Stress-induced pro- and anti-inflammatory cytokine concentrations in panic disorder patients.

BACKGROUND: An attenuated responsivity of the hypothalamus-hypophysis-adrenal (HPA) axis upon challenge and an increased risk for cardiac events are relatively consistent findings in panic disorder (PD) patients. Due to cytokine-HPA interactions, an altered HPA-axis responsivity may be accompanied by altered cytokine concentrations. Immunological reactions under stress might be considered the missing link for explaining an increased cardiac risk. This study analyzed stress-induced cytokine levels in PD patients. METHODS: A total of n = 32 PD patients and n = 32 healthy control individuals performed the Trier Social Test (TSST). Blood sample collection accompanied the TSST for the collection of cortisol and pro- (IL-6, TNF-α) and anti-inflammatory cytokines (IL-10). Established self-report questionnaires were handed out for the clinical characterization and the assessment of subjective levels of distress during testing. Repeated measures ANCOVA were conducted to evaluate main effects of time or group and time x group interaction effects. Additional ANCOVAS with disease severity as between-subjects factor (healthy, borderline, mild, moderate, severe) took global panic severity into account. Pearson correlation analyses were carried out to test for an association of panic specific symptoms and peak cytokine release. RESULTS: The TSST resulted in a significantly increased secretion of cortisol, IL-6 and IL-10. The data analysis further revealed a significant time x group interaction effect for cortisol and IL-10. Compared to the healthy volunteers, the PD patients showed significantly higher baseline and challenged IL-10 concentrations but lower challenged cortisol concentrations. Mildly and moderately affected patients showed the highest levels of IL-10 compared to the healthy individuals. There were no differential secretion patterns of IL-6 and TNF-α between both groups in the course of the TSST. The peak IL-6 release was found to be significantly associated with global disease severity. CONCLUSION: We found evidence for altered levels of cytokines with primarily anti-inflammatory properties in PD patients under baseline and a psychosocial stress condition. The results provide tentative evidence for a low-grade inflammatory process in PD patients, possibly representing a missing link factor between PD diagnosis and the increased risk for cardiac disease.

The Rodent-versus-wild Snake Paradigm as a Model for Studying Anxiety- and Panic-like Behaviors: Face, Construct and Predictive Validities.

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.

µ-Opioid and 5-HT1A receptors in the dorsomedial hypothalamus interact for the regulation of panic-related defensive responses.

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.

Disinhibition of the rat prelimbic cortex promotes serotonergic activation of the dorsal raphe nucleus and panicolytic-like behavioral effects.

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.

Association between genes on chromosome 19p13.2 and panic disorder.

Panic disorder (PD) is a severe and disabling mental disorder, which is moderately heritable. In a previous study, we carried out a genome-wide association study using patients with PD and control individuals from the isolated population of the Faroe Islands and identified chromosome 19p13.2 as a candidate region. To further investigate this chromosomal region for association with PD, we analysed eight single nucleotide polymorphisms (SNPs) in three candidate genes - small-nuclear RNA activating complex, polypeptide 2 (SNAPC2), mitogen-activated protein kinase kinase 7 (MAP2K7) and leucine-rich repeat containing 8 family, member E (LRRC8E) - these genes have previously been directly or indirectly implicated in other mental disorders. A total of 511 patients with PD and 1029 healthy control individuals from the Faroe Islands, Denmark and Germany were included in the current study. SNPs covering the gene region of SNAPC2, MAP2K7 and LRRC8E were genotyped and tested for association with PD. In the Faroese cohort, rs7788 within SNAPC2 was significantly associated with PD, whereas rs3745383 within LRRC8E was nominally associated. No association was observed between the analysed SNPs and PD in the Danish cohorts. In the German women, we observed a nominal association between rs4804833 within MAP2K7 and PD. We present further evidence that chromosome 19p13.2 may harbour candidate genes that contribute towards the risk of developing PD. Moreover, the implication of the associated genes in other mental disorders may indicate shared genetic susceptibility between mental disorders. We show that associated variants may be sex specific, indicating the importance of carrying out a sex-specific association analysis of PD.

Predisposition or side effect of the duration: the reactivity of the HPA-axis under psychosocial stress in panic disorder.

