Time-Dependent Effects of Buspirone versus Desipramine on the 5-Choice Serial Reaction Time Task in Rats Reared in Social Isolation: Implication of Early Life Experience and Motoric Impulsivity.

BACKGROUND: Early life social experience and the function of the central serotonin (5-Hydroxytryptophan, 5-HT) system are involved in development of behavioral impulsivity in which individuals act without forethought or before all necessary information is available. However, most of the evidence has been obtained from acute 5-HT manipulation, whereas, the present study aimed to investigate the effects of subchronic regimen targeting of 5-HT1A receptors on motoric waiting impulsivity in socially isolated rats. METHODS: A two-week protocol of buspirone (0.5 mg/kg/day) and desipramine (2.5 mg/kg/day) was employed for rats following social isolation rearing (IR) to examine their behavioral performance in a 5-choice serial reaction time task (5-CSRTT) during the treatment regimen. Responses in any one of the apertures prior to an informative signal were recorded as a premature response. RESULTS: IR rats presented with more locomotor activity than socially reared (SR) rats. Buspirone progressively increased the baseline level of premature responding in a time-dependent manner that was not observed in IR rats. Both IR and SR rats exhibited less premature responding following acute buspirone challenge. For a subchronic desipramine regimen, IR rats followed the same trend of SR controls to increase the prematurity of baseline response. CONCLUSIONS: Buspirone but not desipramine-induced time-dependent effects of motoric waiting impulsivity can be reversed by IR, indicating a role for early life social experience on 5-HT1A receptor-associated ability to control impulsiveness.

Spectral analysis of cardiovascular oscillations in the 7-day regimen of losartan administration with and without cold stress.

Spectral analysis of heart rate (HR) and blood pressure (BP) variabilities (BPV and HRV) is widely available and utilized in understanding the dynamic cardiovascular autonomic regulation in a variety of pathophysiological conditions. In conscious cold-stressed (CS) rats, we examined the effect of a 7-day regimen administration of losartan, a selective nonpeptide angiotensin AT1 receptor blockade, on BPV and HRV at three frequency components: very-low frequency (VLF), low frequency (LF), and high frequency (HF). Key findings in changes of systolic BP (SBP), HR, and spectral power densities for cardiopulmonary oscillations (HF), sympathetic oscillations (LF), cardiovascular myogenic oscillations (VLF), and overall autonomic activity total power (TP) showed: (I) In the resting PreCS trial, compared with the saline, losartan increased HFBPV, TPHRV, all three HRV frequency powers, and the occurrence of the dicrotic notch (DN). However, it decreased SBP, HR, and the LFBPV frequency power. (II) In the CS trial, losartan significantly decreased SBP and DN occurrence and HR and LF/HFHRV but significantly increased HFHRV, TPBPV, and all three BPV frequency powers. In addition, similar to the saline, losartan showed positively correlated LFBPV and VLFBPV. Conversely, losartan converted the original inverse correlations between LFHRV and LFBPV of CS to a positive correlation. (III) Compared with saline in PreCS and CS trials, losartan detached the corresponding sympathetic oscillations between LFBPV and LFHRV. The overall result indicates that endogenous angiotensin II, through stimulation of the AT1 receptor, augments sympathetic tone but attenuates sympathetic oscillations in rats, particularly under the stressful cooling impacts.

Effects of sinoaortic denervation on hemodynamic perturbations of prolonged paradoxical sleep deprivation and rapid cold stress in rats.

