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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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

The electrical and chemical stimulation of the dorsal periaqueductal grey matter (dPAG) elicits panic-like explosive escape behaviour. Although neurons of the ventromedial hypothalamus (VMH) seem to organise oriented escape behaviour, when stimulated with excitatory amino acids at higher doses, non-oriented/explosive escape reactions can also be displayed. The aim of this work was to examine the importance of reciprocal projections between the VMH and the dPAG for the organisation of this panic-like behaviour. The chemical stimulation of the VMH with 9nmol of N-methyl-d-aspartic acid (NMDA) elicited oriented and non-oriented escape behaviours. The pretreatment of the dPAG with a non-selective blocker of synaptic contacts, cobalt chloride (CoCl 2 ), followed by stimulation of the dorsomedial part of the ventromedial hypothalamus (dmVMH) with 9nmol of NMDA, abolished the non-oriented/explosive escape and freezing responses elicited by the stimulation of the dmVMH. Nonetheless, the rats still showed oriented escape to the burrow. On the other hand, when the blockade of the dmVMH with CoCl 2 was followed by stimulation of the dPAG with 6nmol of NMDA, no effect was observed either on the non-oriented/explosive escape or on the freezing behaviour organised by the dPAG. Furthermore, Fos protein-labelled neurons were observed in the dPAG after the stimulation of the dmVMH with 9nmol of NMDA. Additionally, when the anterograde neurotracer biotinylated dextran amine (BDA) was deposited in the dmVMH subsequent stimulation of the dmVMH produced BDA-labelled neural fibres with terminal boutons surrounding Fos-labelled neurons in the dPAG, suggesting synaptic contacts between dmVMH and dPAG neurons for eliciting panic-like behavioural responses. The current data suggest that the dPAG is the key structure that organises non-oriented/explosive escape reactions associated with panic attack-like behaviours., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Understanding behavioral avoidance associated with generalized anxiety disorder (GAD) has implications for the classification, theoretical conceptualization, and clinical management of the disorder. This study describes the development and preliminary psychometric evaluation of a self-report measure of avoidant behaviors associated with GAD: the Worry Behaviors Inventory (WBI)., Methods: The WBI was administered to treatment-seeking patients (N=1201). Convergent validity was assessed by correlating the WBI with measures of GAD symptom severity. Divergent validity was assessed by correlating the WBI with measures of general disability and measures of depression, social anxiety and panic disorder symptom severity., Results: Exploratory and confirmatory factor analyses supported a two-factor structure (Safety Behaviors and Avoidance). Internal reliability was acceptable for the 10-item WBI scale (α=.86), Safety Behaviors (α=.85) and Avoidance subscales (α=.75). Evidence of convergent, divergent, and discriminant validity is reported. WBI subscales demonstrated differential associations with measures of symptom severity. The Safety Behaviors subscale was more strongly associated with GAD symptoms than symptoms of other disorders, whereas the Avoidance subscale was as strongly correlated with GAD severity as it was with depression, social anxiety and panic disorder severity., Limitations: Structured diagnostic interviews were not conducted therefor validity analyses are limited to probable diagnoses based on self-report. The cross-sectional design precluded examination of the WBI's temporal stability and treatment sensitivity., Conclusions: Preliminary evidence supports the use of the WBI in research and clinical settings and may assist clinicians to identify behaviors that are theorized to maintain GAD and that can be targeted during psychological treatment., (Copyright © 2016 Elsevier B.V. All rights reserved.)