BACKGROUND: Panic disorder (PD) has been associated with an altered reactivity of the hypothalamic­pituitary­adrenocortical (HPA) system under psychosocial stress. Until now it remains unclear whether a diminished cortisol release is an early risk factor predisposing for PD or a consequence of PD. In order to unravel this point, the present study compares the cortisol secretion between patients with a recent onset and a chronic course of PD. METHODS: The Trier Social Stress Test (TSST) was applied in patients with a duration of PD ≤ 1.5 years (N = 35), patients with a duration of PD > 1.5 years (N = 56) and healthy controls (N = 95). Salivary cortisol and heart rate (HR) were assessed as primary outcomes. RESULTS: According to baseline cortisol/baseline HR and HR response there was no significant difference. Both patient groups (≤ 1.5/> 1.5 years) showed a blunted cortisol response with no significant group difference. In multiple linear regression models the attenuation of the HPA-axis was largely accounted for by group, smoking status, use of contraceptive pill and the interaction group by gender. Female patients with a chronic course showed the lowest cortisol response under the TSST. CONCLUSIONS: It might be assumed that a decreased reactivity of the HPA-axis could be considered as etiological risk factor in the preliminary stages of PD. Above, female gender, smoking status and the use of contraceptive pill seem to further moderate the attenuated HPA-axis response pattern in patients with PD.

Sex determinants of experimental panic attacks.

Panic disorder is twice a common in women than in men. In women, susceptibility to panic increases during the late luteal (premenstrual) phase of the menstrual cycle, when progesterone secretion is in rapid decline. This article considers the evidence for the midbrain periaqueductal grey (PAG) as a locus for panic and for the use of PAG stimulation as an animal model of panic in both sexes. We show in females how a rapid fall in progesterone secretion, such as occurs during the late dioestrus phase of the ovarian cycle in rats (similar to the late luteal phase in women), triggers a neuronal withdrawal response during which the excitability of the midbrain panic circuitry increases as a result of upregulation of extrasynaptic GABAA receptors on inhibitory interneurones in the PAG. The withdrawal effect is due not to the native hormone but to its neuroactive metabolite allopregnanolone. Differences in the kinetics of allopregnanolone metabolism may contribute to individual differences in susceptibility to panic in women.

Gender-specific association of variants in the AKR1C1 gene with dimensional anxiety in patients with panic disorder: additional evidence for the importance of neurosteroids in anxiety?

BACKGROUND: Neurosteroids are synthesized both in brain and peripheral steroidogenic tissue from cholesterol or steroidal precursors. Neurosteroids have been shown to be implicated in neural proliferation, differentiation, and activity. Preclinical and clinical studies also suggest a modulatory role of neurosteroids in anxiety-related phenotypes. However, little is known about the contribution of genetic variants in genes relevant for the neurosteroidogenesis to anxiety disorders. METHODS: We performed an association analysis of single nucleotide polymorphisms (SNPs) in five genes related to the neurosteroidal pathway with emphasis on progesterone and allopregnanolone biosynthesis (steroid-5-alpha-reductase 1A (SRD5A1), aldo-keto reductase family 1 C1-C3 (AKR1C1-AKR1C3) and translocator protein 18 kDA (TSPO) with panic disorder (PD) and dimensional anxiety in two German PD samples (cases N = 522, controls N = 1,115). RESULTS: Case-control analysis for PD and SNPs in the five selected genes was negative in the combined sample. However, we detected a significant association of anticipatory anxiety with two intronic SNPs (rs3930965, rs41314625) located in the gene AKR1C1 surviving correction for multiple testing in PD patients. Stratification analysis for gender revealed a female-specific effect of the associations of both SNPs. CONCLUSIONS: These results suggest a modulatory effect of AKR1C1 activity on anxiety levels, most likely through changes in progesterone and allopregnanolone levels within and outside the brain. In summary, this is the first evidence for the gender-specific implication of the AKR1C1 gene in the expression of anticipatory anxiety in PD. Further analyses to unravel the functional role of the SNPs detected here and replication analyses are needed to validate our results.

Determination of serum antioxidant vitamins, glutathione and MDA levels in panic disorder patients.