BACKGROUND: Sleep disturbances and aversive cold stress (CS) are cardiovascular risk factors. This study investigates how homeostatic control autonomic baroreflex influences the hemodynamic perturbations evoked by paradoxical sleep deprivation (PSD) and CS. METHODS: Conscious adult male rats were randomly divided into four groups (Sham/CON [control], Sham/PSD, sinoaortic denervation [SAD]/CON, and SAD/PSD). Spectral analysis and SAD were employed to evaluate the effects of a 72-hr PSD with 10-min CS on blood pressure variability and heart rate variability (BPV and HRV) at total power (TP) and three frequency power densities, very-low-frequency (VLF), low frequency (LF), and high frequency (HF). RESULTS: Key findings showed: (I) Compared with the control sham surgery (Sham/CON), in the natural baseline (PreCS) trial, SAD surgery (SAD/CON) causes high systolic blood pressure (SBP), heart rate (HR), increases LFBPV (low-frequency power of BPV), LF/HFHRV (the ratio LF/HF of HRV), and TPBPV (the total power of BPV), but decreases HFHRV (high-frequency power of HRV) and VLFHRV (very-low-frequency power of HRV) than the Sham/CON does. In the CS trial, SAD/CON increases the CS-induced pressor, increases the CS-elicited spectral density, LF/HFHRV, but decreases HFBPV than the Sham/CON does. (II) Compared with SAD/CON and Sham/PSD (PSD under sham surgery), in both PreCS and CS trials, SAD/PSD (PSD under SAD) causes high SBP and HR than both SAD/CON and Sham/PSD their SBP and HR. In PreCS, SAD-PSD also changes the spectral density, including increasing Sham-PSD's LFBPV, LF/HFHRV, VLFBPV, and TPBPV but decreasing Sham-PSD's VLFHRV and TPHRV. However, in CS, SAD-PSD changes the CS-elicited spectral density, including increasing Sham-PSD's VLFBPV, LF/HFHRV, and TPHRV but decreasing Sham-PSD's HFBPV and LFBPV. CONCLUSION: The results suggest baroreflex combined with other reflex pathways, such as inhibitory renorenal reflex, modulates the vascular and cardiorespiratory responses to PSD under PreCS and subsequent CS trials.

The Association between Migraine and Abdominal Aortic Aneurysms: A Nationwide Population-Based Cohort Study.

Previous studies have indicated that patients with migraine have a higher prevalence of risk factors known to be associated with cardiovascular diseases. There are also shared epidemiology and molecular mechanisms between migraine and abdominal aortic aneurysm (AAA). We hypothesized that patients with migraine could have an increased risk of AAA. To test this hypothesis, we used the National Health Insurance Research Database (NHIRD) to evaluate whether associations exist between migraine and AAA. The data for this nationwide population-based retrospective cohort study were obtained from the NHIRD in Taiwan. The assessed study outcome was the cumulative incidence of AAA in patients with migraine during a 15-year follow-up period. Among the 1,936,512 patients from the NHIRD, 53,668 (2.77%) patients were identified as having been diagnosed with migraine. The patients with migraine had a significantly higher cumulative risk of 3.558 of developing an AAA 5 years after the index date compared with the patients without migraine. At the end of the 15-year follow-up period, a significantly higher incidence of AAA (0.98%) was observed in the patients with migraine than in those without migraine (0.24%). We revealed an association between the development of migraine and AAA.

Laminar shear stress upregulates the expression of PPARs in vascular endothelial cells under high free fatty acid-induced stress.

Shear stress has been reported to result in various metabolic effects in endothelial cells (ECs), which in turn contribute to the regulation of their vascular functions. Peroxisome proliferator-activated receptors (PPARs) have been reported to regulate lipid metabolism and have been implicated in metabolic disorders. The present study assessed the effects of laminar shear stress on the expression of PPARs in ECs in the presence of high concentrations of free fatty acids (FFAs). Human aortic ECs (HAECs) were treated with a high concentrations of palmitic acid (PA) and exposed to high shear stress (HSS) or low shear stress (LSS). Western blotting and ELISA were performed to quantify protein expression and assess prostacyclin production. The results revealed that long-term application of HSS to PA-treated HAECs induced PPAR-α, -δ and -γ protein expression. Additionally, LSS induced higher levels of PPAR-α protein expression in PA-treated HAECs compared with those after HSS. HAECs exposed to HSS also released prostacyclin (PGI2). However, HAECs treated with high concentrations of PA also produced high levels of PGI2 in the perfusion media in response to HSS compared with the static PA group. HSS also reduced the static PA-induced expression of intercellular adhesion molecule-1 and monocyte chemoattractant protein-1. The results demonstrated that HAECs increases the expression of all three peroxisome proliferator-activated receptor isoforms in response to shear metabolic stress at high FFA concentrations. The present study may provide preliminary insights into the potential roles of PPARs as an effective treatment method against metabolic disturbances that can result in EC dysfunction.

Portal vein innervation underlying the pressor effect of water ingestion with and without cold stress.

