Norepinephrine Concentrations Research Articles

Ground-based adaptive horsemanship lessons for veterans with post-traumatic stress disorder: a randomized controlled pilot study

IntroductionEquine-assisted services (EAS) has received attention as a potential treatment strategy for post-traumatic stress disorder (PTSD), as existing literature indicates that symptoms may decrease following EAS. Relatively little is known about the mechanisms at play during lessons and if physiological measures are impacted. The objectives of this pilot study were to 1) explore the effects of adaptive horsemanship (AH) lessons on symptoms of PTSD, hormone concentrations, and social motor synchrony; 2) determine if physiological changes occur as veterans interact with horses; and 3) explore if the interaction between veteran and horse changes over the 8-week session.MethodsVeterans with PTSD were randomly assigned to control (CON, n = 3) or AH (n = 6) groups for an 8-week period (clinical trial; NCT04850573; clinicaltrials.gov). Veterans completed the PTSD Checklist (PCL-5) and Brief Symptom Inventory (BSI) at pre-, post-, and 2- and 6-month follow-up time points. They also completed a social motor synchrony test (pendulum swinging) and blood draw at pre- and post-time points. In weeks 1, 4, and 8, blood samples were drawn at 0 min, 3 min, 5 min, 25 min, and 30 min during the 30-min AH lessons. Veterans completed the Human–Animal Interaction Scale (HAIS) after each lesson. Blood samples were assayed for plasma cortisol, epinephrine, norepinephrine, and oxytocin. Data were analyzed with repeated measure ANOVAs. Changes in PTSD symptoms from pre- to post-time point were analyzed with paired t-tests.ResultsChanges in PCL-5 scores tended to differ (p = 0.0989), and global BSI scores differed (p = 0.0266) between AH (−11.5 ± 5.5, mean ± SE; −0.5 ± 0.2) and CON (5.3 ± 5.4; 0.4 ± 0.2) groups. Social motor synchrony and hormone concentrations did not differ between groups or time points (p > 0.05). Cortisol, norepinephrine, and oxytocin concentrations did not differ across sessions (p > 0.05). Epinephrine concentrations tended (p = 0.0744) to decrease from week 1 to 4 of sessions. HAIS scores increased (p ≥ 0.0437) in week 3 and remained elevated as compared to week 1.DiscussionParticipant recruitment was the greatest challenge. These preliminary results agree with the literature suggesting that EAS can reduce symptoms of PTSD.

Presynaptic Adrenoceptors.

Presynaptic α2-adrenoceptors are localized on axon terminals of many noradrenergic and non-noradrenergic neurons in the peripheral and central nervous systems. Their activation by exogenous agonists leads to inhibition of the exocytotic release of noradrenaline and other transmitters from the neurons. Most often, the α2A-receptor subtype is involved in this inhibition. The chain of molecular events between receptor occupation and inhibition of the exocytotic release of transmitters has been determined. Physiologically released endogenous noradrenaline elicits retrograde autoinhibition of its own release. Some clonidine-like α2-receptor agonists have been used to treat hypertension. Dexmedetomidine is used for prolonged sedation in the intensive care; It also has a strong analgesic effect. The α2-receptor antagonist mirtazapine increases the noradrenaline concentration in the synaptic cleft by interrupting physiological autoinhibion of release. It belongs to the most effective antidepressive drugs. β2-Adrenoceptors are also localized on axon terminals in the peripheral and central nervous systems. Their activation leads to enhanced transmitter release, however, they are not activated by endogenous adrenaline.