There are sufficient experimental evidences to establish the relationship between the elevated level of malondealdehyde (MDA)-the lipid peroxidation product and depleted level of antioxidants (Vitamin A, E, C and glutathione) in several psychiatric disorders. But previously no study was carried out to determine these components in panic disorder (PD) patients of Bangladesh. This study was conducted to assess the serum concentration of antioxidant vitamins, MDA and glutathione in 54 panic disorder patients and 52 healthy volunteers. Patients were recruited from Bangabandhu Sheikh Mujib Medical University, Bangladesh by random sampling. Serum level of MDA, glutathione and vitamin C were determined by UV spectrophotometric method whereas Vitamins A and E were detected by RP-HPLC method. Data were analyzed by independent t test and Pearson's correlation analysis. It had been found that the PD patients had low level of antioxidants like vitamin A (p=0.041) and vitamin E (p=0.018) than the healthy controls whereas the change of vitamin C is not significant. It had been found that the MDA content was significantly higher (p<0.05) in PD patients than that of controls. There was no significant difference for the glutathione content between the 2 groups. Pearson's correlation coefficient suggested that there were significant negative correlation between the glutathione level and vitamin C (p=0.013) and a positive correlation between the vitamin E and vitamin A (p=0.020) in patient group. Our study reveals that panic disorder patients have considerably higher level of MDA, lower level of antioxidant vitamins and glutathione than the healthy control subjects.

Panic-like defensive behavior but not fear-induced antinociception is differently organized by dorsomedial and posterior hypothalamic nuclei of Rattus norvegicus (Rodentia, Muridae)

The hypothalamus is a forebrain structure critically involved in the organization of defensive responses to aversive stimuli. Gamma-aminobutyric acid (GABA)ergic dysfunction in dorsomedial and posterior hypothalamic nuclei is implicated in the origin of panic-like defensive behavior, as well as in pain modulation. The present study was conducted to test the difference between these two hypothalamic nuclei regarding defensive and antinociceptive mechanisms. Thus, the GABA A antagonist bicuculline (40 ng/0.2 µL) or saline (0.9% NaCl) was microinjected into the dorsomedial or posterior hypothalamus in independent groups. Innate fear-induced responses characterized by defensive attention, defensive immobility and elaborate escape behavior were evoked by hypothalamic blockade of GABA A receptors. Fear-induced defensive behavior organized by the posterior hypothalamus was more intense than that organized by dorsomedial hypothalamic nuclei. Escape behavior elicited by GABA A receptor blockade in both the dorsomedial and posterior hypothalamus was followed by an increase in nociceptive threshold. Interestingly, there was no difference in the intensity or in the duration of fear-induced antinociception shown by each hypothalamic division presently investigated. The present study showed that GABAergic dysfunction in nuclei of both the dorsomedial and posterior hypothalamus elicit panic attack-like defensive responses followed by fear-induced antinociception, although the innate fear-induced behavior originates differently in the posterior hypothalamus in comparison to the activity of medial hypothalamic subdivisions.

Genetics.

The present state of knowledge on the genetics of anxiety disorders, in particular panic disorder, comprising clinical and molecular genetic studies, interaction analyses, as well as meta-analyses of single association studies will be presented in detail. A particular focus will be on the most robust findings in panic disorder to date in the serotonergic, noradrenergic, and dopaminergic system, such as the catechol-O-methyltransferase (COMT) gene. Additionally, findings on the adenosine receptor 2A (A2A) gene, which has been reported to be associated with panic disorder and also with anxiety levels after caffeine administration in a gene--environment interactional model, will be discussed. Furthermore, the first imaging genetic findings in panic disorder, social phobia, and anxiety-related traits using fMRI and PET techniques in combination with molecular genetic association analyses are reviewed, taking into account the present intermediate phenotype discussion in the investigation of complex genetic disorders. Finally, the first exemplary pharmacogenetic studies in panic disorder and generalized social phobia will be presented. The pathomechanism of anxiety disorders and in particular panic disorder is considered to be multifactorial with converging evidence for a pivotal role of genetic factors in particular, which will be presented in detail in this chapter.

A striking pattern of cortisol non-responsiveness to psychosocial stress in patients with panic disorder with concurrent normal cortisol awakening responses.