Water-induced pressor response appears mediated through the activation of transient receptor potential channel TRPV4 on hepatic portal circulation in animals. We sought to elucidate the mechanism of portal vein signaling in this response. Forty-five rats were divided into four groups: control rats without water ingestion (WI), control rats with WI, portal vein denervation rats with WI (PVDWI), and TRPV4 antagonist-treated rats with WI (anti-TRPV4WI). Cardiovascular responses were monitored throughout the experiments. Data analysis was performed using descriptive methods and spectral and cross-spectral analysis of blood pressure variability (BPV) and heart rate variability (HRV). Key results showed that at baseline (PreCS) before cold stress trial (CS), WI elicited robust pressor and tachycardia responses accompanied by spectral power changes, in particular, increases of low-frequency BPV (LFBPV) and very-LFBPV (VLFBPV), but decrease of very-low-frequency HRV. PVDWI, likewise, elicited pressor and tachycardia responses accompanied by increases of high-frequency BPV, high-frequency HRV, LFBPV, low-frequency HRV, and VLFBPV. When compared with WI at PreCS, WI at CS elicited pressor and tachycardia responses accompanied by increases of high-frequency BPV, LFBPV, and VLFBPV, whereas in WI, the CS-evoked pressor response and the accompanied LFBPV and VLFBPV increases were all tended augmented by PVDWI. When compared with WI and PVDWI at both PreCS and CS, however, anti-TRPV4WI attenuated their pressor responses and attenuated their increased LFBPV, VLFBPV, and very-low-frequency HRV. The results indicate that the portal vein innervation is critical for a buffering mechanism in splanchnic sympathetic activation and water-induced pressor response.

Differential effects of sympatholytic agents on the power spectrum of rats during the cooling-induced hemodynamic perturbations.

Cold stress-elicited hemodynamic perturbations (CEHP) its underlying mechanisms still not clear. We examined the difference of two effector arms of sympathetic outflows, the sympathoadrenal system, and postganglionic sympathetic neurons, their role in CEHP genesis by using two sympatholytic agents, fusaric acid (FA, dopamine-ß-hydroxylase inhibitor) and guanethidine (GUA, norepinephrine-depleting drug). Adult male Sprague-Dawley rats were divided into three groups (n = 6, each), an intraperitoneal injection of control vehicle saline or FA or GUA and then all rats were subjected to a 10-min CS trial. Systolic blood pressure (SBP), heart rate (HR), dicrotic notch (Dn), power spectrum of blood pressure variability and HR variability (BPV, HRV), and coherence spectrum at very-low, low, and high frequency regions (VLF: 0.02-0.2 Hz, LF: 0.2-0.6 Hz, and HF: 0.6-3.0 Hz) were monitored using telemetry throughout the experiment course. We observed both FA and GUA attenuated SBP and HR and the spectral powers of BPV at VLF, LF, and HF in both baseline (PreCS) and cold stimuli (CS) conditions, but apparently, FA exerted stronger effects than GUA did. Both FA and GUA generally attenuated the responses of CS-induced pressor and tachycardia and the CS-increased VLFBPV, LFBPV, and HFBPV, but different effects between FA and GUA, when compared with control vehicle under CS. FA reduced the CS-reduced VLFHRV and the CS-increased LFBPV and HFBPV more than GUA did. We further observed in both PreCS and CS, GUA but not FA increased HFHRV; FA reduced but apparently, GUA increased the occurrence of Dn. Finally, we observed FA weakened, but GUA strengthened the coherence between BPV and HRV at both LF and HF regions. Taken together, the different effects between FA and GUA on CEHP indicate a role of the sympathoadrenal mechanism in response to CS.

Role of vasopressin V1 antagonist in the action of vasopressin on the cooling-evoked hemodynamic perturbations of rats.