It has been shown that electrical stimulation of the mesencephalic tectum (MT) provokes defensive responses in both humans and rodents. During an emotional aversive state, some convergent studies have also demonstrated the existence of a complex interaction between endogenous opioid peptide- and γ-aminobutyric acid (GABA)-containing connections during fear-induced responses. It has been proposed that opioid neurons exert an influence on GABAergic interneurons, which, in turn, exert inhibitory tonic control on the mesencephalic excitatory pathways. Thus, opioid peptides can disinhibit neurons that are tonically inhibited by GABA, therefore, modulating the expression of defensive behavioural reactions. In the present work, we used both electric stimulation and microinjections of the GABAA receptor antagonist bicuculline in the inferior colliculus (IC) of Wistar rats in combination with microinjections of µ- and κ-opioid receptor selective agonists into the dorsal columns of periaqueductal grey matter (dPAG) to evaluate the effects on panic-like behaviours elicited by IC electrical and chemical stimulation. The present results showed that neurochemical lesions of the dPAG caused a significant impairment in the organisation of defensive responses by IC neurons, reducing the duration [t(14)=3.0; p<0.01] of defensive immobility and the duration [t(14)=2.8; p<0.05] and frequency [t(14)=2.5; p<0.05] of escape. Paradoxically, treating the dPAG with the µ-opioid receptor agonist met-enkephalin caused a significant reduction of panic-like behaviours induced by both electrical and chemical stimulation of the IC, increasing the escape behaviour threshold [F(2,23)=13.5; p<0.001] and decreasing the frequency [F(3,36)=11.7; p<0.001] and duration [F(3,36)=11.6; p<0.001] of escape and the duration of defensive immobility [F(3,36)=16.1; p<0.05]. In contrast, treating the dPAG with the κ-opioid receptor agonist salvinorin-A increased the frequency [F(3,36)=12.4; p<0.01] and duration [F(3,34)=16.1; p<0.01] of defensive immobility induced by GABAA receptor blockade in the IC. The present results suggest the existence of a complex neuronal network in the MT in which endogenous opioid peptides and GABAergic pathways interact in the control of fear-related behavioural responses., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Depression often involves anxiety symptoms and shows a strong comorbidity with panic disorder. However, the neural basis is unclear. The aim of the current study was to use semantic priming to investigate the neural correlates of panic and anxiety-related information processing in depression. In a lexical decision task, panic/agoraphobia-disorder-related and neutral word-pairs were presented during functional magnetic resonance imaging. Participants comprised 19 patients with major depression but without comorbid anxiety and 19 demographically matched controls. On a behavioral level, comparable significant priming effects were found for the neutral condition, while only patients showed a significant inhibition effect (slower reaction time for panic-related stimuli) for the panic condition. On a neural level, significant group differences emerged in left fronto-parietal (enhanced activation for patients) and left temporo-occipital regions (reduced activation for patients). The results showed that depressed patients recruit not only areas related to the interaction of emotion and semantic processing but also regions that are related to fear circuitry to process panic-related information. Hence, in the context of depression, there seems to be a pathological processing of panic-related information that could play an important role during the disorder and should be considered., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

The hypothalamo-pituitary-adrenal (HPA) axis is involved in stress, depression and anxiety. Controversy exists on HPA axis activation during panic attacks (PAs). We examined whether the HPA axis is involved in the escape or panic-like response in an animal model of PAs induced by electrical stimulation of the dorsolateral periaqueductal gray (dlPAG) in rats. Additionally, rats were also treated with chronic administration of buspirone (BUSP) and escitalopram (ESCIT), respectively; and they were stimulated in the open-field arena for panic-like reaction. Levels of stress hormone corticosterone were measured following 30 min after escape or panic condition. Our results demonstrated that the levels of plasma corticosterone were significantly increased after the induction of escape or panic-like response in comparison with the sham animals. The levels of corticosterone were significantly decreased in the dlPAG stimulated groups after rats were treated chronically with the ESCIT but not the BUSP as compared to the saline treated animals. Importantly, the increase of corticosterone level after escape or panic-like response was paralleled by an increase of neuronal activation of c-Fos in both the parvocellular and magnocellular paraventricular nucleus of the hypothalamus. Moreover, the c-Fos data also showed a decrease in the number of positive cells particularly for the ESCIT as well as the BUSP in comparison with the saline stimulated animals. In conclusion, the present study clearly demonstrated that PA or escape response activates the HPA axis and it remains difficult to anticipate the mechanism underlying HPA axis during PAs and its relationship with 5-HT drugs., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Activation of 5-HT1A receptors in the dorsal periaqueductal gray (dPAG) impairs escape behavior, suggesting a panicolytic-like effect. Cannabidiol (CBD), a major non-psychotomimetic compound present in Cannabis sativa, causes anxiolytic-like effects after intra-dPAG microinjections by activating 5-HT1A receptors. In the present work we tested the hypothesis that CBD could also impair escape responses evoked by two proposed animal models of panic: the elevated T-maze (ETM) and electric stimulation of dPAG. In experiment 1 male Wistar rats with a single cannula implanted in the dPAG received a microinjection of CBD or vehicle and, 10 min later, were submitted to the ETM and open field tests. In experiment 2 escape electrical threshold was measured in rats with chemitrodes implanted in the dPAG before and 10 min after CBD microinjection. In experiment 3 similar to experiment 2 except that the animals received a previous intra-dPAG administration of WAY-100635, a 5-HT1A receptor antagonist, before CBD treatment. In the ETM microinjection of CBD into the dPAG impaired inhibitory avoidance acquisition, an anxiolytic-like effect, and inhibited escape response, a panicolytic-like effect. The drug also increased escape electrical threshold, an effect that was prevented by WAY-100635. Together, the results suggest that CBD causes panicolytic effects in the dPAG by activating 5-HT1A receptors., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

