Stress-induced Sympathetic Activation Research Articles

Harnessing adrenergic blockade in stress-promoted TNBC in vitro and solid tumor in vivo: disrupting HIF-1α and GSK-3β/β-catenin driven resistance to doxorubicin.

Sympathetic activation triggered by chronic stress afflicting cancer survivors is an emerging modulator of tumorigenesis. Adrenergic blockade was previously associated with improving response to doxorubicin (DOX) in triple-negative breast cancer (TNBC), yet the precise underlying mechanisms remain obscure. The resilience of cancer stem cells (CSCs) during chemotherapy fosters resistance and relapse. Hypoxia-inducible factor-1α (HIF-1α) and β-catenin are intertwined transcriptional factors that enrich CSCs and evidence suggests that their expression could be modulated by systemic adrenergic signals. Herein, we aimed to explore the impact of adrenoreceptor blockade using carvedilol (CAR) on DOX and its potential to modulate CSCs overcoming chemoresistance. To achieve this aim, in vitro studies were conducted using adrenaline-preincubated MDA-MB-231 cells and in vivo studies using a chronic restraint stress-promoted solid tumor mouse model. Results revealed that adrenaline increased TNBC proliferation and induced a phenotypic switch reminiscent of CSCs, as evidenced by enhanced mammosphere formation. These results paralleled an increase in aldehyde dehydrogenase-1 (ALDH-1) and Nanog expression levels as well as HIF-1α and β-catenin upsurge. In vivo, larger tumor volumes were observed in mice under chronic stress compared to their unstressed counterparts. Adrenergic blockade using CAR, however, enhanced the impact DOX had on halting TNBC cell proliferation and tumor growth via enhanced apoptosis. CAR also curbed HIF-1α and β-catenin tumor levels subsequently suppressing ALDH-1 and SOX2. Our study unveils a central role for HIF-1α linking stress-induced sympathetic activation fueling CSC enrichment via the β-catenin pathway. It also highlights novel insights into CAR's capacity in reversing DOX chemoresistance in TNBC.

Yokukansan, a Traditional Japanese Medicine, Suppresses Stress-Induced Sympathetic Activation via Central Responses in Rats

Objectives: Yokukansan (YKS) is a traditional Japanese Kampo medicine approved by the Ministry of Health, Labour and Welfare of Japan. Recently, in addition to its indications as a drug treatment, YKS has been shown to have ameliorative effects on various psychological and behavioral responses such as anxiety, aggression, and stress responses. Stress exposure activates not only the hypothalamic–pituitary–adrenal axis but also the sympathetic nervous system. Sympathetic activation in brain regions such as the paraventricular hypothalamic nucleus (PVN) stimulates elevation of plasma catecholamine (noradrenaline and adrenaline) levels. We previously reported that various stress-related neuropeptides and several kinds of stressors, such as restraint stress (RS), increase plasma catecholamine and that brain prostanoids and their synthases mediate these responses in rats. In the present study, to determine if YKS treatment can affect stress-induced sympathetic activation, we examined the effects of YKS treatment on the RS-induced elevation of plasma catecholamine levels and related prostanoid production in the PVN of rats. Methods: YKS (1000 mg/10 mL/kg, p.o.) or vehicle was administered to rats daily for 14 days, and all rats were exposed to RS for 60 min on day 14. Before and during stress exposure on day 14, blood samples and PVN dialysates were collected and analyzed by high-performance liquid chromatography and liquid chromatography-ion trap tandem mass spectrometry, respectively. Results: Our results showed that repeated administration of YKS suppressed the RS-induced increase in plasma adrenaline but not noradrenaline. Furthermore, YKS administration also suppressed the RS-induced elevation of both prostaglandin E2 and thromboxane B2 levels in the PVN. In addition, we found that repeated administration of YKS suppressed the RS-induced increase in serotonin, gamma-aminobutyric acid, and acetylcholine in the PVN. Conclusion: Our results suggest that YKS can ameliorate stress-induced sympathetic activation via inhibition of stress responses in the brain.