We aimed to investigate the role of arginine vasopressin (AVP) acting via the AVPV1 receptor in the autonomic cardiovascular responses to cold stress (CS). The study was conducted on adult male Sprague-Dawley rats with telemetry transmitters implanted to monitor heart rate (HR) and systolic blood pressure (SBP) throughout the experiment course. Rats were divided into four groups and were given, respectively, saline (control group), AVPV1 antagonist (V1880) alone, and V1880 following the removal of sympathetic outflows using hexamethonium (HEX+V1880) or guanethidine (GUA + V1880). Rats were subjected to the CS stimuli (rapid immersion of the rat's limbs into 4 °C water). Hemodynamic responses were recorded at baseline (PreCS), during CS, and after CS. Data analysis was performed using descriptive methods and spectral and cross-spectral analysis of blood pressure variability (BPV) and heart rate variability (HRV). Key results showed that at PreCS, inhibition of AVPV1 increases SBP and HR as well as very-low-frequency BPV and low-frequency BPV, which is attenuated by hexamethonium (effect on SBP only) and guanethidine (effect on both SBP and HR). HEX+V1880 results in increased high-frequency BPV and attenuated very-low-frequency HRV, while GUA + V1880 results in increased high-frequency HRV and attenuated very-low-frequency HRV. During CS, we observed that SBP and HR, as well as very-low-frequency BPV and low-frequency BPV, were similar in the control group and the group with AVPV1 inhibition, while AVPV1 inhibition results in attenuated high-frequency BPV. Furthermore, we observed that changes produced by AVPV1 inhibition alone were affected differently by HEX+V1880 and GUA + V1880, particularly in low-frequency HRV and very-low-frequency HRV. The results support that AVPV1 mediates autonomic cardiovascular responses at both baseline and CS stimuli conditions are associated with central mechanism engagement.

Effects of oxytocin on prosocial behavior and the associated profiles of oxytocinergic and corticotropin-releasing hormone receptors in a rodent model of posttraumatic stress disorder.

BACKGROUND: Traumatic experience may lead to various psychological sequelae including the unforgettable trauma-associated memory as seen in posttraumatic stress disorder (PTSD), with a mechanism of impaired fear extinction due to biological imbalance among hypothalamic-pituitary-adrenal (HPA) axis and fear circuit areas such as medial prefrontal cortex (mPFC), hippocampus, and amygdala. Recently the impaired sociability seen in PTSD patients received great attention and the involvement of oxytocin (OXT) mediation is worth being investigated. This study examined whether the trauma-altered prosocial behavior can be modulated by OXT manipulation and its relationship with corticotropin-releasing hormone (CRH) signaling. METHODS: Male rats previously exposed to a single prolonged stress (SPS) were evaluated for their performance in social choice test (SCT) and novel object recognition test (NORT) following the introduction of intranasal oxytocin (OXT) and OXT receptor antagonist atosiban (ASB). OXT receptors (OXTR) and CRH receptors (CRHR1, CRHR2) were quantified in both protein and mRNA levels in medial prefrontal cortex (mPFC), hippocampus, and amygdala. RESULTS: SPS reduced inclination of rats staying at the sociable place with performing less prosocial contacts. OXT can amend the deficit but this effect was blocked by ASB. Expression of OXTR became reduced following SPS in mPFC and amygdala, the latter exhibited higher therapeutic specificity to OXT. Expression of CRHR1 appeared more sensitive than CRHR2 to SPS, higher CRHR1 protein levels were found in mPFC and amygdala. CONCLUSION: Psychological trauma-impaired sociability is highly associated with OXT signaling pathway. Intranasal OXT restored both the SPS-impaired prosocial contacts and the SPS-reduced OXTR expressions in mPFC and amygdala. OXT may have therapeutic potential to treat PTSD patients with impaired social behaviors.

Subchronic administration of aripiprazole improves fear extinction retrieval of Pavlovian conditioning paradigm in rats experiencing psychological trauma.

People may suffer from an intruded fear memory when the attributable traumatic events no longer exist. This is of highly clinical relevance to trauma-induced mental disorders, such as posttraumatic stress disorder (PTSD). Mechanism underlying PTSD largely lies in the abnormal process of fear extinction and a functional imbalance within amygdala associated fear circuit areas. Previous evidence suggested central dopamine plays a key role in the regulation of the fear memory process, yet it remains unclear whether the intervention of dopamine modulators would be beneficial for the fear extinction abnormalities. The present study examined the performance of Pavlovian conditioned fear and the changes of dopamine profiles following a subchronic 14-day regimen of aripiprazole (a partial agonist of dopamine D2 receptors to normalize the condition caused by dopamine imbalance) in rats previously experienced a psychologically traumatic procedure of single prolonged stress (SPS). The results demonstrated that aripiprazole at 5.0 mg/kg reversed the SPS-impaired fear memory dysfunction and the SPS-reduced dopamine efflux in the amygdala. The present study suggests a therapeutic potential of subchronic treatment with aripiprazole in managing patients suffered from fear extinction problem.