Electrical stimulation of the dorsolateral periaqueductal gray (dlPAG) and one of its target structures, the ventromedial hypothalamus (VMH), produces a typical behaviour in rats consisting of vigorous running and jumping which is known as "escape behaviour". Escape behaviour in rodents closely mimics panic attacks in humans. Since electrical stimulation at higher frequencies generally inhibits the stimulated region, we tested in this study the hypothesis that deep brain stimulation (DBS) of the dlPAG and VMH at higher frequencies (> 100 Hz) would not induce escape behaviour. More specifically, we evaluated whether experimental DBS could be used to inhibit panic-like behaviour. Rats underwent implantation of DBS-electrodes at the level of the dlPAG and VMH and the effects of various stimulation parameters were assessed. In addition, we studied the neural activation pattern resulting from DBS of the dlPAG and VMH using c-Fos immunohistochemistry. We found that stimulation amplitude is the most important stimulation parameter in the induction of escape behaviour. Remarkably, stimulation frequency (1-300 Hz) had no effect on stimulation-induced escape behaviour and therefore it was not possible to prevent the induction of escape behaviour with higher frequencies. The neuronal activation pattern resulting from dlPAG and VMH DBS was similar. These findings suggest that DBS of the dlPAG and VMH induces panic-related behaviours even at higher frequencies.

In the last years, the role played by the medial nucleus of the amygdala (MeA) in the modulation of fear- and anxiety-related behaviors has been increasingly investigated. This nucleus plays an important role in the processing of predator odor-induced defensive reactions, i.e. freezing and risk-assessment behaviors. Immunohistochemical evidence also indicates that the MeA may be involved in the regulation of escape, a defensive behavior related to panic attacks. In this study, we further addressed this question by investigating the effects of the reversible inactivation of the nucleus on escape behavior generated in male Wistar rats by two different aversive stimuli, electrical stimulation of the dorsal periaqueductal gray matter (dPAG) and exposure to one of the open arms of the elevated T-maze. Results showed that intra-MeA administration of either the reversible sodium channel blocker lidocaine (34 nmol/0.2 microl) or the GABA(A) receptor agonist muscimol (0.22 nmol/0.2 microl) raised the threshold of aversive electrical stimulation, increasing the amount of current that applied to the dPAG evokes escape, an antiaversive effect. Local microinjection of muscimol (0.22 nmol/0.2 microl) inhibited escape behavior in the elevated T-maze, also suggesting an antiaversive effect. In this latter test, muscimol did not affect inhibitory avoidance, a behavior associated with generalized anxiety disorder. Muscimol effect in the elevated T-maze was independent of changes in general exploratory activity as measured in an open-field. Taken together, our data corroborate previous evidences suggesting that the MeA is involved in the modulation of escape. Dysfunction of this regulatory mechanism may be of relevance in the genesis/maintenance of panic disorder.

Paradoxically, the pituitary-adrenal axis is not activated during sodium lactate-induced panic. We measured the response of another stress-sensitive hormone, prolactin, to standard lactate and placebo infusion in a double-blind randomised design in eight patients with panic disorder and eight matched normal controls. Prolactin release was significantly elevated (P < 0.05) in panickers compared with non-panickers, whereas ACTH secretion was not activated at all. This differential stress response needs further investigation.