Measurement of stress-induced sympathetic nervous activity using multi-wavelength PPG

The onset of stress triggers sympathetic arousal (SA), which causes detectable changes to physiological parameters such as heart rate, blood pressure, dilation of the pupils and sweat release. The objective quantification of SA has tremendous potential to prevent and manage psychological disorders. Photoplethysmography (PPG), a non-invasive method to measure skin blood flow changes, has been used to estimate SA indirectly. However, the impact of various wavelengths of the PPG signal has not been investigated for estimating SA. In this study, we explore the feasibility of using various statistical and nonlinear features derived from peak-to-peak (AC) values of PPG signals of different wavelengths (green, blue, infrared and red) to estimate stress-induced changes in SA and compare their performances. The impact of two physical stressors: and Hand Grip are studied on 32 healthy individuals. Linear (Mean, s.d.) and nonlinear (Katz, Petrosian, Higuchi, SampEn, TotalSampEn) features are extracted from the PPG signal’s AC amplitudes to identify the onset, continuation and recovery phases of those stressors. The results show that the nonlinear features are the most promising in detecting stress-induced sympathetic activity. TotalSampEn feature was capable of detecting stress-induced changes in SA for all wavelengths, whereas other features (Petrosian, AvgSampEn) are significant (AUC ≥ 0.8) only for IR and Red wavelengths. The outcomes of this study can be used to make device design decisions as well as develop stress detection algorithms.

Sympathetic and blood pressure reactivity to acute stress in young adults with major depressive disorder: the influence of depressive symptomatology

Major depressive disorder (MDD) is episodic in nature, highly recurrent, and associated with increased cardiovascular disease (CVD) risk. Sympathetic overactivation in response to acute stress may contribute to MDD-CVD comorbidity. However, few studies have investigated acute sympathetic stress reactivity in young adults with MDD or considered the potential influence of depressive symptom severity on these responses. We hypothesized that 1) acute stress-induced increases in muscle sympathetic nerve activity (MSNA) and blood pressure (BP) would be greater in young adults with MDD (unmedicated) compared to healthy non-depressed adults (HA) and 2) the magnitude of responsiveness would be graded in relation to symptom severity. Twenty-nine HA (22±5 yrs; 17 female) and 40 adults with MDD having mild-to-moderately severe depressive symptoms (23±6 yrs; 32 female) participated. Adults with MDD were also subclassified as having either low (l-MDD, n=25) or high symptom severity (h-MDD, n=15). MSNA (microneurography) and beat-to-beat BP (photoplethysmography) were measured at rest and during the cold pressor test (CPT) and the Stroop color word test (SCWT). There were no group differences in either resting MSNA (17±9 HA vs. 14±6 bursts/min MDD, p=0.39) or mean arterial pressure (MAP; 86±6 HA vs. 84±5 mmHg MDD, p=0.25). The CPT elicited increases in MSNA and MAP (both p<0.01), but the magnitude was not different between groups (MSNA: Δ24±12 HA vs. Δ19±9 bursts/min MDD, p=0.22; MAP: Δ24±8 HA vs. Δ23±9 mmHg MDD, p=0.45). The SCWT also elicited increases in MAP (p<0.01) that were not different between groups (Δ10±7 HA vs Δ10±6 mmHg MDD; p=0.76). Surprisingly, the SCWT failed to cause increases in MSNA (p>0.05), which also did not differ between groups (Δ-2±7 HA vs. Δ-2±8 bursts/min MDD, p=0.92). When further classifying adults with MDD into symptom severity subgroups, there likewise were no differences in MSNA reactivity to either acute stressor (both p>0.05). Interestingly, adults with h-MDD exhibited greater increases in MAP than adults with l-MDD during the CPT (Δ28±9 h-MDD vs. Δ20±8 mmHg l-MDD, p<0.01) but not during the SCWT (Δ9±4 h-MDD vs. Δ11±7 mmHg l-MDD, p=0.63). Contrary to our hypothesis, these data demonstrate that neither acute stress-induced sympathetic activation nor the ensuing increase in BP are exaggerated in young adults with MDD. However, the severity of active depressive symptomatology may influence BP reactivity to generalized stress stimuli, thereby influencing CVD risk profiles. NIH R21MH123928 and R00 HL133414 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Isoproterenol-induced Upregulation of HPSE Accelerates Triple-negative Breast Cancer Cell Proliferation and Migration through Enhancing the Transcriptional Activity of HIF-1α.