Hyperbaric oxygen therapy restored traumatic stress-induced dysregulation of fear memory and related neurochemical abnormalities.

Individuals with posttraumatic stress disorder (PTSD) are characterized by fear memory problems and hypocortisolemia of which traumatic stress-induced monoaminergic disruption over infralimbic (IL) cortex is considered the key mechanism. Hyperbaric oxygen therapy (HBOT) has recently proven its utility in treating several mental disorders but remains unexplored for PTSD. The present study aimed to examine the effects of 5-day HBO paradigm on traumatic stress (single prolonged stress, SPS, an animal model of PTSD)-induced dysregulation of fear memory/anxiety profiles and related abnormalities in IL monoamines and plasma corticosterone. Rats were randomly assigned to four groups (CON-sham, CON-HBOT, SPS-sham, and SPS-HBOT) and received Pavlovian fear conditioning test or elevated-T maze (ETM). The extracellular and tissue levels of monoamines over the IL cortex and the activity of the hypothalamus-pituitary-adrenal axis (i.e., the plasma corticosterone level and expression of the glucocorticoid receptor (GR) in the IL, hippocampus, amygdala, and hypothalamus) were measured. The results demonstrated that HBOT restored behaviorally the SPS-impaired fear extinction retrieval ability and SPS-induced conditioned anxiety, and neurochemically the SPS-reduced IL monoamines efflux level, and the corticosterone profiles. The present study shows some positive effects of HBOT in both behavioral and neurochemical profiles of PTSD outcomes.

Effects of prolonged paradoxical sleep deprivation with or without acute cold stress on hemodynamic perturbations in rats.

Prolonged paradoxical sleep deprivation (PSD) and cold stress (CS) are known to cause sympathoexcitation and increase the risk of cardiovascular disease. The present study examined the effect of PSD with CS on hemodynamic perturbations by investigating blood pressure and heart rate variability (BPV and HRV) in conscious rats. Adult male Sprague-Dawley rats were divided into three groups (n = 10, each): normal sleep (NS), PSD of 72 h, and recovery sleep of 7 days after PSD. When compared with NS, PSD increased systolic blood pressure in all three conditions: before CS (PreCS), CS, and after CS (PostCS). The PSD also increased heart rate in both PreCS and PostCS. Furthermore, spectral power changes were observed throughout the experiment. The PSD increased very-low-frequency BPV in PreCS, decreased very-low-frequency HRV in CS, and increased low-frequency BPV in all three conditions. The PSD increased low-frequency HRV in PreCS, increased high-frequency BPV in both CS and PostCS, and also increased high-frequency HRV in both PreCS and CS but decreased that in PostCS. On the other hand, when compared with PSD, recovery sleep has reversed most cardiovascular changes in PSD toward the NS level. However, when compared with NS, spectral powers of very-low-frequency BPV in the recovery phase showed a lower level. These results showed that in the resting condition, PSD might evoke sympathoexcitation with a tendency to increase both very-low-frequency BPV and very-low-frequency HRV, as the intensified myogenic oscillations. However, in the CS condition, PSD evoked the sympathoexcitation yet might attenuate such myogenic oscillations.

Importance of intervention timing in the effectiveness of antipsychotics.