Sleep-deprived rats exhibit defensive fighting as well as explosive flights very similar to the wild-running of audiogenic seizures. In order to determine why sleep deprivation is a common factor that facilitates both panic and convulsive manifestations, the present study was undertaken to investigate whether rats that display sleep deprivation-induced fighting (SDIF) are the same as those that are susceptible to audiogenic wild-running (WR). Twenty-eight male adult Wistar rats were divided into two groups assigned to two experimental schemes. In the first, 18 subjects were submitted to REM-sleep deprivation for 5 days and had their SDIF evaluated in social grouping. After 1 week for recovery, their susceptibility to WR was tested in an acoustic stimulation trial (104 dB, 200 Hz, 60 s). Rats that did not present WR received a lactate infusion and were tested again by acoustic stimulation 40 min later. In the second experimental scheme, 10 subjects were initially evaluated for WR susceptibility and the number of SDIF was recorded in social grouping after 1 week. Three categories of WR-susceptibility were determined: WR-sensitive rats, intermediate WR-sensitive rats and WR-insensitive rats. The number of SDIF in each category was significantly different and there was a high positive correlation (r=0.89; Spearman test) between the number of SDIF and the level of WR-susceptibility. We conclude that the reasons why sleep deprivation exerts facilitatory effects on both panic and convulsive manifestations are due to overlappings of neural pathways responsible for both behavioral patterns and for the property of sleep deprivation to increase neuronal excitability.

Our aim was to determine whether panic disorder (PD) patients, major depressive patients without panic attacks (MD) and major depressive patients with panic attacks (MDP) respond similarly to hyperventilation challenge tests. We randomly selected 35 PD patients, 33 MDP patients, 27 MD patients and 30 normal volunteers with no family history of anxiety or mood disorder. The patients had not been treated with psychotropic drugs for at least 1 week. They were induced to hyperventilate (30 breaths/min) for 4 min, and anxiety was assessed before and after the test. A total of 16 (45.7%) PD patients, 12 (36.4%) MDP patients, four (11.1%) MD patients, and two (6.7%) normal volunteers had a panic attack after hyperventilating. The PD and MDP patients were significantly more responsive to hyperventilation than the MD patients and the normal volunteers. The MD patients had a significantly lower heart-rate response to the test than all the other groups. There is growing evidence that PD patients are more sensitive to the vasoconstrictive effects on basilar arterial blood flow caused by hyperventilation-induced hypocapnia than are comparison subjects. Our data suggest that there is an association between panic attacks and hyperreactivity to an acute hyperventilation challenge test.

Background: Although some previous research has focused on the relationship between panic disorder (PD) and a high total cholesterol (TC) level, it is still controversial. Recently, researchers have reported the heterogeneity of clinical symptoms in PD and the complexity of the correlations found among them. Therefore, the controversy on the TC level in PD may be due to the existence of clinical subgroups in PD. It is important to ascertain whether or not an elevated TC level in patients with PD is associated with specific panic symptoms., Methods: In 104 drug-free patients with PD, we examined the relationship between TC level and each of several panic symptoms occurring at the time of panic attacks (PAs), which included anticipatory anxiety, agoraphobia, and 13 panic symptoms based on the DSM-III-R., Results: Stepwise regression analysis revealed a significant effect of the presence of the symptom 'fear of dying' on TC levels. Patients with a fear of dying had a significantly higher TC level than those without it., Limitations: The relatively small sample size may limit the generalizability of our findings., Discussion: These data suggest that TC level may be associated with panic symptoms in patients with PD.

Results of an earlier study in healthy volunteers suggest that the serotonergic system is involved in anxiety-related mechanisms. We studied the influence of tryptophan depletion on the response to a 35% carbon dioxide challenge. Twenty-four panic disorder patients received a mixture of amino acids, either with or without tryptophan, under double-blind conditions. There was a significant increase in anxiety as well as in neurovegetative symptoms in the depletion group, compared to the placebo condition. Furthermore, when we compare the results of the placebo group with earlier panic provocation studies, it also seems that a balanced amino acid mixture might have a protective effect against a panic provocation. We conclude that the panic-enhancing effect of tryptophan depletion as well as the potential protective effect of tryptophan administration in panic disorder patients can be explained by the Deakin-Graeff theory of anxiety.