3 The impact of early-life cecal microbiota transplantation on injurious behaviors in egg-laying chickens

Abstract Injurious behaviors in laying hens are a critical issue facing the poultry egg industry. Recent studies have shown that the gut microbiota influences host brain function and behavioral characteristics in humans and various animals. In laying hens, it has been reported that injurious behaviors (such as aggression, feather pecking and cannibalism) are associated with dysregulation of the microbiota-gut-brain axis. To further interrogate the role of the microbiota-gut-brain axis on bird behavior, we used two inbred layer chicken lines, 63 and 72 (line 72 displays more aggressive behavior), and transferred pooled cecal contents from either line to day of hatch chicks. Cecal microbiota transplantation (CMT) from each line was conducted once daily, by gavage, from d 1 to 10, then boosted once weekly from wk 3 to 5. We hypothesized that the cecal microbiota composition and animal behavior in recipient birds would be similar to that of their donor animals because of the microbiota-gut-brain axis. Microbial communities were compared using 16S rRNA gene amplicon sequencing, behavior was recorded in home cages as well as in paired aggression tests, and physiological measurements were taken from brain tissue and blood to measure levels of neurotransmitters and immune function. When examining the differences in the donor birds, hypothalamic serotonin and tryptophan concentrations were greater for line 63 compared with line 72 birds (P < 0.05). Plasma corticosterone, heterophil/lymphocyte ratios, and central norepinephrine concentrations were less for line 63 birds (P < 0.05). Cecal microbial diversity was not statistically different between the lines, but many bacterial taxa were differentially abundant between the two lines. After cecal transplantation, 63-CMT (recipient) birds displayed less aggressive behavior with a greater hypothalamic serotonergic activity at wk 5, similar to donor birds. Correspondingly, two amplicon sequence variants (ASVs) belonging to Lachnospiraceae and one Ruminococcaceae UCG-005 ASV were positively correlated with the concentrations of brain tryptophan and serotonin, respectively. Along with greater aggression, 72-CMT birds seemed to have greater physical growth traits (increased body weight, ileal villus/crypt; P ≤ 0.05), but decreased concentrations of brain norepinephrine and dopamine, and the greatest ileal serotonin turnover in the ileum at wk 5 (P < 0.05). ASVs belonging to Mollicutes RF39 and GCA-900066225 in 72-CMT birds were negatively correlated with the brain 5-hydroxyindoleacetic acid (5-HIAA) at wk 5, and one Bacteroides ASV was negatively correlated with plasma serotonin at wk 16. Meanwhile, 63-CMT birds potentially had better gut health and immune function (greater concentrations of ileal mucosal secretory IgA, plasma IL-10; P < 0.05). These results suggest linkages among serotonergic activity, stress response, innate immunity, and gut microbiota populations and that CMT could be a novel strategy for reducing aggressive behavior through regulating signaling along the microbiota-gut-brain axis.

Angiotensin II-Induced Heart Failure Disrupts Cardiac Sympathetic Innervation

About 26 million people worldwide live with heart failure (HF), and 25% have hypertension (HTN) as the primary cause. These patients have a high risk for cardiac arrhythmias and sudden cardiac death. Autonomic dysfunction and sympathetic hyperactivity accompany these diseases, and sympathetic activation is crucial for triggering fatal arrhythmias. However, changes in cardiac sympathetic innervation in HF are not well understood. We hypothesized that cardiac sympathetic innervation is disrupted in a mouse model of Angiotensin II (AngII)-induced HF. To test this hypothesis, C57BL6 male (N=6, 10) and female (N=6, 10) mice 12-20 weeks old were implanted with minipumps releasing either AngII (712ng/min/Kg, N=6-10) or saline (N=6-10) for 4 weeks. HTN and cardiac function were measured with tail cuff quantification and echocardiography, respectively. Fibrosis was assessed using Trichrome staining. Cardiac sympathetic innervation was quantified using immunohistochemistry for Tyrosine Hydroxylase (TH). Cardiac norepinephrine (NE) was measured by High-Performance Liquid Chromatography with electrochemical detection. Values were compared with a Student’s unpaired t-test unless noted, data were represented as mean ± SD, and significance was defined as p<0.05. AngII-treated mice had significantly increased mean arterial pressure (Saline 91.0±15.6 vs. AngII 152.9±22.3 mmHg, p<0.05, N=6-7) 7 days after minipump implantation. Four weeks of AngII treatment led to HF, as indicated by reduced ejection fraction (Saline 54.8±3.8 vs. AngII 43.1±8.2 %, p<0.05, N=10) and fractional shortening (Saline 14.3±2.6 vs. AngII 10.6±3.3 %, p<0.05, N=10). Cardiac hypertrophy was also observed in AngII-treated mice and was reflected by increased heart weight to body weight ratio (Saline 5.2±0.2 vs. AngII 7.7±1.0, p<0.05, N=6). Fibrosis was detected in the intraventricular septum (IVS) and left ventricle (LV) of AngII-treated mice. TH+ fibers in the LV and IVS were decreased significantly (LV: Saline 0.6±0.2 vs. AngII 0.4±0.1 %; IVS: Saline 0.3±0.1 vs. AngII 0.09±0.04 %, p<0.05, N=6), while no differences were detected in the right ventricle (Saline 1.1±0.2 vs. AngII 0.8±0.3 %, P>0.05, N=6). In addition, the subepicardium-subendocardium (EPI-ENDO) gradient was altered (EPI: Saline 0.9±0.2 vs. AngII 0.8±0.3 %, P>0.05; ENDO: Saline 0.3±0.05 vs. AngII 0.1±0.1 %, p<0.05; EPI:ENDO ratio: Saline 2.7±0.7 vs. AngII 15.7±16.8, p<0.05, Mann-Whitney test, N=6). A significant decrease in NE content accompanied the loss of TH+ fibers in the LV (LV: Saline 3.9±0.4 vs. AngII 1.6±0.2 pmol/mg, p<0.05; RV: Saline 4.4±1.0 vs. AngII 3.8±0.8 pmol/mg, P>0.05, N=4-6). Our data demonstrate that AngII-induced HF disrupts cardiac sympathetic nerve density, distribution, and NE content, confirming our initial hypothesis. This evidence contrasts with sympathetic hyperactivity seen in cardiac diseases. Future studies will assess the overall cardiac innervation and, determine whether the loss of TH+ fibers is due to a reduced sympathetic innervation after cardiac remodeling or the cholinergic transdifferentiation of TH+ fibers. A better understanding of the cardiac sympathetic nervous system in HF is imperative to deciphering the mechanistic changes to cardiac innervation in disease, and may help to develop and implement novel and precise neuromodulatory therapies for patients with autonomic imbalance. Supported by NIH R01 HL146833 to Dr. Habecker. This is the full abstract presented at the American Physiology Summit 2024 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.