The use of early pharmacological intervention in treating young patients with schizophrenia is a debating issue for psychiatrists. However, on the basis of developmental theory, early antipsychotic intervention can be beneficial in terms of protecting neurons from further deterioration. This study investigated whether the initiation of second-generation antipsychotic (SGA) treatment at a younger age can effectively reverse schizophrenia-relevant behavioral and neurochemical features, namely acoustic prepulse inhibition (PPI) and accumbal dopamine (DA) efflux, respectively. Risperidone (RIS, 1mg/kg/day) or olanzapine (OLA, 2.5mg/kg/day) was administered for 6weeks in rats subjected to isolation rearing (IR) in adolescence or young adulthood. Behavioral testing was performed at 3 and 5 (for locomotor activity) and 2 and 4 (for PPI) weeks after the initiation of the pharmacological regimen. An additional PPI test was performed 6weeks after the initiation of the pharmacological regimen to assess the acute add-on effect of RIS or OLA. Dopamine (DA) efflux of the nucleus accumbens was evaluated through in vivo microdialysis at the end of the study, for measuring both the baseline levels after the chronic regimen and the responsiveness to acute add-on RIS or OLA treatment. Our results demonstrated that the effects of SGAs on PPI and accumbal DA efflux were dissociated. Specifically, RIS intervention was more beneficial for adolescent than young adult IR rats in restoring their PPI deficit, whereas OLA was age-independently effective in stimulating the accumbal DA efflux. Both PPI and accumbal DA could be employed to reflect IR-induced abnormalities, in which accumbal DA appeared to be more suitable in depicting the long-term effect of IR, whereas PPI might be a more accurate biological index for revealing the advantages of early RIS intervention.

Characterization of the role of endogenous nitric oxide in myogenic vascular oscillations during cooling-evoked hemodynamic perturbations of rats.

Rapid immersion of a rat's limbs into 4 °C water, a model of cold stress, can elicit hemodynamic perturbations (CEHP). We previously reported that CEHP is highly relevant to sympathetic activation and nitric oxide production. This study identifies the role of nitric oxide in CEHP. Conscious rats were pretreated with the nitric oxide synthase inhibitor L-NAME (NG-nitro-l-arginine methyl ester) alone or following the removal of sympathetic influences using hexamethonium or guanethidine. Rats were then subjected to a 10 min cold-stress trial. Hemodynamic indices were telemetrically monitored throughout the experiment. The analyses included measurements of systolic blood pressure; heart rate; dicrotic notch; short-term cardiovascular oscillations and coherence between blood pressure variability and heart rate variability in regions of very low frequency (0.02-0.2 Hz), low frequency (0.2-0.6 Hz), and high frequency (0.6-3.0 Hz). We observed different profiles of hemodynamic reaction between hexamethonium and guanethidine superimposed on L-NAME, suggesting an essential role for a functional adrenal medulla release of epinephrine under cold stress. These results indicate that endogenous nitric oxide plays an important role in the inhibition of sympathetic activation and cardiovascular oscillations in CEHP.

The neurotoxic mechanisms of amphetamine: Step by step for striatal dopamine depletion.

Amphetamine (AMPH) is a commonly abused psychostimulant that induces neuronal cell death/degeneration in humans and experimental animals. Although multiple neurotoxic mechanisms of AMPH have been intensively investigated, the interplay between these mechanisms has remained elusive. In this study, we used a rat model of AMPH-induced long-lasting striatal dopamine (DA) depletion and identified mechanisms of neurotoxicity, energy failure, excitotoxicity, and oxidative stress. Pretreatment with nicotinamide (NAM, a co-factor for the electron transport chain) blocked AMPH-induced free radical formation, energy failure, and striatal DA decrease. Also, MK-801 (a NMDA receptor antagonist) blocked AMPH-induced free radical formation and striatal DA but not energy failure decrease, indicating excitotoxicity may occur before free radical formation and after energy failure. Thus, these results show that during AMPH intoxication, energy failure, excitotoxicity, and free radical formation are orchestrated consecutively to mediate the depletion of striatal DA.

The Osmopressor-Induced Angiopoietin-1 Secretion in Plasma and Subsequent Activation of the Tie-2/Akt/eNOS Signaling Pathway in Red Blood Cell.