The amygdala is a critical temporal lobe structure involved in the expression of anxiety and stress responses. The basolateral nucleus (BLA) of the amygdala in particular, may play a key role in anxiety. Furthermore, corticotropin-releasing factor (CRF), a 41 amino acid peptide, has been strongly implicated in the regulation of stress and anxiety responses. Centrally administered CRF has been shown to increase the anxiety-like behaviors of rodents in several animal models. A recently cloned related peptide, Urocortin (Ucn), appears to have similar affinity for the CRF1 receptor, but higher affinity at the CRF2 receptor. When microinjected into the BLA, we found Ucn was substantially more potent than CRF in producing anxiogenic-like behavior as assessed in the social interaction test. Furthermore, repetitive administration of subthreshold doses of Ucn and CRF resulted in 'priming'. Once primed, these animals exhibited behavioral and cardiovascular responses to intravenous sodium lactate, a panicogenic agent in susceptible human patients. These results suggest central CRF and Ucn play a role in generating anxiety which may be similar to that seen in pathological conditions such as panic disorder.

The behavioural indices of anxiety/fear/panic range from freezing/inhibition of ongoing behaviour to active defence strategies i.e. fight/flight, depending on the proximity or intensity of the aversive stimulus. However, evidence suggests that when the initial stressor is sufficiently intense, the neural defence circuitry may undergo a long-term increase in sensitivity. Such sensitization has been evoked to explain the chronically hyper-aroused fight/flight state of patients suffering from extreme anxiety states. The purpose of this study was to establish whether direct activation of the rodent midbrain defence system could result in a similar long-term alteration of the animal's responses to subsequent stressful events. This was achieved by studying the behaviour of animals in a threatening environment after repetitive electrical stimulation of the superior colliculus. Animals were then placed on an unstable, elevated and exposed plus maze and their behaviour recorded. Testing was carried out regularly over 3 months. Stimulated animals reliably exhibited significantly increased levels of behaviours designed to escape the aversive conditions of the unstable plus maze. These included visual scanning, end-reaching, preparing to jump, and jumping off the apparatus. Unstimulated control animals, on the other hand, exhibited decreased levels of these behaviours post-stimulation. In contrast, the experimental animals' performance on standard anxiety tests did not differ from controls. These results demonstrate that repetitive tactile stimulation can produce a long-term change in reactions to threat, and is proposed as a functional model of extreme anxiety.

Measurements of regional cerebral blood flow (rCBF) were performed in 16 women suffering from spider phobia. The non-invasive 133Xe inhalation method, giving information about the blood flow of superficial areas, was used. The subjects were studied under three conditions: during resting, when exposed to a videotape showing nature scenery, and finally when watching a video with living spiders. During the rCBF measurements the subjects' behaviour was registered systematically and respiration, blood pressure, Pco2, and heart rate were monitored. Eight subjects who showed and reported severe panic during the spider exposure had marked rCBF decreases in frontal areas, especially in the right hemisphere. The remaining eight subjects displayed a more efficient control of their emotions and became frightened, but not panic-stricken, during the spider exposure. These showed a consistent rCBF increase in the right frontal area compared to neutral stimulation. Thus, results revealed significant functional changes in the frontal cortex in subjects with spider phobia during phobogenic exposure. It seems likely that these frontal changes are related to the experience and control of phobic anxiety.

Results of several studies suggest that anxiety is under serotonergic control. We studied the influence of tryptophan depletion on generalized anxiety and on the response to a 35% carbon dioxide (CO2) challenge. Fifteen healthy male volunteers received both a mixture of amino acids without tryptophan and a placebo mixture under double-blind conditions. The tryptophan-free mixture led to an 80% decrease in blood tryptophan levels compared to the placebo. There was a significant increase in anxiety on the Spielberger Anxiety Inventory and a trend towards more tension on the Profile of Mood States-'tension' items, both of which were interpreted as increased nervousness. Furthermore, a significant increase in neurovegetative panic symptoms occurred after the CO2 challenge. We conclude that the serotonergic system is causally involved in anxiety-related mechanisms and that it may be worth pursuing the role of tryptophan depletion on CO2-induced panic in patients with anxiety disorders.