Duloxetine protected indomethacin-induced gastric mucosal injury by increasing serotonin-dependent RANTES expression and activating PI3K-AKT-VEGF pathway

Antidepressant duloxetine has been shown protective effect on indomethacin-induced gastric ulcer, which was escorted by inflammation in the gastric mucosa. Cytokines are the principal mediators of inflammation. Thus, by screening the differential expression of cytokines in the gastric mucosa using cytokine array at 3 h after indomethacin exposure, when the gastric ulcer began to format, we found that indomethacin increased cytokines which promoted inflammation responses, whereas duloxetine decreased pro-inflammatory cytokines increased by indomethacin and increased RANTES expression. RANTES was consistently increased by pretreated with both 5 mg/kg and 20 mg/kg duloxetine at 3 h and 6 h after indomethacin exposure in male rats. Selective blockade of RANTES-CCR5 axis by a functional antagonist Met-RANTES or a CCR5 antagonist maraviroc suppressed the protection of duloxetine. Considering the pharmacologic action of duloxetine on reuptake of monoamine neurotransmitters, we examined the serotonin (5-HT), norepinephrine and dopamine contents in the blood and discovered 20 mg/kg duloxetine increased 5-HT levels in platelet-poor plasma, while treatment with 5-HT promoted expression of RANTES in the gastric mucosa and alleviated the indomethacin-induced gastric injury. Furthermore, duloxetine activated PI3K-AKT-VEGF signaling pathway, which was regulated by RANTES-CCR5, and selective inhibitor of VEGF receptor axitinib blocked the prophylactic effect of duloxetine. Furthermore, duloxetine also protected gastric mucosa from indomethacin in female rats, and RANTES was increased by duloxetine after 6 h after indomethacin exposure too. Together, our results identified the role of cytokines, particularly RANTES, and the underlying mechanisms in gastroprotective effect of duloxetine against indomethacin, which advanced our understanding in inflammatory modulation by monoamine-based antidepressants.

Divergent roles of purinergic 2X receptors in the pressor response to treadmill exercise in male and female rats

