaLac)-induced panic responses and normalized fear extinction deficits. Finally, in a subset of patients with comorbid PD, treatment with mGluR2 PAM resulted in complete remission of panic symptoms. These data demonstrate that a panic-prone state leads to specific reduction in mGluR2 function within the amygdala network and facilitates fear, and mGluR2 PAMs could be a targeted treatment for panic symptoms in PD and PTSD patients.

Dorsal raphe nucleus (DRN) neurons are reciprocally connected to the locus coeruleus (LC) and send neural pathways to the medial hypothalamus (MH). The aim of this work was to investigate whether the blockade of α 1 -, α 2 - or β-noradrenergic receptors in the DRN or the inactivation of noradrenergic neurons in the LC modify defensive behaviours organised by MH neurons. For this purpose, Wistar male rats received microinjections of WB4101, RX821002, propranolol (α 1 - , α 2 - and β-noradrenergic receptor antagonists, respectively) or physiological saline in the DRN, followed 10 min later by MH GABA A receptor blockade. Other groups of animals received DSP-4 (a noradrenergic neurotoxin), physiological saline or only a needle insertion (sham group) into the LC, and 5 days later, bicuculline or physiological saline was administered in the MH. In all these cases, after MH treatment, the frequency and duration of defensive responses were recorded over 15 min. An anterograde neural tract tracer was also deposited in the DRN. DRN neurons send pathways to lateral and dorsomedial hypothalamus. Blockade of α 1 - and β-noradrenergic receptors in the DRN decreased escape reactions elicited by bicuculline microinjections in the MH. In addition, a significant increase in anxiety-like behaviours was observed after the blockade of α 2 -noradrenergic receptors in the DRN. LC pretreatment with DSP-4 decreased both anxiety- and panic attack-like behaviours evoked by GABA A receptor blockade in the MH. In summary, the present findings suggest that the norepinephrine-mediated system modulates defensive reactions organised by MH neurons at least in part via noradrenergic receptors recruitment on DRN neurons., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Anxiety and panic symptoms are widespread in the general population. The physical manifestations of anxiety and panic commonly account for people presenting to Emergency Departments (EDs). It is therefore important for ED clinicians to be informed of the numerous causes of anxiety and panic and equipped to respond effectively. This paper describes the underlying pathophysiology of the physical symptoms of anxiety and panic and differential diagnoses to consider. Organic conditions that are associated with symptoms of anxiety and panic are highlighted. Brief interventions are tabled for ED clinicians to use when explaining symptoms, and to promote individual self-management., (Copyright © 2019. Published by Elsevier Ltd.)

Exposure of rats to an environment with low O 2 levels evokes a panic-like escape behavior and recruits the dorsal periaqueductal gray (dPAG), which is considered to be a key region in the pathophysiology of panic disorder. The neurochemical basis of this response is, however, currently unknown. We here investigated the role played by nitric oxide (NO) within the dPAG in mediation of the escape reaction induced by hypoxia exposure. The results showed that exposure of male Wistar rats to 7% O 2 increased nitrite levels, a NO metabolite, in the dPAG but not in the amygdala or hypothalamus. Nitrite levels in the dPAG were correlated with the number of escape attempts during the hypoxia challenge. Injections of the NO synthesis inhibitor NPA, the NO-scavenger c- PTIO, or the NMDA receptor antagonist AP-7 into the dorsolateral column of the periaqueductal gray (dlPAG) inhibited escape expression during hypoxia, without affecting the rats' locomotion. Intra-dlPAG administration of c-PTIO had no effect on the escape response evoked by the elevated-T maze, a defensive behavior that has also been associated with panic attacks. Altogether, our results suggest that NO plays a critical role in mediation of the panic-like defensive response evoked by exposure to low O 2 concentrations., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Rationale: The endocannabinoid system plays an important role in the organization of panic-like defensive behavior. Threatening situations stimulate brain areas, such as the dorsomedial hypothalamus (DMH). However, there is a lack of studies addressing the role of the DMH endocannabinoid system in panic-like responses., Objectives: We aimed to verify which mechanisms underlie anandamide-mediated responses in the DMH., Methods: To test the hypothesis that the anandamide produces panicolytic-like effects, we treated mice with intra-DMH microinjections of vehicle or increasing doses of anandamide (0.5, 5, or 50 pmol) and then performed confrontation with the South American snake Epicrates cenchria assisi., Results: Intra-DMH anandamide treatment yielded a U-shaped dose-response curve with no effect of the lowest (0.5 pmol) or the highest (50 pmol) dose and significant inhibition of panic-like responses at the intermediate (5 pmol) dose. In addition, this panicolytic-like effect was prevented by pretreatment of the DMH with the CB1 receptor antagonist AM251 (100 pmol). However, pretreatment of the DMH with the TRPV1 receptor antagonist 6-iodo-nordihydrocapsaicin (3 nmol) restored the panicolytic-like effect of the highest dose of anandamide. Immunohistochemistry revealed that CB1 receptors were present primarily on axonal fibers, while TRPV1 receptors were found almost exclusively surrounding the perikarya in DMH., Conclusions: The present results suggest that anandamide exerts a panicolytic-like effect in the DMH by activation of CB1 receptors and that TRPV1 receptors are related to the lack of effect of the highest dose of anandamide.

Panic attacks (PAs) are episodes of intense fear or discomfort that are accompanied by a variety of both psychological and somatic symptoms. Panic induction in preclinical models (e.g. rats) has largely been assayed through flight and avoidance behavioral tests and cardiorespiratory activity. Yet, the literature pertaining to PAs shows that thermal sensations (hot flushes/heat sensations and chills) are also a common symptom during PAs in humans. Considering that temperature alterations are objectively measurable in rodents, we hypothesized that select panicogenic drugs and stimuli induce consistent changes in thermoregulation related to hot flushes and chills. Specifically, we challenged male rats with intraperitoneal injections of the GABAergic inverse agonist FG-7142; the α2 adrenoceptor antagonist yohimbine; the serotonin agonist D-fenfluramine, and 20% CO2 (an interoceptive homeostatic challenge). We assayed core body temperature and tail skin temperature using implanted radiotelemetry probes and tail thermistors/thermal imaging camera, respectively, and found that all challenges elicited rapid, high-amplitude (~7-9°C) increase in tail skin temperature and delayed decreases (~1-3°C) in core body temperature. We propose that thermal sensations such as these may be an additional indicator of a panic response in rodents and humans, as these panicogenic compounds or stimuli are known to precipitate PAs in persons with panic disorder.