BACKGROUND: Water ingestion induces the osmopressor response, which typically presents as increased total peripheral vascular resistance in young healthy subjects. A previous study has suggested that the RBC membrane receptor is involved in osmopressor stress. Recent studies have indicated nitric oxide synthase phosphorylation in RBCs. However, the main process in signaling pathway activation to elicit such a response is unknown. Herein, we hypothesized that hypo-osmotic stress following water ingestion modulates the eNOS/NO pathway, thereby alternating vascular resistance. METHODS: We included 24 young, healthy subjects. Physiological parameters and blood samples were collected at 5 minutes before and 25 and 50 minutes after 50 ml water, 500 ml water, or 500 ml normal saline ingestion. A human receptor tyrosine kinase (RTK) phosphorylation antibody array was used to simultaneously detect and monitor the biological activation pathways in RBCs. RESULTS: Of the 71 RTKs assayed during the osmopressor response, several RTKs were significantly upregulated, including Tie-2 and Tie-1. Plasma angiopoietin-1 levels significantly increased at 25 minutes after 500 ml water ingestion compared to those at baseline. Simultaneous phosphorylation of Tie-2, Akt, and eNOS in RBCs occurred. RBCs in vitro were stimulated with angiopoietin-1, Tie-2, or 0.8% saline and showed significant increase in Tie-2, Akt, and eNOS phosphorylation upon angiopoietin-1 treatment and enhanced activation upon cotreatment of angiopoietin-1 and 0.8% saline. CONCLUSIONS: The hypo-osmotic stimulus of water ingestion increases angiopoietin-1 secretion and subsequently activates the Tie-2/Akt/eNOS signaling pathway in RBCs, thereby revealing a novel biological mechanism simultaneously occurring with the osmopressor response.

7,8-Dihydroxyflavone, a Tropomyosin-Kinase Related Receptor B Agonist, Produces Fast-Onset Antidepressant-Like Effects in Rats Exposed to Chronic Mild Stress.

OBJECTIVE: Brain-derived neurotrophic factor (BDNF) and its specific receptor, tropomyosin-related kinase (TrkB), play important roles in treating depression. In this experiment, we examined whether 7,8-dihydroxyflavone, a novel potent TrkB agonist, could reverse the behavioral and biochemical abnormalities induced by the chronic mild stress (CMS) paradigm in rats. METHODS: SD rats were exposed to a battery of stressors for 56 days. 7,8-dihydroxyflavone (5 and 20 mg/kg) were administered intraperitoneally during the last 28 days of the CMS paradigm. Rats were tested in sucrose consumption test (SCT), forced-swimming test (FST) and elevated T-maze (ETM). Serum corticosterone levels and hippocampal BDNF levels of the rats were measured. RESULTS: Four-week CMS on the rats induced their depression-like behavior in SCT. The CMS-reduced sucrose consumption was reversed starting from 7 days after the 7,8-dihydroxyflavone (20 mg/kg) treatment and remained across the subsequent treatment regime. 7,8-dihydroxyflavone, when given at 5 mg/kg for 3 weeks, reduced the immobility time in the FST in the CMS-subjected rats. Additionally, the 4-week treatment with 7,8-dihydroxyflavone (20 mg/kg) attenuated the CMS-induced increase in anxiety-like behavior in the ETM. For the CMS-subjected rats, 7,8-dihydroxyflavone treatment dose-dependently reduced their serum corticosterone levels but increased their hippocampal BDNF levels only at 5 mg/kg. CONCLUSION: 7,8-dihydroxyflavone was beneficial for both depression and anxiety-like behaviors, and may exert fast-onset antidepressant effects. This provides a new insight into the pharmacological management of depression.

Traumatic stress causes distinctive effects on fear circuit catecholamines and the fear extinction profile in a rodent model of posttraumatic stress disorder.

Central catecholamines regulate fear memory across the medial prefrontal cortex (mPFC), amygdala (AMYG), and hippocampus (HPC). However, inadequate evidence exists to address the relationships among these fear circuit areas in terms of the fear symptoms of posttraumatic stress disorder (PTSD). By examining the behavioral profile in a Pavlovian fear conditioning paradigm together with tissue/efflux levels of dopamine (DA) and norepinephrine (NE) and their reuptake abilities across the fear circuit areas in rats that experienced single prolonged stress (SPS, a rodent model of PTSD), we demonstrated that SPS-impaired extinction retrieval was concomitant with the changes of central DA/NE in a dissociable manner. For tissue levels, diminished DA and increased NE were both observed in the mPFC and AMYG. DA efflux and synaptosomal DA transporter were consistently reduced in the AMYG/vHPC, whereas SPS reduced NE efflux in the infralimbic cortex and synaptosomal NE transporter in the mPFC. Furthermore, a lower expression of synaptosomal VMAT2 was observed in the mPFC, AMYG, and vHPC after SPS. Finally, negative correlations were observed between retrieval freezing and DA in the mPFC/AMYG; nevertheless, the phenomena became invalid after SPS. Our results suggest that central catecholamines are crucially involved in the retrieval of fear extinction in which DA and NE play distinctive roles across the fear circuit areas.