Triple-negative breast cancer (TNBC) is considered to be the most malignant subtype of breast cancer (BC). Heparanase (HPSE) has been reported to contribute to tumor development, but its potential function in TNBC is not clear. The intention of this study was to investigate whether HPSE affects TNBC progression and to explore the possible mechanisms. Bioinformatics analyses were applied to analyze the expression of HPSE in TNBC samples and normal breast samples. The mRNA and protein levels of HPSE in TNBC cells were detected by RT-qPCR and western blot. Function assays, including CCK-8 assay, colony formation assay, transwell assay and wound healing assay, were conducted to validate the effects of HPSE silencing on TNBC cell proliferation and migration. Mechanism experiments were performed to explore the upstream molecular mechanism of HPSE in TNBC cells. Silencing of HPSE suppressed the proliferation and migration of TNBC cells. Moreover, hypoxia-inducible factor-1 alpha (HIF-1α) interacted with the HPSE promoter and promoted the transcription of HPSE. Isoproterenol (ISO), a pharmacological substitute for chronic stress-induced sympathetic activation, was proven to induce HIF-1α upregulation, so as to transcriptionally activate HPSE in TNBC cells. Furthermore, it manifested that ISO facilitated TNBC cell proliferation and migration in an HPSE-dependent way. HPSE activated by ISO-induced HIF-1α promoted TNBC cell proliferation and migration, which might offer a novel insight for TNBC treatment.

Cortical-Hypothalamic Integration of Autonomic and Endocrine Stress Responses.

The prevalence and severity of cardiovascular disease (CVD) are exacerbated by chronic stress exposure. While stress-induced sympathetic activity and elevated glucocorticoid secretion impair cardiovascular health, the mechanisms by which stress-responsive brain regions integrate autonomic and endocrine stress responses remain unclear. This review covers emerging literature on how specific cortical and hypothalamic nuclei regulate cardiovascular and neuroendocrine stress responses. We will also discuss the current understanding of the cellular and circuit mechanisms mediating physiological stress responses. Altogether, the reviewed literature highlights the current state of stress integration research, as well unanswered questions about the brain basis of CVD risk.

Yokukansan, a traditional Japanese medicine, suppresses stress-induced sympathetic activation and central responses to stress in rats

Stress exposure activates the sympathetic nervous system. We previously reported that restraint stress and stress-related neuropeptides increases plasma catecholamine levels and that brain prostanoids medicate these responses in rats. Yokukansan (YKS), a traditional Japanese medicine, has been used for neurosis, night crying and irritability. Additionally, it has been reported that YKS is also effective against the behavioral and psychological symptoms of dementia in patients with Alzheimer's disease, stress-related anxiety-like behavior and stress-induced increase in plasma corticosterone in rodents. These previous findings raise the possibility that YKS can exert its action in the brain and has suppressive effects on stress responses. In this study, we examined effects of YKS on stress-induced sympathetic activation and stress responses in the brain using rats. Repeated administration with YKS suppressed stress-induced increase in plasma adrenaline level. YKS also suppressed stress-induced elevation of prostaglandin E2 and thromboxane B2 levels in the paraventricular hypothalamic nucleus (PVN). In addition, YKS suppressed stress-induced increases of acetylcholine, GABA and serotonin in the PVN. Our results suggest that YKS can ameliorate stress-induced sympathetic activation via inhibition of stress responses in the brain.

Astrocytes in the PVN are involved in corticotropin-releasing factor-induced sympathetic activation in rats

Corticotropin-releasing factor (CRF) plays a key role in stress responses in the brain. CRF activates not only the hypothalamic-pituitary-adrenal axis but also the sympathetic nervous system. We previously reported that both central administration of CRF and exposure to acute restraint stress (RS) increase plasma catecholamine levels and activate presympathetic neurons in the paraventricular hypothalamic nucleus (PVN). However, it is unclear whether glial cells in brain regions including the PVN are involved in CRF- or stress-induced sympathetic activation. In this study, we examined roles of astrocytes in the CRF-induced elevation of plasmas catecholamine levels (noradrenaline and adrenaline) using fluorocitrate which blocks glial metabolic function. Intracerebroventricular pretreatment of fluorocitrate suppressed the CRF-induced elevation of plasma levels of noradrenaline and adrenaline. On the other hand, microinjection of fluorocitrate into the PVN suppressed the CRF-induced elevation of adrenaline, but not of noradrenaline. Furthermore, we tried to examine effects of inhibition of astrocytes on RS-induced sympathetic activation. Our results suggest that astrocytic function in the brain is important for the CRF-induced sympathetic activation and the effects might be brain region-dependent.