Although the etiology of panic disorder (PD) remains elusive, accumulating evidence suggests a key role for the dorsal periaqueductal gray matter (dPAG). There is also evidence that this midbrain area is critically involved in mediation of the panicolytic effect of antidepressants, which with high potency benzodiazepines (e.g. alprazolam and clonazepam) are first line treatment for PD. Whether the dPAG is also implicated in the antipanic effect of the latter drugs is, however, still unknown. We here investigated the consequences of blocking GABA A or benzodiazepine receptors within the dPAG, with bicuculline (5 pmol) and flumazenil (80 nmol), respectively, on the panicolytic and anxiolytic effects of alprazolam (4 mg/kg). Microinjection of these antagonists fully blocked the anti-escape effect, considered as a panicolytic-like action, caused by a single systemic injection of alprazolam in male Wistar rats submitted to the elevated T-maze. These antagonists, however, did not affect the anxiolytic effect of the benzodiazepine on inhibitory avoidance acquisition and punished responding, measured in the elevated T-maze and Vogel conflict tests, respectively. Altogether, our findings show the involvement of GABA A /benzodiazepine receptors of the dPAG in the panicolytic, but not the anxiolytic effect caused by alprazolam. They also implicate the dPAG as the fulcrum of the effects of different classes of clinically effective antipanic drugs., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The role of 5-HT2C receptors (5-HT2CRs) in the regulation of anxiety has been widely acknowledged. However, conflicting results have been reported on whether stimulation of these receptors increases or decreases anxiety. We here investigated the role of 5-HT2CRs of the dorsal hippocampus (DH) in the mediation of anxiety- or panic-associated defensive behaviors and in the anxiolytic effect of the tricyclic antidepressant imipramine. In the Vogel conflict test, administration of the mixed 5-HT2CR agonist mCPP into the DH of male Wistar rats was anxiogenic, whereas infusions of the more selective agonists MK-212 and RO-600175 were anxiolytic. The 5-HT2CR antagonist SB-242084, on the other hand, was anxiogenic. A sub-effective dose of this antagonist blocked the anxiolytic effect of RO-600175, but not the increase in anxiety observed with mCPP, indicating that the latter effect was not due to 5-HT2CR activation. In full agreement with these findings, MK-212 and RO-600175 in the DH also inhibited inhibitory avoidance acquisition in the elevated T-maze, whereas SB-242084 caused the opposite effect. None of these drugs interfered with escape expression in this test, which has been associated with panic. Chronic administration of imipramine (15 mg/kg, ip, 21 days) caused an anxiolytic effect in the elevated T-maze and light-dark transition tests, which was not blocked by previous infusion of SB-242084 into the DH. Therefore, facilitation of 5-HT2CR-mediated neurotransmission in the DH decreases the expression of anxiety-, but not panic-related defensive behaviors. This mechanism, however, is not involved in the anxiolytic effect caused by imipramine., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objectives: Psychogenic nonepileptic seizures (PNES) resemble seizures but are psychological in origin. The etiology of PNES remains poorly understood, yet several theories argue for the importance of autonomic dysregulation in its pathophysiology. We therefore conducted a retrospective study to investigate autonomic dynamics leading up to a seizure to inform their mechanistic relevance., Methods: One hundred one patients with PNES and 45 patients with epileptic seizure (ES) were analyzed for preictal heart rate (HR) and respiratory rate (RR) at baseline and at minute intervals from 5 min to onset., Results: Patients with PNES showed rising HR (p < 0.001, repeated-measures analysis of variance (ANOVA)) and rising RR (p = 0.012, repeated-measures ANOVA) from baseline to the onset of their seizures. Patients with ES did not exhibit significant preictal HR or RR increase. Patients with PNES had nonsignificantly higher preictal HR and RR than patients with ES., Significance: Patients with PNES exhibit increasing autonomic arousal prior to seizure events unlike patients with epilepsy. This may reflect increasing levels of preictal anxiety, and future studies could study patients' subjective experiences of the preictal period, and more definitive measures of ventilation to see if this supported a model of PNES as "panic without panic"., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Internalizing disorders such as anxiety may be characterized by an imbalance between bottom-up (stimulus-driven) and top-down (goal-directed) attention. The late positive potential (LPP) can be used to assess these processes when task-irrelevant negative and neutral pictures are presented within a working memory paradigm. Prior work using this paradigm has found that working memory load reduces the picture-elicited LPP across participants; however, anxious individuals showed a reduced effect of working memory load on the LPP, suggesting increased distractibility., Methods: The current study assessed transdiagnostic associations between specific symptom dimensions of anxiety, the LPP, and behavior in a clinically representative, heterogeneous group of 76 treatment-seeking patients with internalizing disorders, who performed a working memory task interspersed with negative and neutral pictures., Results: As expected, negative pictures enhanced the LPP, and working memory load reduced the LPP. Participants with higher social anxiety showed increased LPPs to negative stimuli during early and late portions of picture presentation. Panic symptoms were associated with reduced LPPs to negative pictures compared with neutral pictures as well as a reduced effect of working memory load on the LPP during the late time window. Reduced positive affect was associated with greater behavioral interference from negative pictures., Conclusions: Hypervigilance for negative stimuli was uniquely explained by social anxiety symptoms, whereas panic symptoms were associated with the opposing effect-blunted processing/avoidance of these stimuli. Panic symptoms were uniquely associated with reduced top-down control. Results reveal distinct associations between neural reactivity and anxiety symptom dimensions that transcend traditional diagnostic boundaries., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: The 35% CO2 challenge is a well-established method triggering panic attacks under laboratory-controlled conditions. There is an ongoing debate whether single or the joined effects of the instructional set and anxiety sensitivity (AS) can alter the outcome of the challenge., Objectives: The present study investigated the effects of instruction manipulation and AS on panic-like response to the 35% CO2 challenge., Methods: Eighty healthy subjects, with high or low levels of AS, were randomized into 4 groups based on standard/manipulated instructional sets as well as 35% CO2 mixture/room air inhalation. Subjects filled in the Visual Analogue Scale of Anxiety (VAAS), the Visual Analogue Scale of Fear (VAS-F), the VAS of Discomfort (VAS-D), and the Panic Symptom List (PSL). Blood pressure and heart rate were measured at pre- and posttest., Results: Hierarchical multiple regression analyses showed greater psychological responses at VAAS, VAS-F, VAS-D, and PSL and higher systolic blood pressure under 35% CO2 challenge if compared to room air inhalation while instructional set and AS did not influence the response., Conclusions: The present study confirms that neither instructional test nor AS alter the outcome of the 35% CO2 challenge., (© 2019 S. Karger AG, Basel.)