Escitalopram reversed the traumatic stress-induced depressed and anxiety-like symptoms but not the deficits of fear memory.

RATIONALE: Posttraumatic stress disorder (PTSD) is a trauma-induced mental disorder characterised by fear extinction dysfunction in which fear circuit monoamines are possibly associated. PTSD often coexists with depressive/anxiety symptoms, and selective serotonin reuptake inhibitors (SSRIs) are recommended to treat PTSD. However, therapeutic mechanisms of SSRIs underlying the PTSD fear symptoms remain unclear. OBJECTIVES: Using a rodent PTSD model, we examined the effects of early SSRI intervention in mood and fear dysfunctions with associated changes of monoamines within the fear circuit areas. METHODS: A 14-day escitalopram (ESC) regimen (5 mg/kg/day) was undertaken in two separate experiments in rats which previously received a protocol of single prolonged stress (SPS). In experiment 1, sucrose preference and elevated T-maze were used to index anhedonia depression and avoidance/escape anxiety profiles. In experiment 2, the percentage of freezing time was measured in a 3-day fear conditioning paradigm. At the end of our study, tissue levels of serotonin (5-HT) in the medial prefrontal cortex, amygdala, hippocampus, and striatum were measured in experiment 1, and the efflux levels of infralimbic (IL) monoamines were measured in experiment 2. RESULTS: In experiment 1, ESC corrected both behavioural (depression/anxiety) and neurochemical (reduced 5-HT tissue levels in amygdala/hippocampus) abnormalities. In experiment 2, ESC was unable to correct the SPS-impaired retrieval of fear extinction. In IL, ESC increased the efflux level of 5-HT but failed to reverse SPS-reduced dopamine (DA) and noradrenaline (NA). CONCLUSIONS: PTSD-induced mood dysfunction is psychopathologically different from PTSD-induced fear disruption in terms of disequilibrium of monoamines within the fear circuit areas.

Role of Efferent Sympathoadrenal Effects in Cooling-Induced Hemodynamic Perturbations in Rats: An Investigation by Spectrum Analysis.

Cold stress may produce hemodynamic perturbations but the underlying mechanisms are still not clear. Spectral analysis was used in this study to explore that sympathoadrenal activation could be involved in mechanisms of hemodynamic perturbations to cooling. Conscious rats after treatment with a control vehicle (saline) compared with withdrawal of sympathetic influences by ganglion blocker hexamethonium (HEX) or chemical sympathectomy guanethidine (GUA) were challenged by stressful cooling as acute immersing all four extremities in ice water (4 ± 2°C) for 10 min. Plasma nitric oxide (NO) and the appearance of Dichroitic notch (DN) were measured in comparison between treatment groups throughout the experimental course. Hemodynamic indices were telemetrically monitored, and variability of blood pressure and heart rate (BPV; HRV) were assessed over a range of frequencies: very-low frequency (VLF: 0.02-0.2 Hz), low frequency (LF: 0.2-0.6 Hz), high frequency (HF: 0.6-3 Hz), normalized (n)LF, nHF, ratio LF/HF of HRV (LF/HF(HRV)), and total power (TP: ≤3 Hz). Results showed that the concomitant reciprocal changes of spectral powers existed between frequencies of BPV and HRV to the stressful cooling (i.e. VLF(BPV) versus VLF(HRV), LF(BPV) versus LF(HRV), and nLF(BPV) versus nLF(HRV)) which contribute to the underlying mechanisms of sympathetic efferent influences and myogenic cardiovascular responsiveness. Furthermore, compared with the control vehicle in the stressful cooling, HEX restrained the increase of the pressor, tachycardia and VLF(BPV), except that VLF(HRV) was reduced. GUA abolished pressor, however, restrained the increase of the tachycardia, VLF(BPV) and LF(BPV). In addition, GUA reversed the downward tendency of nLF(BPV) into an upward tendency and attenuated both nLF(HRV) and LF/HF(HRV). DN was virtually undetectable after HEX management but was apparently noticeable after GUA management. Finally, the increase of plasma NO after cooling was diminished after HEX or GUA management. Taken together, these results substantiate that the spectral changes during stressful cooling are highly relevant to the efferent sympathetic rhythmicity and subsequent NO production.