BACKGROUND: Subtle and inconsistent differences in hypothalamic-pituitary-adrenal (HPA) axis activity have been reported for patients with panic disorder. While these patients show little or no alterations in basal ACTH and cortisol levels, it has been hypothesized that HPA hyperresponsivity was a trait in panic patients when exposed to novel and uncontrollable stimulation. METHODS: Thirty-four patients (23 females, mean age 35 yrs) diagnosed with panic disorder were compared to 34 healthy controls matched for age, gender, smoking status, and use of oral contraceptives. Both groups were exposed twice to a potent laboratory stress protocol, the Trier Social Stress Test (TSST) on consecutive days. Free salivary cortisol levels and heart rate responses were repeatedly measured before and following the TSST. In addition, the cortisol awakening response (CAR) was assessed to further investigate HPA reactivity in PD patients. RESULTS: While the TSST induced similar heart rate stress responses in both groups, cortisol responses were clearly absent in the panic patients with normal responses in the controls (F(1.96, 66)=20.16; p<0.001). No differences in basal cortisol levels were observed in the extended baseline period. The same cortisol stress non-response patterns were observed when patients with/without comorbid depression, or with/without psychotropic medication were compared. In contrast to their non-response to the psychosocial stressor, panic patients showed a significant CAR. CONCLUSION: These findings provide strong evidence to suggest that PD patients present with a striking lack of cortisol responsivity to acute uncontrollable psychosocial stress under laboratory conditions. This unresponsiveness of the HPA axis appears to be rather specific, since a normal CAR in the morning could be documented in these patients. Thus, the present results do not support the hypothesis that PD patients show a trait HPA hyperresponsiveness to novel and uncontrollable stimulation. In contrast, the data provide support for a hyporesponsive HPA axis under emotional stress in PD patients.

Acid-sensing by the T cell death-associated gene 8 (TDAG8) receptor cloned from rat brain.

The T cell death-associated gene 8 (TDAG8) is a pH-sensing GPCR with a reported immune-specific expression profile. Here, we demonstrate pH-induced activation of TDAG8 receptor cloned from rodent brain (rTDAG8). Cloned rTDAG8 transcript showed 88-95% homology with human and mouse transcripts of lymphoid origin. RT-PCR revealed high expression of TDAG8 in forebrain limbic regions. Extracellular acidification induced significantly elevated intracellular cyclic AMP, and phosphorylated CREB in TDAG8 expressing cells. Acidification-induced LDH release was significantly attenuated in cells expressing TDAG8, suggesting neuroprotective potential against acidosis-related cell injury. Our results open up new areas of investigation into the relevance of TDAG8 in pH homeostasis and pathological states associated with acid-base dys-regulation in the brain such as ischemia and panic disorder.

beta-adrenoceptor affinity as a biological predictor of treatment response to paroxetine in patients with acute panic disorder.

BACKGROUND: Few studies have reported on the functional differences of the beta-adrenoceptor between treatment responders and non-responders in panic disorder (PD). The aim of this study was to compare the nature of the beta-adrenoceptor function and clinical variables between treatment responders and non-responders to paroxetine treatment in acute PD patients. METHOD: Paroxetine was administered to all of the panic patients for 12 weeks. The lymphocyte beta-adrenoceptor density (Bmax), affinity (1/Kd), and sensitivity (cAMP ratio) were measured in 22 untreated outpatients with acute PD and 22 age, sex and BMI matched control subjects. Psychological assessments were conducted using the HAM-A, and HAM-D, STAI-S and STAI-T, Anxiety sensitivity index (ASI), and Acute panic inventory (API). RESULTS: A significantly higher Kd was observed in the panic patients before treatment as compared with the control subjects, but there was no significant difference in Kd between the panic patients and control subjects after the treatment. Among the 22 patients, the 11 treatment responders (50%) showed a significantly higher Kd and lower mean scores of HAM-D, STAI-S, STAI-T, and ASI at baseline, compared with the non-responders. Logistic regression revealed that the pretreatment Kd and HAM-D were significantly reliable predictors for treatment response (p<0.05). CONCLUSION: The beta-adrenoceptor affinity (1/Kd) was decreased and adaptively normalized after treatment with paroxetine in the acute panic patients. In addition, a low pretreatment beta-adrenoceptor affinity (1/Kd) was found to predict the treatment response and can be suggested as a biological predictor of treatment response in acute PD.

Neuropeptide S: anatomy, pharmacology, genetics and physiological functions.