Predators induce defensive responses and fear behaviours in prey. The rat exposure test (RET) is frequently used as an animal model of panic. Nitric oxide (NO) which has been reported to be activated by the NMDA receptor, in turn mediates calcium/calmodulin-dependent protein kinase II (CaMKII) signalling pathways in defensive responses. ACCN2, the orthologous human gene of acid-sensing ion channel 1a (ASIC1a), is also associated with panic disorder; however, few studies have focused on the role of ASIC1a in the modulation of panic and calcium/CaMKII signalling by NO. In the present study, NG-nitro-L-arginine-methyl-ester (L-NAME; non-selective NOS inhibitor), S-nitroso-N-acetyl-D,L-penicillamine (SNAP; NO donor), and psalmotoxin (PcTx-1; selective ASIC1a blocker) were administered to the dorsal periaqueductal grey (dPAG) before the predator stimulus, and the roles of NO in the expression of ASIC1a, phosphorylation of CaMKIIα (p-CaMKIIα) and expression of calmodulin (CaM) were investigated. The effects of ASIC1a, p-CaMKIIα and CaM regulation were also examined. Our results showed that intra-dPAG infusion of L-NAME weakened panic-like behaviour and decreased ASIC1a, p-CaMKIIα and CaM expression levels, whereas intra-dPAG infusion of SNAP enhanced panic-like behaviour and increased ASIC1a, p-CaMKIIα and CaM levels. Intra-dPAG infusion of PcTx-1 also weakened panic-like behaviour and decreased p-CaMKIIα expression level. Taken together, these results indicate that NO and ASIC1a are involved in the modulation of RET-induced panic-like behaviour in the dPAG. NO regulates the calcium/CaMKII signalling pathways, and ASIC1a participates in this regulation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Panic arising from physical or psychological stress is a common issue in reported incidents and accidents in scuba diving. Due to its effect on perception, thinking and diver behavior, the panic reaction is often a significant factor in the generation or escalation of problems, potentially leading to injuries and fatalities. The instinctive behaviors associated with panic are incompatible with the constraints of scuba diving (e.g., flight response to threat, leading to rapid ascent). Although the dangers are well known, the psychological mechanisms of panic and the implications for prevention/risk reduction are not sufficiently highlighted to recreational divers. In applied psychology, there are grounded theoretical models which describe the onset and maintenance of anxiety and panic, and an evidence base for approaches to anxiety management. For example, these models are used within structured psychological approaches for people experiencing anxiety disorders; and panic attacks are resolvable. Based on these models and underlying theory, this article proposes a new, accessible model for panic in divers. The potential uses of the model are to: (1) provide a simple framework for divers to understand the onset of panic; (2) promote the need for adequate training; (3) describe the importance of staying within training standards, qualifications and personal limitations; (4) support diver and dive educator understanding of individual factors in panic reactions (e.g. psychiatric conditions) placing greater emphasis on psychological fitness to dive; and (5) draw attention to approaches to improved regulation of emotion and promote individual responsibility., Competing Interests: The author of this paper declar no conflicts of interest exist with this submission., (Copyright© Undersea and Hyperbaric Medical Society.)

The purpose of the current paper was to review the empirical literature on the cooccurrence of panic and epilepsy, in order to determine whether there is an increased risk of panic attacks and panic disorder among adults with epilepsy and an increased risk of epilepsy among adults with panic disorder. Given the overlap between panic and ictal fear, a preliminary aim of the current review was to critically evaluate the methodology used to differentiate between diagnoses of panic disorder and epilepsy in existing research. A literature search was conducted in relevant electronic databases, and articles that directly focused on panic and epilepsy among adults were selected for the current review (n = 17). Overall, results suggest that rates of epilepsy are elevated among individuals with panic disorder and that panic attacks are elevated among individuals with epilepsy, but rates of panic disorder among people with epilepsy are inconsistent. However, most studies did not use sufficiently rigorous methods to differentiate between panic disorder and epilepsy. Therefore, a critical next step in this area of research is to develop a standard procedure for differentiating ictal fear from panic attacks and panic disorder., (Copyright © 2018. Published by Elsevier Inc.)