Our objective was to investigate the role played by ATP sensitive purinergic 2X (P2X) receptors in evoking the pressor response to treadmill running in male and female rats with and without simulated peripheral artery disease (PAD). We hypothesized that PPADS (P2X receptor antagonist, 10 mg i.v.), would reduce the pressor and end-exercise plasma norepinephrine (NE) response to four minutes of treadmill exercise (15 m×min−1; 1° incline) in male and female rats with a greater magnitude of effect in rats with simulated PAD compared to sham-operated rats. Methods: Ten rats had both femoral arteries ligated ~72 hours prior to experimental protocols. Fourteen rats had sham procedures performed in which the femoral arteries were exposed, and 5-0 suture was passed under the arteries but not tied. These groups are referred to as “ligated” and “sham”, respectively. In all rats, the right carotid artery was cannulated (PE-25) for blood pressure measurement and arterial blood samples and the right jugular vein was cannulated (PE-25) for administration of PPADS. After the rats recovered (~2 hrs), treadmill exercise was initiated (15 m·min−1, 1° incline) and the rat completed a four minute exercise bout. While the rat was still running, an arterial blood sample (~100 μl) was drawn for plasma NE assessment. Following a 20 minute rest, PPADS (10 mg, dissolved in 0.2 mL saline) was infused into the jugular vein over 10 min. After PPADS infusion, a second treadmill exercise bout and blood collection were performed as described for the control condition. The pressor and plasma NE responses to submaximal treadmill running before and after the injection of PPADS (10 mg) were compared. Data are expressed as mean ± SD. Statistical significance was defined as P≤0.05. Results: In male rats, PPADS significantly reduced the mean arterial pressure (MAP) response to exercise in both sham ( n=6, Peak ΔMAP control: 19±6; PPADS: 11±9 mmHg; P=0.033) and ligated rats ( n=4; control: 24±3 mmHg; PPADS: 16±6 mmHg; P=0.021) with a similar magnitude of effect observed between groups (p=0.544). In female rats, PPADS had no effect on the MAP response to exercise in either sham (n=6, 13±8; PPADS: 10±5 mmHg; P=0.171) or ligated (n=6, 17±5; PPADS: 18±6 mmHg; P=0.375) rats. When NE values were grouped by sex independent of ligation/sham status, PPADS significantly reduced end-exercise plasma NE concentration in both male (n=11, 200±131; PPADS: 139±61 pg/mL; P=0.016) and female (n=10, 199±133; PPADS: 140±101 pg/mL; P=0.027) rats. Conclusions: The data indicate that P2X receptors contribute to the sympathetic response to exercise in both male and female sham and ligated rats, but that sympathoexcitatory roles for P2X receptors translates into an obligatory role in the blood pressure response to treadmill exercise in male but not female rats. National Institutes of Health R01HL161160. This is the full abstract presented at the American Physiology Summit 2024 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.

Amyloid-β neuropathology induces bone loss in male mice by suppressing bone formation and enhancing bone resorption

Alzheimer's disease (AD) and osteoporosis often coexist in the elderly. Although observational studies suggest an association between these two diseases, the pathophysiologic link between AD and skeletal health has been poorly defined. We examined the skeletal phenotype of 5xFAD mice, an AD model with accelerated neuron-specific amyloid-β accumulation causing full-blown AD phenotype by the age of 8 months. Micro-computed tomography indicated significantly lower trabecular and cortical bone parameters in 8-month-old male, but not female, 5xFAD mice than sex-matched wild-type littermates. Dynamic histomorphometry revealed reduced bone formation and increased bone resorption, and quantitative RT-PCR showed elevated skeletal RANKL gene expression in 5xFAD males. These mice also had diminished body fat percentage with unaltered lean mass, as determined by dual-energy X-ray absorptiometry (DXA), and elevated Ucp1 mRNA levels in brown adipose tissue, consistent with increased sympathetic tone, which may contribute to the osteopenia observed in 5xFAD males. Nevertheless, no significant changes could be detected between male 5xFAD and wild-type littermates regarding the serum and skeletal concentrations of norepinephrine. Thus, brain-specific amyloid-β pathology is associated with osteopenia and appears to affect both bone formation and bone resorption. Our findings shed new light on the pathophysiologic link between Alzheimer's disease and osteoporosis.

Resolution of tonic concentrations of highly similar neurotransmitters using voltammetry and deep learning.

With advances in our understanding regarding the neurochemical underpinnings of neurological and psychiatric diseases, there is an increased demand for advanced computational methods for neurochemical analysis. Despite having a variety of techniques for measuring tonic extracellular concentrations of neurotransmitters, including voltammetry, enzyme-based sensors, amperometry, and in vivo microdialysis, there is currently no means to resolve concentrations of structurally similar neurotransmitters from mixtures in the in vivo environment with high spatiotemporal resolution and limited tissue damage. Since a variety of research and clinical investigations involve brain regions containing electrochemically similar monoamines, such as dopamine and norepinephrine, developing a model to resolve the respective contributions of these neurotransmitters is of vital importance. Here we have developed a deep learning network, DiscrimNet, a convolutional autoencoder capable of accurately predicting individual tonic concentrations of dopamine, norepinephrine, and serotonin from both in vitro mixtures and the in vivo environment in anesthetized rats, measured using voltammetry. The architecture of DiscrimNet is described, and its ability to accurately predict in vitro and unseen in vivo concentrations is shown to vastly outperform a variety of shallow learning algorithms previously used for neurotransmitter discrimination. DiscrimNet is shown to generalize well to data captured from electrodes unseen during model training, eliminating the need to retrain the model for each new electrode. DiscrimNet is also shown to accurately predict the expected changes in dopamine and serotonin after cocaine and oxycodone administration in anesthetized rats in vivo. DiscrimNet therefore offers an exciting new method for real-time resolution of in vivo voltammetric signals into component neurotransmitters.