Neuropeptide S (NPS) is one of the most recent examples of a neurotransmitter identified by the orphan receptor strategy. Impressive progress has been made in the short time since its identification to determine physiological functions modulated by NPS. The anatomical distribution of NPS and its receptor, NPSR, suggests possible functions in the regulation of vigilance states and modulation of emotional behaviors. Early studies provided evidence that NPS induces behavioral arousal and promotes wakefulness by suppressing all stages of sleep. NPS was also found to produce anxiolytic-like effects in behavioral paradigms that measure fear or responses to novelty. Recent studies have demonstrated that NPS can modulate energy and endocrine homeostasis. Differential regulation of NPS and NPSR transcripts was observed after caffeine or nicotine treatment, indicating complex interactions with adenosine and cholinergic systems. NPS has been found co-localized with other excitatory transmitters such as glutamate, acetylcholine, or corticotropine-releasing factor. Activation of NPSR triggers mobilization of intracellular Ca2+ and stimulation of cAMP synthesis, therefore increasing cellular excitability. A functional polymorphism in NPSR has been identified that produces a gain-of-function phenotype by increasing agonist potency up to tenfold. Finally, a gender-specific association of this NPSR polymorphism with panic disorder was found in male patients, indicating that the NPS system might be involved in modulating anxiety responses in humans. Further studies about interactions of the NPS system with other transmitter systems might help to discover additional functions of NPS and define its role within complex neural networks.

Ansiedade, pânico e o eixo hipotálamo-pituitária-adrenal / Anxiety, panic and the hypothalamic-pituitary-adrenal axis

OBJETIVO: Este artigo discute a ativação diferencial do eixo hipotálamo-pituitária-adrenal no transtorno de ansiedade generalizada e no transtorno de pânico. MÉTODO: Resultados de recentes revisões da literatura são resumidos e discutidos. RESULTADOS: Os resultados de estudos experimentais que dosaram o hormônio adrenocorticotrópico, o cortisol e a prolactina mostram que ataques de pânico naturais, bem como os provocados por agentes panicogênicos seletivos - como lactato de sódio e dióxido de carbono -, não ativam o eixo hipotálamo-pituitária-adrenal. Agonistas do receptor de colecistocinina do tipo B, como o peptídeo colecistocinina-4 e a pentagastrina, elevam os hormônios de estresse, independentemente da ocorrência de um ataque de pânico, parecendo ativar diretamente o eixo hipotálamo-pituitária-adrenal. O antagonista benzodiazepínico flumazenil não eleva o nível dos hormônios de estresse; porém, este agente farmacológico não induz ataques de pânico de modo consistente. Agentes farmacológicos que aumentam a ansiedade em pacientes de pânico (cafeína, ioimbina, agonistas serotonérgicos), assim como em pessoas saudáveis, elevam o nível dos hormônios de estresse. CONCLUSÕES: Além das diferenças na sintomatologia e na resposta farmacológica, o transtorno de ansiedade generalizada e o transtorno de pânico afetam os hormônios de estresse de modo distinto. Enquanto a ansiedade antecipatória e o transtorno de ansiedade generalizada ativam tanto o eixo hipotálamo-pituitária-adrenal como o simpático-adrenal, o ataque de pânico causa acentuada ativação simpática; porém, afeta pouco o eixo hipotálamo-pituitária-adrenal.

OBJECTIVE: This article focuses on the differential activation of the hypothalamic-pituitary-adrenal axis in generalized anxiety disorder and panic disorder. METHOD: The results of recently reported reviews of the literature are summarized and discussed. RESULTS: The results of experimental studies that assayed adrenocorticotropic hormone, cortisol and prolactin show that real-life panic attacks, as well as those induced by selective panicogenic agents such as lactate and carbon dioxide, do not activate the hypothalamic-pituitary-adrenal axis. Agonists of the cholecystokinin receptor B such as the cholecystokinin-4 peptide and pentagastrin increase stress hormones regardless of the occurrence of a panic attack and, thus, seem to activate the hypothalamic-pituitary-adrenal axis directly. The benzodiazepine antagonist flumazenil does not increase stress hormones, but this agent does not reliably induce panic attacks. Pharmacological agents that increase anxiety in both normal people and panic patients (caffeine, yohimbine, serotonergic agonists) raise stress hormone levels. CONCLUSIONS: In addition to the differences in symptomatology and pharmacological response, generalized anxiety disorder and panic disorder affect stress hormones in distinct ways. While anticipatory anxiety and generalized anxiety disorder activate both the hypothalamic-pituitary-adrenal and the sympathoadrenal axes, panic attack causes major sympathetic activation, but has little effect on the hypothalamic-pituitary-adrenal axis.

Differential responses to anxiogenic drugs in a mouse model of panic disorder as revealed by Fos immunocytochemistry in specific areas of the fear circuitry.