Background: Previous research has shown that hypoventilation therapy reduces panic symptoms in part by increasing basal partial pressure of carbon dioxide (PCO 2 ) levels. We tested an additional pathway by which hypoventilation therapy could exert its therapeutic effects: through repeated interoceptive exposure to sensations of dyspnea., Methods: A total of 35 patients with panic disorder were trained to perform exercises to raise their end-tidal PCO 2 levels using a portable capnometry device. Anxiety, dyspnea, end-tidal PCO 2 , and respiratory rate were assessed during each exercise across 4 weeks of training. Mixed-model analysis examined whether within-exercise levels of dyspnea were predictive of reduction of panicogenic cognitions., Results: As expected, within-exercise anxiety and respiratory rate decreased over time. Unexpectedly, PCO 2 dropped significantly from the beginning to the end of exercise, with these drops becoming progressively smaller across weeks. Dyspnea increased and remained consistently above basal levels across weeks. As hypothesized, greater dyspnea was related to significantly lower panicogenic cognitions over time even after controlling for anxiety and PCO 2 . Additional exploratory analyses showed that within-exercise increases in dyspnea were related to within-exercise increases in anxiety but were not related to within-exercise increases in PCO 2 ., Conclusions: In support of the interoceptive exposure model, we found that greater dyspnea during hypoventilation exercises resulted in lower panicogenic cognitions even after the effect of PCO 2 was taken into account. The findings offer an additional important target in panic treatment., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The present study examined whether early life maternal separation (MS), a model of childhood separation anxiety, predisposes to panic at adulthood. For this purpose, male pups were submitted to 3-h daily maternal separations along postnatal (PN) days of either the 'stress hyporesponsive period' (SHRP) from PN4 to PN14 (MS11) or throughout lactation from PN2 to PN21 (MS20). Pups were further reunited to conscious (CM) or anesthetized (AM) mothers to assess the effect of mother-pup interaction upon reunion. Controls were subjected to brief handling (15 s) once a day throughout lactation (BH20). As adults (PN60), rats were tested for the thresholds to evoke panic-like behaviors upon electrical stimulation of dorsal periaqueductal gray matter and exposed to an elevated plus-maze, an open-field, a forced swim and a sucrose preference test. A factor analysis was also performed to gain insight into the meaning of behavioral tests. MS11-CM rather than MS20-CM rats showed enhanced panic responses and reductions in both swimming and sucrose preference. Panic facilitations were less intense in mother-neglected rats. Although MS did not affect anxiety, MS11-AM showed robust reductions of defecation in an open-field. Factor analysis singled out anxiety, hedonia, exploration, coping and gut activity. Although sucrose preference and coping loaded on separate factors, appetite (adult weight) correlated with active coping in both forced swim and open-field (central area exploration). Concluding, whereas 3h-daily maternal separations during SHRP increased rat's susceptibility to experimental panic attacks, separations throughout lactation had no effects on panic and enhanced active coping., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Exposure to elevated concentrations of CO 2 or hypoxia has been widely used in psychiatric research as a panic provoking stimulus. However, the use of these respiratory challenges to model panic-like responses in experimental animals has been less straightforward. Little data is available, from behavioral and endocrine perspectives, to support the conclusion that a marked aversive situation, such as that experienced during panic attacks, was evoked in these animals. We here compared the behavioral responses of male CB57BL/6 mice during exposure to 20% CO 2 or 7% O 2 and its consequence on plasma levels of corticosterone. We also evaluated whether clinically-effective panicolytic drugs affect the behavioral responses expressed during CO 2 exposure. The results showed that whereas hypoxia caused a marked reduction in locomotion, inhalation of CO 2 -enriched air evoked an active escape response, characterized by bouts of upward leaps directed to the border of the experimental cage, interpreted as escape attempts. Corticosterone levels were increased 30min after either of the respiratory challenges used, but it was higher in the hypoxia group. Chronic (21days), but not acute, treatment with fluoxetine or imipramine (5, 10 or 15mg/kg) or a single injection of alprazolam (0.025, 0.05 or 0.1mg/kg), but not of the anxiolytic diazepam (0.025, 0.05 or 0.1 and 1mg/kg) reduced the number of escape attempts, indicating a panicolytic-like effect. Altogether, the results suggest that whereas hypoxia increased anxiety, exposure to 20% CO 2 evoked a panic-like state. The latter condition/test protocol seems to be a simple and validated model for studying in mice pathophysiological mechanisms and the screening of novel drugs for panic disorder., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Using an innovative approach to study the neural bases of psychiatric disorders, this study investigated the behavioral, morphological and pharmacological bases of panic attack-induced responses in a prey-versus-coral snake paradigm. Mesocricetus auratus was chronically treated with intraperitoneal administration of the selective serotonin uptake inhibitor paroxetine or the gamma aminobutyric acid (GABA)/benzodiazepine receptor agonist alprazolam at three different doses and were then confronted with a venomous coral snake (Micrurus frontalis, Reptilia, Elapidae). The threatened rodents exhibited defensive attention, flat back approaches, defensive immobility, and escape defensive responses in the presence of the venomous snake, followed by increases in Fos protein in limbic structure neurons. Chronic administration of both paroxetine and alprazolam decreased these responses with morphological correlates between the panicolytic effect of both drugs administered at the highest dose and decreases in Fos protein-immunolabeled perikarya found in the amygdaloid complex, hypothalamus and periaqueductal gray matter columns, which are structures that make up the encephalic aversion system. These findings provide face, construct and predictive validities of this new experimental model of anxiety- and panic attack-like behavioral responses displayed by threatened prey confronted with venomous coral snakes., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: Abnormal patterns of attention to threat and reward have been proposed as potential mechanisms of dysfunction in anxiety and mood disorders. However, research on this topic has been inconsistent, perhaps because of both clinical heterogeneity in the samples assessed and measurement of attentional biases that is temporally imprecise., Methods: The present study measured transdiagnostic symptoms of anxiety and depression in 205 young adults and recorded affect-modulated event-related potentials in response to task-irrelevant pictures in a speeded response task., Results: Low positive affect was uniquely associated with reduced modulation of later event-related potentials (i.e., the P300 and the late positive potential) by rewarding images, suggesting deficits in sustained attention to reward. Low positive affect was also associated with a blunted threat-elicited late positive potential. Symptoms of panic were associated with an increased N1 to rewarding images, as well as an increased late positive potential to all picture types., Conclusions: These data suggest that dysfunction in neural markers of sustained attention to threat and reward relate in specific ways to transdiagnostic symptom dimensions of anxiety and depression. Moreover, event-related potentials are likely to be useful in investigations of the time course of attentional abnormalities associated with these symptom dimensions., (Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: In patients with post-traumatic stress disorder (PTSD) two open pilot studies about the effects of 35% carbon dioxide (CO 2 ) exist. One shows an augmented panicogenic and anxiogenic response (Muhtz et al., 2011), the other does not (Talesnik et al. 2007). We further characterized the CO 2 reactivity in PTSD using for the first time placebo-controlled and double-blind conditions., Methods: In 20 patients with PTSD we assessed panic, anxiety, dissociative and PTSD symptoms after a single vital capacity inhalation of 35% CO 2 compared to a placebo gas condition in a within-participant cross-over, placebo-controlled, double-blind and randomized design., Results: Inhalation of 35% CO 2 versus placebo provoked significantly increased panic, anxiety, dissociative and PTSD symptoms. The reaction to placebo gas was minimal. Order of inhalation, patients' sex or age did not influence the results. The panic and anxiety response under CO 2 was considerably higher in the PTSD patients than in healthy controls from our previous open study., Conclusions: The results corroborate that our preceding findings of an increased CO 2 reactivity in patients with PTSD are not false positive due to the open design or the lack of placebo control. Replication in a larger number of PTSD patients and matched control subjects is needed. The potential role of childhood traumatisation, psychiatric comorbidity, psychotropic medication and trait dissociation in prior contradictory reports should be clarified., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