Sixty-seven subjects, including normal volunteers and patients with obsessive-compulsive disorder, social phobia, and borderline personality disorder, received ratings of depersonalization after double-blind, placebo-controlled challenges with the partial serotonin agonist meta-chlorophenylpiperazine (m-CPP). Challenge with m-CPP induced depersonalization significantly more than did placebo. Subjects who became depersonalized did not differ in age, sex, or diagnosis from those who did not experience depersonalization. There was a significant correlation between the induction of depersonalization and increase in panic, but not nervousness, anxiety, sadness, depression, or drowsiness. This report suggests that serotonergic dysregulation may in part underlie depersonalization.

The psychological and physiological effects of acute low-potency benzodiazepine administration on lactate-induced panic were examined in 10 patients with panic disorder (PD). The patients, who had panicked during a standard sodium-lactate infusion, underwent a repeat infusion modified by pretreatment with intravenous diazepam (5 mg). Acute Panic Inventory (API) scores preceding the second lactate infusion, which were associated with diazepam pretreatment, were significantly reduced in compared with those measured before the first lactate infusion. However, the second visit "fear of doom" item of the API was significantly reduced relative to the same time point of the first visit 35 min before lactate infusion, when diazepam had not yet been administered. Thus, the reduction of prelactate anxiety preceding the second infusion appeared to reflect both pharmacological and nonpharmacological contributions. The diazepam pretreatment condition was associated with a significantly increased infusion duration and a significant attenuation of rate of API symptom increase in response to lactate. Despite significant attenuation of lactate infusion effects associated with the diazepam pretreatment condition, 7 of 10 patients experienced a second panic attack. This pilot study suggests that diazepam pretreatment is associated with a marked reduction of symptomatic response during a second lactate infusion, although the magnitude of attenuation observed was insufficient to block lactate-induced panic in a majority of lactate-vulnerable PD patients.

The effects of alprazolam, a triazolobenzodiazepine, on hormonal and behavioral responses induced by meta-chlorophenylpiperazine (MCPP), a serotonin receptor agonist, were investigated in 10 healthy men. Alprazolam (0.5 mg) or placebo was given 1 hour before MCPP (0.5 mg/kg) or placebo. Cortisol, prolactin, and growth hormone (GH) release, MCPP and alprazolam plasma levels, anxiety level, and panic symptoms were measured over 210 minutes. MCPP was found to increase cortisol, prolactin, GH, and anxiety levels. Alprazolam decreased cortisol and GH levels but had no effect on prolactin. When used in combination with MCPP, alprazolam blunted MCPP-induced cortisol and GH release, and it blocked the anxiogenic effects of MCPP.

To assess the effects of the selective serotonin reuptake blocker fluvoxamine on noradrenergic function in patients with panic disorder, an intravenous yohimbine challenge test was administered to eight patients with panic disorder before and after 8 weeks of fluvoxamine treatment and to a parallel group of eight patients treated with placebo. Fluvoxamine treatment reduced yohimbine-induced anxiety while placebo treatment had no effect on this variable. Both fluvoxamine and placebo treatment had little effect on biochemical or physiologic responses to yohimbine.

This study investigated the relationship between increased serotonin (5-hydroxytryptamine, 5HT) receptor sensitivity and human aggression. A low oral dose of meta-chlorophenylpiperazine (MCPP), a postsynaptic 5HT receptor agonist, was administered in a placebo-controlled design to depressed (n = 22) and panic disorder (n = 20) patients classified with or without signs of outwardly directed aggression, patients with a history of suicide attempts (inwardly directed aggression) (n = 11), and normal controls (n = 19). Hormones under 5HT control were measured at 30-min intervals. Results were as follows: (1) MCPP did not induce or reduce anger, (2) patients with outwardly directed aggression did not have significantly greater MCPP-induced cortisol or prolactin release than did patients without signs of outwardly directed aggression, (3) patients with a history of suicide attempts did not have significantly greater MCPP-induced cortisol or prolactin release than did normal controls, and (4) MCPP-induced hormone release was unrelated to measures of aggression.