Stress-induced sympathetic activity and the retinal vasculature: The SABPA prospective study

ObjectivesRetinal vessels are part of the intracranial vasculature and analysis thereof complements behavioural and brain measures. Mental stress was related to downregulation of norepinephrine in Africans. Hence we continue by assessing prospective associations between sympathetic nervous system activity and retinal vessel calibres.MethodsBlack and Caucasian participants (n = 275; 45 ± 9 years) were stratified into tertiles according norepinephrine:creatinine (NE:Cr) ratio at baseline. Three year prospective % changes (Δ) for depression (PHQ-9), urinary NE:Cr, serum cortisol and High-Density-Lipoprotein (HDL, neuronal-membrane-integrity and ischemic stroke risk marker) were obtained. At 3yr-follow-up, retinal microvascular calibres were quantified from digital images in the mydriatic eye and salivary cortisol (sC) and α-amylase (sAA), adrenergic activity marker were obtained.ResultsOnly the low NE:Cr-tertile group (44% Black; 64% Men), showed chronic depression and hypertension prevalence. Over 3yrs, their NE:Cr increased whereas cortisol and HDL decreased. At 3yr-follow-up, wider venules (stroke risk marker) were apparent in the low- compared to the high-tertile group (Figure 1). In the low-tertile group, chronic depression was associated with stroke risk markers, wider venules [OR 1.7; P = 0.03] and lower HDL [OR 4.8; P = 0.04]. In this group, arteriole narrowing was associated with ΔNE:Cr, Δcortisol and sAA; whilst a wider venule was associated with ΔNE:Cr and sC.ConclusionsIn reaction to depression and low NE:Cr levels, homeostatic reflexes facilitated upregulation of norepinephrine and concurrent downregulation of cortisol. Stress-induced sympathetic nervous system activity however disturbed myogenic tone, neuronal-membrane-integrity and retinal venular widening; increasing the susceptibility for ischemic stroke.Figure 1Comparing (mean ± SE) sympathetic activity marker changes (Δ%) over 3 years and retinal vessel diameters at follow-up in low vs. high norepinephrine creatinine tertiles. Confounders included: age; log gamma glulamyl transferase; high density lipoprotein cholesterol; diastolic ocular perfusion pressure and retinopathy *P ≤ 0.05; **P ≤ 0.001

Psychophysiological evaluation of patients with transient consciousness loss of uncertain origin

Psychological profile (PsyP) of patients with transient loss of consciousness (TLoC) is evidence of high prevalence of anxiety and depression. However, the mechanistic link between abnormal PsyP and TLoC is still unclear. This study aimed to evaluate: 1) prevalence of abnormal PsyP in TLoC patients; 2) cardiac autonomic response to head-up tilt test (HUTT) in patients with (PsyP+) or without abnormal PsyP (PsyP-), developing syncope (HUTT+) or not (HUTT-). Forty-one patients (66% female, mean age 36 ± 15 years), with history of TLoC, underwent PsyP before HUTT. Short-term heart rate variability analysis was carried out under baseline rest condition and at peak heart rate and/or onset of syncope induced by nitroglycerine (NTG), during HUTT. HUTT+ occurred in 17/41 patients, more frequently in females, who had higher levels of anxiety (p < 0.0001). PsyP+ was prevalent in 70.5% of HUTT+ patients (p < 0.05). Among PsyP+ patients HUTT+ had dominant sympathetic modulation (DSM) at rest, which increased at the onset of syncope, whereas in HUTT patients vagal modulation was prevalent at rest. Among NTG-induced HUTT+ patients, fourfold higher increases of very low frequency (VLF) power were found in PsyP- compared with PsyP+. 58% of patients with history of TLoC were PsyP+. In PsyP+ patients, DSM at rest correlates with higher prob-ability of NTG-induced syncope, which occurs with 60% increment of low frequency and 530% increment of VLF power. Conversely, in patients with prevalent vagal modulation at rest and a decrease in VLF power after NTG, syncope did not occur. This supports interpretation of VLF power as an index of stress-induced sympathetic activity.