This paper provides a brief overview of the shift from studies describing the personality profiles of divers to studies exploring associations between personality variables and diving performance in terms of behavioural outcomes. The personality associations that were investigated include performance during training, panic proneness, diving injuries, susceptibility to inert gas narcosis, and the behaviour of tourist divers. The paper concludes with a number of suggested directions for further research on personality and diving that may provide tangible benefits in terms of both enhanced safety and improved performance underwater., (Copyright: This article is the copyright of the authors who grant Diving and Hyperbaric Medicine a non-exclusive licence to publish the article in printed and other forms.)

Anxiety is one of the most common comorbidities of epilepsy, which has major detrimental effects on the quality of life. Generalized anxiety disorder (GAD) associated with epilepsy has been receiving most attention. However, several other forms of anxiety reportedly present in patients with epilepsy, including panic disorder (PD). In this study, using an animal model of limbic epilepsy, we examined the interplay between epilepsy and panic-like behavior (PLB). Further, considering the high degree of comorbidity between depression on the one hand, and both epilepsy and PD on the other hand, we studied whether and how the presence of PLB in animals with epilepsy would affect their performance in depression-relevant tests. Fifty-day-old male Wistar rats were subjected to repeated alternating electrical stimulations of the basolateral amygdala (BLA) to induce kindling of limbic seizures, and the dorsal periaqueductal gray (DPAG) to induce panic-like episodes. Seizure susceptibility and panic reaction threshold were examined before the first and 24h after the last stimulation. At the end of the stimulations, the rats were examined in depression-relevant tests: saccharin preference test (SPT) for anhedonia and forced swimming test (FST) for despair/hopelessness. With regard to kindling, BLA+DPAG stimulation induced more profound increase of seizure susceptibility than BLA stimulation alone (evident as the reduction of the afterdischarge threshold and the increase of the afterdischarge duration). With regard to PLB, the BLA+DPAG stimulation exacerbated the severity of panic-like episodes, as compared with the DPAG stimulation alone. Basolateral amygdala stimulation alone had no effects on panic-like reactions, and DPAG stimulation alone did not modify kindling epileptogenesis. Combined stimulation of BLA and DPAG induced depressive-like behavioral impairments. This is the first experimental study showing bidirectional, mutually exacerbating effect of epilepsy and PLB, and the precipitation of depressive-like state by the epilepsy-PLB comorbidity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Panic disorder is characterized by sudden, repeated, and unexpected attacks of intense fear and overwhelming anxiety about when another attack may strike. Patients with panic disorder and healthy individuals with a history of panic attacks show a hypersensitivity to unpredictable threats, suggesting a possible link between panic and sustained anxiety. The purpose of this study was to determine the degree to which induced symptoms of panic relate to fear and anxiety, as well as activity in the neural systems that mediate and regulate these affective states. Psychological and physiological symptoms of panic were assessed during an 8-min 7.5% CO 2 challenge task. Psychological, physiological, and neural symptoms of fear and anxiety were measured during two sessions (one psychophysiology and one functional magnetic resonance imaging where subjects experienced several blocks of no threat (N), predictable shock (P), and unpredictable shock (U; NPU threat task). We used a principle component analysis to characterize panic susceptibility (PS), and found that PS significantly predicted dorsolateral prefrontal cortex (dlPFC) activity to the unpredictable cue during the NPU threat task. When examining the weighted beta coefficients from this analysis, we observed that self-reported fear/anxiety during the CO 2 challenge negatively loaded onto dlPFC activity during the NPU task. Consistent with this observation, dlPFC activity during the unpredictable cue was also negatively correlated with anxiety during the NPU sessions. Together, these results suggest that panic symptoms and anxiety are regulated by the same prefrontal cognitive control system.

Acute γ-aminobutyric acid (GABA) disinhibition in the posterior hypothalamus (PH) elicits defensive reactions that are considered anxiety- and panic attack-like behaviour, and these defensive reactions are followed by antinociception. Evidence indicates that the PH connects with the medial prefrontal cortex, particularly the anterior cingulate cortex (ACC), which seems to regulate these unconditioned fear-induced defensive responses. However, few studies have shown the participation of cortical regions in the control of behavioural and antinociceptive responses organised by diencephalic structures. It has been suggested that the glutamatergic system can mediate this cortical influence, as excitatory imbalance is believed to play a role in both defensive mechanisms. Thus, the aim of the present study was to investigate the involvement of ACC glutamatergic connections via blockade of local N-methyl-D-aspartate (NMDA) receptors to elaborate panic-like defensive behaviours and unconditioned fear-induced antinociception organised by PH neurons. Wistar rats were treated with microinjections of 0.9% NaCl or LY235959 (a selective NMDA receptor antagonist) in the ACC at different concentrations (2, 4 and 8 nmol/0.2μL), followed by GABA A receptor blockade in the PH. Defensive reactions were analysed for 20min, and the nociceptive threshold was then measured at 10-min intervals for 60min. Pretreatment of the ACC with LY235959 reduced both panic-like defensive behaviour and fear-induced antinociception evoked by PH GABAergic disinhibition. Our findings suggest that ACC NMDA receptor-signalled glutamatergic inputs play a relevant role in the organisation of anxiety- and panic attack-like behaviours and in fear-induced antinociception., (Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.)