Sensitivity to pharmacological challenges has been reported in patients with panic disorder. We have previously validated transgenic mice overexpressing the neurotrophin-3 (NT-3) receptor, TrkC (TgNTRK3), as an engineered murine model of panic disorder. We could determine that TgNTRK3 mice presented increased cellularity in brain regions, such as the locus ceruleus, that are important neural substrates for the expression of anxiety in severe anxiety states. Here, we investigated the sensitivity to induce anxiety and panic-related symptoms by sodium lactate and the effects of various drugs (the alpha2-adrenoceptor antagonist, yohimbine and the adenosine antagonist, caffeine), in TgNTRK3 mice. We found enhanced panicogenic sensitivity to sodium lactate and an increased intensity and a differential pattern of Fos expression after the administration of yohimbine or caffeine in TgNTRK3. Our findings validate the relevance of the NT-3/TrkC system to pathological anxiety and raise the possibility that a specific set of fear-related pathways involved in the processing of anxiety-related information may be differentially activated in panic disorder.

Withdrawal from progesterone increases expression of alpha4, beta1, and delta GABA(A) receptor subunits in neurons in the periaqueductal gray matter in female Wistar rats.

Premenstrual dysphoric disorder (PMDD) shows comorbidity with other psychiatric conditions such as panic disorder (PD). The symptoms of both conditions are exacerbated during the late luteal phase of the menstrual cycle, when progesterone levels fall sharply. The present study investigated the effect of withdrawal from progesterone (PWD) on expression of alpha4, beta1, and delta GABA(A) receptor subunits in neurons within the panic circuitry of the midbrain periaqueductal gray matter (PAG) in adult female Wistar rats. Immunostaining for alpha4, beta1, and delta GABA(A) receptor subunits was present in neurons throughout the PAG in vehicle-treated animals (VEH), in rats after 24 hours withdrawal from a progesterone dosing regime (PWD, 5 mg kg(-1) i.p. twice daily for 6 days), and in animals maintained on progesterone for 7 days (HP). Compared to HP and VEH animals, which did not differ significantly from each other, the number of immunostained neurons present in the PAG of PWD rats was significantly higher. The effect was most pronounced in the dorsolateral column of the PAG. The parallel changes in the three GABA(A) receptor subunits suggests that falling progesterone levels may be associated with expression of new receptors of the alpha4beta1delta subtype. This could lead to functional changes in GABAergic transmission within the PAG. We suggest that changes in GABA(A) receptor-mediated inhibitory tone in the PAG consequent to withdrawal from progesterone may contribute to the increased anxiety and susceptibility to panic seen during the late luteal phase of the menstrual cycle in PMDD and PD patients.

Serotonina, matéria cinzenta periaquedutal e transtorno do pânico / Serotonin, periaqueductal gray matter and panic disorder

Este artigo é uma revisäo de evidências experimentais e construtos teóricos que implicam a modulaçäo do comportamento de defesa pela serotonina (5-HT), atuando na matéria cinzenta periaquedutal do mesencéfalo (MCP) no transtorno do pânico. Resultados obtidos com testes de conflito em animais de laboratório indicam que a 5-HT aumenta a ansiedade, enquanto que a estimulaçäo aversiva da MCP aponta para um papel ansiolítico. Para resolver esta contradiçäo, sugeriu-se que os estados emocionais determinados pelos dois paradigmas säo diferentes. Testes de conflito gerariam ansiedade antecipatória, enquanto que a estimulaçäo da MCP produziria medo de perigo iminente. Clinicamente, o primeiro estado estaria relacionado com o transtorno de ansiedade generalizada e o segundo, com o transtorno do pânico. Assim sendo, supöe-se que a 5-HT facilita a ansiedade, porém inibe o pânico. Esta hipótese tem sido testada por meio de um modelo animal de ansiedade e pânico, denominado labirinto em T-elevado, e de dois procedimentos experimentais que geram ansiedade, aplicados tanto em voluntários sadios como em pacientes de pânico. Em geral, os resultados obtidos até agora mostram que drogas que aumentam a açäo da 5-HT elevam diferentes índices de ansiedade, enquanto reduzem índices de pânico. Portanto, as prediçöes baseadas na hipótese em questäo têm se cumprido. As principais implicaçöes clínicas säo as de que um déficit de 5-HT na MCP possa participar da fisiopatogenia do transtorno de pânico e que a intensificaçäo da 5-HT na mesma regiäo medeie a açäo antipânico dos medicamentos antidepressivos