Parasympathetic activation enhanced by slow respiration modulates early auditory sensory gating.

Sensory gating is a preattentional mechanism to filter irrelevant information from the environment. It is typically reflected as a suppression of the event-related P50 component for successive sounds in the auditory modality. Although stress-induced sympathetic activation has been reported to disrupt P50 suppression, little is known about the modulatory effect of parasympathetic activation on early auditory sensory gating. We determined the parasympathetic effect on the magnetic P50 (P50m) suppression by controlling the respiratory rhythm and recording data simultaneously with magnetoencephalography and electrocardiography, using three successive click sounds as stimulus and ten normal individuals as study participants. The respiratory rhythm was guided by visual cues and set at 0.3, 0.25, or 0.2 Hz for distinct auditory stimulus sequence blocks. Heart rate variability analysis showed that slow respiration leads to significantly large high-frequency power, which is known as the parasympathetic index, whereas low-frequency/high-frequency ratio, known as the sympathetic index, did not differ with the respiratory rhythm. Although P50m suppression was observed in the left and right primary auditory areas for every respiratory condition, the left P50m intensity for the first sound was significantly decreased in the case of slow respiration, thereby indicating disruption of the left P50m suppression. Since background alpha oscillatory power, reflecting the arousal level, was similar for every respiratory rhythm, it is concluded that parasympathetic activation enhanced by slow respiration modulates P50m gating by reducing the initial neural sensitivity for an auditory input. Not only sympathetic but also parasympathetic effects should be considered in the evaluation of P50/P50m biomarkers.

Effects of cold-pressor and mental arithmetic on pupillary light reflex

Dynamic pupillary light reflex (PLR) is a simple neurological test that can be useful for assessment of autonomic disorders. In this study, we investigated the changes in PLR induced by mental arithmetic task and cold pressor trials which are often applied in research as model systems to elicit autonomic responses. PLR was recorded before, during and after mental arithmetic and cold pressor tasks in 20 healthy adults (ten males and ten females). Stress-induced sympathetic activation was evident as shown in the increased blood pressure during both tasks. Although the pupillary constriction amplitude did not show significant changes, both constriction time and redilation time changed during the tasks. A significant gender effect was observed in cold pressor that suggested more sympathetic activation in males and faster parasympathetic activation in females in response to light stimulation under cold pressor.

Transient β2-Adrenoceptor Activation Confers Pregnancy Loss by Disrupting Embryo Spacing at Implantation

Pregnancy loss is a serious social and medical issue, with one important cause associated with aberrant embryo implantation during early pregnancy. However, whether and how the process of embryo implantation is affected by environmental factors such as stress-induced sympathetic activation remained elusive. Here we report an unexpected, transient effect of β2-adrenoreceptor (β2-AR) activation (day 4 postcoitus) in disrupting embryo spacing at implantation, leading to substantially increased midterm pregnancy loss. The abnormal embryo spacing could be prevented by pretreatment of β2-AR antagonist or genetic ablation of β-AR. Similar β2-AR activation at day 5 postcoitus, when implantation sites have been established, did not affect embryo spacing or pregnancy outcome, indicating that the adverse effect of β2-AR activation is limited to the preimplantation period before embryo attachment. In vitro and in vivo studies demonstrated that the transient β2-AR activation abolished normal preimplantation uterine contractility without adversely affecting blastocyst quality. The contractility inhibition is mediated by activation of the cAMP-PKA pathway and accompanied by specific down-regulation of lpa3, a gene previously found to be critical for uterine contraction and embryo spacing. These results indicated that normal uterine contraction-mediated correct intrauterine embryo distribution is crucial for successful ongoing pregnancy. Abnormal β2-AR activation at early pregnancy provided a molecular clue in explaining how maternal stress at early stages could adversely affect the pregnancy outcome.