Reported results have shown that the pentapeptide opiorphin inhibits oligopeptidases that degrade brain neuropeptides, and has analgesic and antidepressant effects in experimental animals, without either tolerance or dependency after chronic administration. In a previous study we showed that opiorphin has a panicolytic-like effect in the dorsal periaqueductal gray (dPAG) electrical stimulation test (EST), mediated by the μ-opioid receptor (MOR). This study further analyzes the mechanism of opiorphin panicolytic action, using the EST and drug injection inside the dPAG. The obtained results showed that blockade of the 5-HT 1A receptors with WAY-100635 did not change the escape-impairing effect of opiorphin, and combined injection of sub-effective doses of opiorphin and the 5-HT 1A -agonist 8-OH-DPAT did not have a significant anti-escape effect. In contrast, the anti-escape effect of opiorphin was antagonized by pretreatment with the kinin B2 receptor blocker HOE-140, and association of sub-effective doses of opiorphin and bradykinin caused a significant anti-escape effect. The anti-escape effect of bradykinin was not affected by previous administration of WAY-100635. Therefore, the anti-escape effect of opiorphin in the dPAG seems to be mediated by endogenous bradykinin, acting on kinin B2 receptors, which previous results have shown to interact synergistically with MOR in the dPAG to restrain escape in two animal models of panic. Chemical compounds: Opiorphin (PubChem CID: 25195667); WAY100635 maleate salt (PubChem CID: 11957721); 8-OH-DPAT hydrobromide (PubChem CID: 6917794); Bradykinin (PubChem CID: 439201); HOE-140 (Icatibant) (PubChem CID: 6918173)., (Copyright © 2017 Elsevier Inc. All rights reserved.)

It is known that diabetic (DBT) animals present dysregulation on the serotonergic system in several brain areas associated with anxiety-like responses. The aim of this study was to investigate the involvement of 5-HT1A receptors on dorsal periaqueductal gray (dPAG) in the behavioral response related to panic disorder in type-1 DBT animals. For this, the escape response by electric stimulation (ES) of dPAG in DBT and normoglycemic (NGL) animals was assessed. Both NGL and DBT animals were exposed to an open-field test (OFT) 28 days after DBT confirmation. The current threshold to induce escape behavior in DBT animals was reduced compared with NGL animals. No impairment in locomotor activity was observed when DBT animals were compared with NGL animals. An intra-dPAG injection of the 5-HT1A receptor agonist (±)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) increased the [INCREMENT] threshold in both DBT and NGL, suggesting a panicolytic-like effect. DBT animals presented a more pronounced panicolytic-like response compared with NGL as a higher [INCREMENT] threshold was observed after 8-OH-DPAT treatment, which could be a consequence of the increased expression of the 5-HT1A receptor in the dPAG from DBT animals. Our results are in line with the proposal that a deficiency in serotonergic modulation of the dPAG is involved in triggering the panic attack and the 5-HT1A receptors might be essential for the panicolytic-like response.

Many stressors cause an increase in ventilation in humans. This is predominantly reported as an increase in minute ventilation (V̇E). But, the same V̇E can be achieved by a wide variety of changes in the depth (tidal volume, V T ) and number of breaths (respiratory frequency, ƒ R ). This review investigates the impact of stressors including: cold, heat, hypoxia, pain and panic on the contributions of ƒ R and V T to V̇E to see if they differ with different stressors. Where possible we also consider the potential mechanisms that underpin the responses identified, and propose mechanisms by which differences in ƒ R and V T are mediated. Our aim being to consider if there is an overall differential control of ƒ R and V T that applies in a wide range of conditions. We consider moderating factors, including exercise, sex, intensity and duration of stimuli. For the stressors reviewed, as the stress becomes extreme V̇E generally becomes increased more by ƒ R than V T . We also present some tentative evidence that the pattern of ƒ R and V T could provide some useful diagnostic information for a variety of clinical conditions. In The Physiological Society's year of 'Making Sense of Stress', this review has wide-ranging implications that are not limited to one discipline, but are integrative and relevant for physiology, psychophysiology, neuroscience and pathophysiology., (© 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.)

A wealth of evidence has shown that opioid and kinin systems may control proximal defense in the dorsal periaqueductal gray matter (dPAG), a critical panic-associated area. Studies with drugs that interfere with serotonin-mediated neurotransmission suggest that the μ-opioid receptor (MOR) synergistically interacts with the 5-HT 1A receptor in the dPAG to inhibit escape, a panic-related behavior. A similar inhibitory effect has also been reported after local administration of bradykinin (BK), which is blocked by the non-selective opioid receptor antagonist naloxone. The latter evidence, points to an interaction between BK and opioids in the dPAG. We further explored the existence of this interaction through the dPAG electrical stimulation model of panic. We also investigated whether intra-dPAG injection of captopril, an inhibitor of the angiotensin-converting enzyme (ACE) that also degrades BK, causes a panicolytic-like effect. Our results showed that intra-dPAG injection of BK inhibited escape performance in a dose-dependent way, and this panicolytic-like effect was blocked by the BK type 2 receptor (B2R) antagonist HOE-140, and by the selective MOR antagonist CTOP. Conversely, the panicolytic-like effect caused by local administration of the selective MOR agonist DAMGO was antagonized by pre-treatment with either CTOP or HOE-140, indicating cross-antagonism between MOR and B2R. Finally, intra-dPAG injection of captopril also impaired escape in a dose-dependent way, and this panicolytic-like effect was blocked by pretreatment with HOE-140, suggesting mediation by endogenous BK. The panicolytic-like effect of captopril indicates that the use of ACE inhibitors in the clinical management of panic disorder may be worth exploring., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