The present study reports adrenocorticotropic hormone (ACTH) and prolactin responses after oral administration of 0.25 mg/kg of the serotonin agonist, meta-chlorophenylpiperazine (MCPP), in patients with panic disorder (PD) and in healthy subjects. MCPP blood levels were similar for the two groups, but almost twice as high in males as in females. Female patients had augmented ACTH and prolactin release as compared to healthy females, while ACTH and prolactin release in male patients was similar to that of male controls. These results suggest that female PD patients have hypersensitive serotonin receptors. Moreover, they indicate that pharmacokinetic gender differences may affect challenge studies, and that different doses may be required to study neuroendocrine responses in males and females.

We have previously reported decreased heart rate variability upon standing in panic disorder patients compared with controls. In this study, we extend our report to include patients with major depression (n = 19). Compared to normal controls (n = 20) and panic disorder patients (n = 30), there was no significant difference in the immediate changes in heart rate upon standing in the depressed group. The standing heart rate variability (R-R variability) was significantly lower in panic disorder patients compared to both normal controls and depressed patients as indicated by the corrected standard deviations, the corrected mean consecutive difference, the corrected standard deviation of the mean consecutive difference of the R-R intervals, and the high frequency variability in successive R-R intervals, suggesting an increased vagal withdrawal in panic disorder patients, especially upon standing. There was no significant difference in any of the heart rate variability measures between depressed patients and normal controls.

The cerebrospinal fluid (CSF) levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5HIAA), the noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), and the dopamine metabolite homovanillic acid (HVA) did not differ significantly in a group of patients with panic disorder (n = 17) as compared to age- and sex-matched normal controls (n = 17). While CSF concentrations of HVA and 5HIAA were significantly correlated in both patients and controls, CSF MHPG levels were significantly correlated with the concentrations of CSF 5HIAA and HVA only in patients. In a small number of subjects (n = 5), successful reduction of anxiety attacks by administration of clomipramine or imipramine (50-150 mg/day) for at least 2 months was associated with a significant decrease in CSF concentrations of 5HIAA and MHPG, but not HVA.

Fourteen panic disorder patients with low 3-methoxy-4-hydroxyphenylglycol (MHPG) were compared to 14 patients with high MHPG. Patients with low MHPG were more likely during the preceding month to have experienced spontaneous panic attacks (P less than 0.008) than were patients with high MHPG. Patients with high MHPG had increased severity ratings on several individual symptoms of anxiety.

Preliminary studies have shown that polymorphonuclear neutrophil (PMN) activity is decreased in a state-dependent manner in patients with endogenous depression. The present study investigates this finding in a larger group of psychiatric patients and attempts to determine the identification of the factor responsible for the abnormal neutrophil function. Chemiluminescence responses of PMNs from patients with diagnoses of endogenous depression, panic disorder, anxiety, schizophrenia and alcoholism were assessed concurrently with age- and sex-matched control subjects. The reduction in PMN activity was observed in panic disorder patients as well as during depression but remained normal in schizophrenia, alcoholism and generalised anxiety. The defect in PMN function appears to be related to an abnormal factor in the serum of the patient which is corrected on clinical recovery. Aspirin-inhibited prostaglandin synthesis resulted in an enhancement of PMN activity in healthy subjects, suggesting a possible role for prostaglandins in the abnormal PMN response.

Resting heart rate, heart rate variability and blood pressure; the heart rate and blood pressure response to standing; and the heart rate response to Valsalva's manoeuvre, have been measured in a group of 12 patients with panic disorder and a group of 12 age- and sex-matched normal subjects. The patients had undergone treatment for their panic attacks with cognitive therapy; all had responded and all had been panic-free for a minimum of 4 months (mean 7.6 months). Mood ratings (BDI, BAI and SSAI) were comparable with established norms. The patients nevertheless had a raised resting systolic blood pressure, a reduced resting heart rate and an abnormal orthostatic response.

Nineteen females with panic disorder were studied using daily prospective home diary ratings of various general health related items, a short anxiety self-rating scale, a survey of late luteal phase dysphoric symptoms, as well as a record of the number and severity of panic attacks. The subjects collected information for 60 consecutive days, and information regarding 30 menstrual cycles was available for analysis. Overall, subjects retrospectively reported increases in their anxiety symptoms during premenstrual days, but this was not demonstrated consistently on daily prospective ratings.