Cyclooxygenase and nitric oxide synthase in the presympathetic neurons in the paraventricular hypothalamic nucleus are involved in restraint stress-induced sympathetic activation in rats

Stress is one of the important factors to activate the sympathetic nervous system. We recently reported that central administration of corticotropin-releasing factor (CRF), known as a stress-related neuropeptide, increases the expression of both cyclooxygenase (COX) and nitric oxide synthase (NOS) in presympathetic neurons in the paraventricular hypothalamic nucleus (PVN). In the present study, therefore, we investigated whether brain COX and NOS can also mediate restraint stress (RS)-induced sympathetic activation by assessing the plasma catecholamine levels and neuronal activation of presympathetic neurons in the PVN. In addition, we examined effects of RS on the expression of both COX and NOS isozymes in the presympathetic PVN neurons. Intraperitoneal administration of an inhibitor for COX-1, COX-2 or inducible NOS (iNOS), but not for neuronal NOS (nNOS), reduced RS-induced elevation of plasma catecholamine levels and Fos expression in the presympathetic PVN neurons. Moreover, RS increased the expression of COX-1, COX-2 and iNOS in the presympathetic PVN neurons, whereas nNOS expression did not change. These results suggest that COX-1, COX-2 and iNOS in the presympathetic PVN neurons mediate acute RS-induced sympathetic activation.

Turo (Qi Dance) Training Attenuates Psychological Symptoms and Sympathetic Activation Induced by Mental Stress in Healthy Women

Vagal withdrawal and sympathetic overactivity accompany various types of stress. Qi training is reported to reduce sympathetic hyper-reactivity in a stressful situation. Turo, which is a type of dance that uses the Meridian Qi System, may reduce the psychological symptoms induced by an imbalance of the autonomic nervous system (ANS). We observed whether Turo training alters psychopathological and psychological symptoms using the Symptom Checklist 90-Revision (SCL-90-R) and examined whether it attenuates the stress response to mental stress in healthy adolescent females using the power spectrum analysis of heart rate variability (HRV). Twenty-one subjects received Turo training and 27 subjects were trained with mimicking movements. The SCL-90-R was measured before and after the 2-month training period. Heart rate (HR), total power (TP) and the LF/HF ratio of HRV were compared between the Turo and control groups during and after mental stress. The somatization and hostility subscales of the SCL-90-R of the Turo group were significantly lower than those of the control group after 2 months. The increases in HR and the LF/HF ratio of HRV induced by the stress test were significantly lower in the Turo group than in the control group. The TP of the Turo group was significantly higher than that of the control group. The psychological symptoms and sympathetic activation induced by the artificial stress were significantly reduced by the Turo training. These findings suggest that Turo training can play a critical role in attenuating psychological symptoms and stress-induced sympathetic activation.

Artificial gravity training improves orthostatic tolerance in ambulatory men and women

Orthostatic intolerance (OI) continues to be a problem experienced by astronauts upon return from spaceflight. Artificial gravity (AG) training via short radius centrifugation has been suggested as a countermeasure to this OI. The purpose of our research was to determine effects of three weeks of intermittent (+1 to +2.5 G z for 35 min/day) AG exposure on normal, ambulatory men and women. The results of this study indicate that 3 weeks of AG training improved orthostatic tolerance in a group of 14 men and 12 women by an average of 13.6%. This improvement was associated with a decrease in arterial pressure and vascular resistance, and increases in stroke volume and low frequency (0.04–0.15 Hz) arterial pressure and heart rate spectral power. These results suggest that improvement may be attributable to increased venous return possibly as a function of increased stress-induced sympathetic activity and/or vascular sympathetic responsiveness.

Insulin-Induced Hypoglycemia Stimulates Gastric Vagal Activity and Motor Function without Increasing Cardiac Vagal Activity

Background/Aims: We investigated whether increasing the efferent vagal activity by insulin-induced hypoglycemia would enhance gastric emptying and volumes in healthy subjects. Methods: Twenty healthy volunteers (10 males) were examined with and without vagal stimulation by insulin-induced hypoglycemia using a glucose clamp technique. Stomach function was tested by drinking meat soup (0.04 kcal ml^–1) at a rate of 100 ml min^–1 until maximal capacity. Intragastric volume at maximal drinking capacity was determined by three-dimensional ultrasound. Respiratory sinus arrhythmia (RSA) was used as an index of cardiac vagal activity and plasma pancreatic polypeptide (PP) as a measure of gastric vagal activity, and skin conductance (SC) as a measure of sympathetic tone. Results: Insulin-induced hypoglycaemia increased drinking capacity (p = 0.002), gastric emptying (p = 0.02), PP (p = 0.004) and SC (p = 0.004), while intragastric volume was unchanged (p = 0.7) and RSA decreased (p = 0.03). Conclusion: Enhancement of gastric vagal activity by insulin-induced hypoglycemia increased drinking capacity and gastric emptying similarly, resulting in an unchanged intragastric volume. Enhanced efferent vagal activity to the stomach (as measured by PP) was not associated by enhanced cardiac vagal activity (as measured by RSA), possibly a consequence of stress-induced sympathetic activation during the procedure.