In patients with anxiety and/or respiratory diseases, body sensations, particularly from the respiratory system, may increase in intensity and aversiveness and thus lead into defensive action (e.g., escape) or panic. The processes, however, that might contribute to the culmination of symptoms and the switch into defensive action have not been well understood yet. The current study aimed at evaluating an experimental paradigm to characterize the dynamics of defensive mobilization to body sensations increasing in intensity and aversiveness. Persons reporting low and high suffocation fear (SF; N = 69) were exposed to increasingly unpleasant feelings of dyspnea induced by inspiratory resistive loads and a breathing occlusion requiring voluntary breath holding. Respiratory responses were assessed along with subjective reports of anxiety and panic symptoms. Presentation of respiratory loads with increasing physical resistance led to increasingly unpleasant feelings of dyspnea. Twenty-eight participants terminated the exposure prematurely at least once. When dyspnea was severe, high compared to low SF persons exhibited an increased respiratory rate that was accompanied by reports of more intense panic symptoms. Premature terminations of exposure were preceded by a surge in anxiety, breathing frequency, and mouth pressure, and a decrease in tidal volume. We successfully established an experimental paradigm to assess changes in defensive responding with increasing intensity of an interoceptive threat. The current data foster our understanding of behavioral expression patterns observed in patients with anxiety and/or respiratory diseases and the processes involved in the culmination of bodily sensations and anxiety into panic., (© 2017 Society for Psychophysiological Research.)

Introduction: Understanding collective behavior of moving organisms and how interactions between individuals govern their collective motion has triggered a growing number of studies. Similarities have been observed between the scale-free behavioral aspects of various systems (i.e. groups of fish, ants, and mammals). Investigation of such connections between the collective motion of non-human organisms and that of humans however, has been relatively scarce. The problem demands for particular attention in the context of emergency escape motion for which innovative experimentation with panicking ants has been recently employed as a relatively inexpensive and non-invasive approach. However, little empirical evidence has been provided as to the relevance and reliability of this approach as a model of human behaviour., Methods: This study explores pioneer experiments of emergency escape to tackle this question and to connect two forms of experimental observations that investigate the collective movement at macroscopic level. A large number of experiments with human and panicking ants are conducted representing the escape behavior of these systems in crowded spaces. The experiments share similar architectural structures in which two streams of crowd flow merge with one another. Measures such as discharge flow rates and the probability distribution of passage headways are extracted and compared between the two systems., Findings: Our findings displayed an unexpected degree of similarity between the collective patterns emerged from both observation types, particularly based on aggregate measures. Experiments with ants and humans commonly indicated how significantly the efficiency of motion and the rate of discharge depend on the architectural design of the movement environment., Practical Applications: Our findings contribute to the accumulation of evidence needed to identify the boarders of applicability of experimentation with crowds of non-human entities as models of human collective motion as well as the level of measurements (i.e. macroscopic or microscopic) and the type of contexts at which reliable inferences can be drawn. This particularly has implications in the context of experimenting evacuation behaviour for which recruiting human subjects may face ethical restrictions. The findings, at minimum, offer promise as to the potential benefit of piloting such experiments with non-human crowds, thereby forming better-informed hypotheses.

Background: Anxiety and panic attacks are more common in chronic obstructive pulmonary disease (COPD) than in the overall population. Individuals with panic attacks often attempt to avoid situations perceived as at risk of eliciting bodily sensations such as dyspnea, which paradoxically may lead to anxiety-related responsivity. Although there is some evidence that COPD individuals restrict their participation in various life activities because they fear that these may trigger breathlessness, little is known about agoraphobic avoidance and its impact on cognitions and emotional distress in this population. It was thus our aim to investigate the degree of agoraphobic avoidance in COPD individuals, its clinical concomitants and consequences., Methods: A total of 48 patients with COPD and 48 matched controlled subjects completed measures of anxiety sensitivity, agoraphobic avoidance, anxiety and depression. Objective COPD severity was measured using forced expiratory volume in the first second., Results: Patients showed significant impairment in respiratory functioning and psychological distress. Relative to the control, the COPD group exhibited greater depression, anxiety, physical symptom concerns and avoidance (alone and accompanied), irrespective of whether they were panickers or not. Patients with high avoidance showed more intense physical concerns when compared to those with low avoidance. Importantly, the level of avoidance predicted emotional distress and increased physical concerns in COPD., Conclusions: Physical concerns scores in COPD patients are partially explained by avoidance in this group. The results of the study provide evidence for the importance of evaluating avoidance in COPD patients and implicate targeting this behavior in therapeutic interventions., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The dorsomedial hypothalamus (DMH) and the dorsal periaqueductal gray (DPAG) have been implicated in the genesis and regulation of panic-related defensive behaviors, such as escape. Previous results point to an interaction between serotonergic and opioidergic systems within the DPAG to inhibit escape, involving µ-opioid and 5-HT1A receptors (5-HT1AR). In the present study we explore this interaction in the DMH, using escape elicited by electrical stimulation of this area as a panic attack index. The obtained results show that intra-DMH administration of the non-selective opioid receptor antagonist naloxone (0.5 nmol) prevented the panicolytic-like effect of a local injection of serotonin (20 nmol). Pretreatment with the selective μ-opioid receptor (MOR) antagonist CTOP (1 nmol) blocked the panicolytic-like effect of the 5-HT1AR agonist 8-OHDPAT (8 nmol). Intra-DMH injection of the selective MOR agonist DAMGO (0.3 nmol) also inhibited escape behavior, and a previous injection of the 5-HT1AR antagonist WAY-100635 (0.37 nmol) counteracted this panicolytic-like effect. These results offer the first evidence that serotonergic and opioidergic systems work together within the DMH to inhibit panic-like behavior through an interaction between µ-opioid and 5-HT1A receptors, as previously described in the DPAG.