Platelet [3H]LSD binding was measured in 15 patients with panic attacks and 15 controls. The mean (+/- SD) Bmax values of the patients (14.1 +/- 6.3 fmol/mg protein) and of the controls (18.5 +/- 4.7 fmol/mg protein) were significantly different (P less than 0.05, Mann-Whitney U-test). Mean (+/- SD) values of Kd for the patients (0.55 +/- 0.34 nM) and for the controls (0.51 +/- 0.12 nM) were not significantly different (P greater than 0.1, Mann-Whitney U-test). The results are discussed in terms of a serotonergic hypothesis of the aetiology of panic disorders.

Echocardiographic comparison of 35 panic disorder patients to 35 normal control subjects found subclinical increases of cardiac left ventricular chamber size in eight panic patients (and one control subject), and of left ventricular mass (corrected for body surface area) in seven panic patients. There was a significantly greater variance of left heart chamber size and corrected mass in panic patients compared with control subjects, without significant group mean differences. Consistent with a previously reported association of panic anxiety and idiopathic dilated cardiomyopathy, this study suggests that some healthy panic patients may have subclinical myocardial changes.

In order to compare the panicogenic effects of hypercarbia and hypocarbia in panic disorder (PD), 12 PD patients and 11 healthy controls underwent a 35% CO2 challenge as well as a hyperventilation provocation test in a random cross-over design. Both anxiety and anxiety symptoms proved to be significantly higher during the 35% CO2 challenge in PD patients as compared to the response during 35% CO2 in normals and during hyperventilation in both patients and normals. The results suggest that PD patients are specifically hypersensitive to an increase in pCO2.

The present study introduces a novel measure of adenosine receptor sensitivity that is based on the action of specific receptor blockers (e.g., caffeine) to potentiate the ability to detect threshold quinine concentrations. The test is used to compare gustatory adenosinergic responses to caffeine challenges in normal controls and patients with panic disorder or posttraumatic stress disorder (PTSD). Panic disorder patients had an exaggerated response to the caffeine challenge that was not found in controls or PTSD patients, although the latter had higher anxiety scores on psychometric tests. The results are related to a model in which A1-adenosine receptors up-regulate in an attempt to modulate hyperactive excitatory neuronal systems.

Sixty-five patients with panic disorder and 37 matched controls collected 24-hour urine specimens for measurement of urinary free cortisol. Although patients with panic disorder had significantly higher urinary free cortisol levels than control subjects, this difference was accounted for by panic disorder patients with concomitant depression, agoraphobia, or both. Urinary free cortisol excretion was not related to the age of onset of panic disorder, the number of spontaneous panic attacks, or the degree of impairment associated with the disorder. They were related, however, to the level of symptoms on both the Hamilton Rating Scale for Depression and the Hamilton Rating Scale for Anxiety in the entire group of panic patients, but this relationship disappeared when those patients with the complications of agoraphobia and depression were excluded. These data suggest that, as with primary depression, depression secondary to panic disorder, as well as to agoraphobia in panic disorder patients, is associated with hyperactivity of the hypothalamic-pituitary-adrenal axis.

Platelet monoamine oxidase (MAO) activity was studied in 21 patients meeting Research Diagnostic Criteria for panic disorder and in 12 healthy controls. Platelet MAO activity in females in both patient and control groups tended to be higher than that in males, but the results did not reach statistical significance. Platelet MAO activity was significantly decreased in panic disorder patients compared to controls.

Platelet alpha 2 binding was measured in 14 patients with panic attacks and 21 controls using the antagonist 3H-rauwolscine as radioligand. The mean (+/- SD) Bmax values of patients (116 +/- 45 fmoles/mg protein) and controls (106 +/- 32 fmoles/mg protein) was not significantly different (p greater than 0.05, Mann-Whitney U test). There was a nonsignificant trend for the Kd of patients (1.25 +/- 0.67 nM) to be higher than that of controls (0.96 +/- 0.32 nM). The results do not support an adrenergic abnormality in panic patients.