A functional subset of serotonergic neurons in the rat ventrolateral periaqueductal gray implicated in the inhibition of sympathoexcitation and panic.

The ability of serotonin (5-HT) to facilitate or attenuate autonomic, endocrine, and behavioral responses to stressful stimuli has received much attention. The effects of 5-HT on physiologic and behavioral responses to stressful stimuli seem to depend on the brain region where it is released and the effector system it acts upon. This and the distinct morphology and topographic organization of subpopulations of serotonergic neurons have led to the hypothesis that subpopulations of serotonergic neurons are functionally distinct. Serotonin's role as a modulator of the "fight-or-flight" response is mediated in part by 5-HT release in the dorsolateral periaqueductal gray (DLPAG) and in the rostral ventrolateral medulla (RVLM), an area that contains sympathoexcitatory C1 adrenergic (A) neurons. The release of 5-HT in either region inhibits stress-induced sympathetic activity in part via actions on 5-HT(1A) receptors. In addition, 5-HT release in the DLPAG inhibits fight-or-flight or "Go" behaviors. The origin of endogenous 5-HT in the DLPAG and RVLM seems to be a subpopulation of serotonergic neurons within the ventrolateral PAG, a region implicated in "freezing" or "No Go" behaviors. These serotonergic neurons are located in the lateral "wings" of the dorsal raphe nucleus (DRN) a region also referred to as the ventrolateral DRN. The existence of a functional subpopulation of serotonergic neurons capable of inhibiting sympathoexcitation and fight-or-flight behavioral responses may be clinically relevant for explaining in part the efficacy of serotonergic drugs in the treatment of hypertension and panic attacks in panic disorder patients.

Cardiovascular Reactivity and Behavioral Health

The purpose of this article is to show that cardiovascular reactivity is an important topic within the field of behavioral health. It has been demonstrated that the cardiovascular system responds differentially to stressors that encourage effortful active coping as opposed to passive coping. However, it is also well established that individuals exposed to the same stressor exhibit marked variability in their cardiovascular responses. Evidence from studies of temporal stability of individual differences to laboratory stressors support the view that cardiovascular reactivity may be considered as a psychophysiological trait. The identification of stable individual-specific patterns of exaggerated cardiovascular reactivity during psychologically challenging tasks appears to be important for understanding the development of essential hypertension. Recurrent episodes of stress-induced sympathetic activation associated with non-adaptive hemodynamic responses (non-adaptive with respect to the immediate metabolic demands), give rise to autoregulatory and structural changes in the resistive vessels. Thus, cardiovascular reactivity may be an important aspect of assessing cardiovascular disease risk. Possible application of reactivity testing in a risk-ascertainment process was discussed.

Neuroendocrine and behavioral effects of vasopressin in resting and mild stress conditions

Neuroendocrine and behavioral effects of subcutaneously administered AVP (6 μg/kg b.wt.) were determined in resting conditions and after the mild stress of transportation to and placement in a novel environment. In resting conditions, systemic administration of AVP caused a rapid increase in blood glucose level and a long-lasting increase in CORT secretion. A decrease in circulating plasma NE level was observed. AVP did not affect adrenal medullary E secretion. The stress-induced sympathetic activation, as reflected in plasma NE level, was inhibited 60 min after AVP administration. Stress-induced increases in blood glucose, CORT, and E secretion were not influenced by AVP. In resting condition, AVP caused a 60-min lasting increase in grooming behavior with a concomitant decrease in time spent resting. Sixty minutes after administration, the behavioral activation after the stress of transportation and placement in a novel environment was more rapidly terminated in AVP-treated rats than in vehicle-treated control rats. The state- and time-dependent modulation of spontaneous behavior suggests that AVP has arousing properties shortly after administration when marked pressor and endocrine effects are apparent. In a later phase, AVP may facilitate dearousal mechanisms following stress-induced behavioral activation.