Although breathing CO 2 -enriched air reliably increases anxiety, there is debate concerning the nature and specificity of CO 2 hypersensitivity to panic risk and panic disorder versus anxiety disorders and related traits broadly, particularly among adolescents and emerging adults. The present study sought to clarify the association of CO 2 hypersensitivity with internalizing conditions and symptoms among adolescents and young adults. Participants (N = 628) self-reported anxiety levels every 2 min while breathing air enriched to 7.5% CO 2 for 8 min. Growth mixture models were used to examine the structure of anxiety trajectories during the task and the association of each trajectory with dimensional and diagnostic assessments of internalizing disorders. Three distinct trajectories emerged: overall low (low), overall high (high), and acutely increased anxiety (acute). Compared to the low class, the acute class reported elevated neuroticism, anxiety sensitivity, and stress whereas the high class reported elevated anxiety symptoms, depression symptoms, neuroticism, anxiety sensitivity, and increased likelihood of an anxiety disorder diagnosis. Moreover, the acute and high classes reported experiencing a panic-like event at a higher rate than the low class while participants in the high class terminated the task prematurely at a higher rate. The present study clarifies the nature of response to CO 2 challenge. Three distinct response profiles emerged, which clarifies the manifestation of CO 2 hypersensitivity in anxiety disorders with strong, though not unique, associations with panic-relevant traits., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Several studies have shown that serotonin plays a dual role in the modulation of defensive behaviors related to anxiety and panic. A major source of serotonergic projections to limbic structures responsible for this modulation is the dorsal raphe nucleus (DR). Anatomical studies indicate that the prelimbic (PL) cortex sends dense glutamatergic projections to the DR, leading to stimulation or inhibition of serotonin release in structures innervated by the DR. The objective of the present study was to investigate if GABAergic disinhibition of the PL by means of local administration of picrotoxin (PIC), a chloride channel blocker, can affect serotonergic tone and the expression of defensive behaviors related to anxiety and panic. We used the elevated T-maze model and Vogel conflict test to evaluate defensive responses associated with anxiety or panic. The results showed that intra-PL PIC caused an increase in c-Fos activation in serotonergic cells in DR subregions. Furthermore, the intra-PL injection of PIC induced a panicolytic-like effect without affecting behaviors associated with anxiety. Our findings suggest that the PL-DR pathway, through DR serotonergic stimulation, is involved in the control of panic-related behaviors by control of serotonin release in structures that modulate panic responses, such as the dorsal periaqueductal gray.

Panic patients may have abnormalities in serotonergic and opioidergic neurotransmission. The dorsal periaqueductal gray (dPAG) plays an important role in organizing proximal defense, related to panic attacks. The 5-HT 1A receptor (5-HT 1A -R) is involved in regulating escape behavior that is organized in the dPAG. Activation of κ-opioid receptor (KOR) in this region causes anxiogenic effects. In this study, we investigated the involvement of KOR in regulating escape behavior, using systemic and intra-dPAG injection of the KOR antagonist Nor-BNI. As panic models, we used the elevated T-maze (ETM) and the dPAG electrical stimulation test (EST). We also evaluated whether activation of the 5-HT 1A -R or the μ-opioid receptor (MOR) in the dPAG contributes to the Nor-BNI effects. The results showed that systemic administration of Nor-BNI, either subcutaneously (2.0 and 4.0mg/kg) or intraperitoneally (2.0mg/kg), impaired escape in the EST, indicating a panicolytic-like effect. Intra-dPAG injection of this antagonist (6.8nmol) caused the same effect in the EST and in the ETM. Association of ineffective doses of Nor-BNI and the 5-HT 1A -R agonist 8-OH-DPAT caused panicolytic-like effect in these two tests. Previous administration of the 5-HT 1A -R antagonist WAY-100635, but not of the MOR antagonist CTOP, blocked the panicolytic-like effect of Nor-BNI. These results indicate that KOR enhances proximal defense in the dPAG through 5-HT 1A -R modulation, independently of MOR. Because former results indicate that the 5-HT 1A -R is involved in the antipanic action of antidepressants, KOR antagonists may be useful as adjunctive or alternative drug treatment of panic disorder., (Copyright © 2017 Elsevier B.V. All rights reserved.)

One of the main neurochemical systems associated with anxiety/panic is the serotonergic system originating from the dorsal raphe nucleus (DR). Previous evidence suggests that the DR is composed of distinct subpopulations of neurons, both morphologically and functionally distinct. It seems that mainly the dorsal region of the DR (DRD) regulates anxiety-related reactions, while lateral wings DR (lwDR) serotonin (5-HT) neurons inhibit panic-related responses. In this study we used the technique of deep brain stimulation (DBS) to investigate the role played by the DRD and lwDR in defense. Male Wistar rats were submitted to high-frequency stimulation (100μA, 100Hz) in one of the two DR regions for 1h and immediately after tested in the avoidance or escape tasks of the elevated T-maze (ETM). In clinical terms, these responses have been related to generalized anxiety and panic disorder, respectively. After being submitted to the ETM, animals were placed in an open field for locomotor activity assessment. An additional group of rats was submitted to DBS of the DRD or the lwDR and used for quantification of c-Fos immunoreactive (Fos-ir) neurons in brain regions related to the modulation of defense. Results showed that stimulation of the DRD decreased avoidance latencies, an anxiolytic-like effect. DRD stimulation also led to increases in Fos-ir in the medial amygdala, lateral septum and cingulate cortex. DBS applied to the lwDR increased escape latencies, a panicolytic-like effect. This data highlights the importance of raphe topography and the potential benefit of the DBS technique for the treatment of anxiety-related disorders., (Copyright © 2017 Elsevier B.V. All rights reserved.)