Impact of Serotonergic 5HT1A and 5HT2A Receptor Activation on the Respiratory Response to Hypercapnia in a Rat Model of Parkinson's Disease.

In Parkinson's disease (PD), along with typical motor dysfunction, abnormal breathing is present; the cause of which is not well understood. The study aimed to analyze the effects of stimulation of the serotonergic system with 5-HT1A and 5-HT2A agonists in a model of PD induced by injection of 6-hydroxydopamine (6-OHDA). To model PD, bilateral injection of 6-OHDA into both striata was performed in male Wistar rats. Respiratory disturbances in response to 7% hypercapnia (CO2 in O2) in the plethysmographic chamber before and after stimulation of the serotonergic system and the incidence of apnea were studied in awake rats 5 weeks after 6-OHDA or vehicle injection. Administration of 6-OHDA reduced the concentration of serotonin (5-HT), dopamine (DA) and norepinephrine (NA) in the striatum and the level of 5-HT in the brainstem of treated rats, which have been associated with decreased basal ventilation, impaired respiratory response to 7% CO2 and increased incidence of apnea compared to Sham-operated rats. Intraperitoneal (i.p.) injection of the 5-HT1AR agonist 8-OH-DPAT and 5-HT2AR agonist NBOH-2C-CN increased breathing during normocapnia and hypercapnia in both groups of rats. However, it restored reactivity to hypercapnia in 6-OHDA group to the level present in Sham rats. Another 5-HT2AR agonist TCB-2 was only effective in increasing normocapnic ventilation in 6-OHDA rats. Both the serotonergic agonists 8-OH-DPAT and NBOH-2C-CN had stronger stimulatory effects on respiration in PD rats, compensating for deficits in basal ventilation and hypercapnic respiration. We conclude that serotonergic stimulation may have a positive effect on respiratory impairments that occur in PD.

Increased β2-adrenergic signaling promotes fracture healing through callus neovascularization in mice.

Traumatic brain injury (TBI) leads to skeletal changes, including bone loss in the unfractured skeleton, and paradoxically accelerates healing of bone fractures; however, the mechanisms remain unclear. TBI is associated with a hyperadrenergic state characterized by increased norepinephrine release. Here, we identified the β2-adrenergic receptor (ADRB2) as a mediator of skeletal changes in response to increased norepinephrine. In a murine model of femoral osteotomy combined with cortical impact brain injury, TBI was associated with ADRB2-dependent enhanced fracture healing compared with osteotomy alone. In the unfractured 12-week-old mouse skeleton, ADRB2 was required for TBI-induced decrease in bone formation and increased bone resorption. Adult 30-week-old mice had higher bone concentrations of norepinephrine, and ADRB2 expression was associated with decreased bone volume in the unfractured skeleton and better fracture healing in the injured skeleton. Norepinephrine stimulated expression of vascular endothelial growth factor A and calcitonin gene-related peptide-α (αCGRP) in periosteal cells through ADRB2, promoting formation of osteogenic type-H vessels in the fracture callus. Both ADRB2 and αCGRP were required for the beneficial effect of TBI on bone repair. Adult mice deficient in ADRB2 without TBI developed fracture nonunion despite high bone formation in uninjured bone. Blocking ADRB2 with propranolol impaired fracture healing in mice, whereas the ADRB2 agonist formoterol promoted fracture healing by regulating callus neovascularization. A retrospective cohort analysis of 72 patients with long bone fractures indicated improved callus formation in 36 patients treated with intravenous norepinephrine. These findings suggest that ADRB2 is a potential therapeutic target for promoting bone healing.

Vasopressor reduction effect of polymyxin B hemoperfusion in patients with peritonitis-induced septic shock: a propensity score-matched analysis.

This study aimed to evaluate the effect of polymyxin B hemoperfusion (PMX-HP) in patients with peritonitis-induced septic shock who still required high dose vasopressors after surgical source control. This retrospective study included adult patients admitted to the surgical intensive care unit (ICU) at Seoul National University Hospital between July 2014 and February 2021 who underwent major abdominal surgery to control the source of sepsis. Patients were divided into two groups based on whether PMX-HP was applied after surgery or not. The primary and secondary endpoints were the vasopressor reduction effect, and in-ICU mortality, respectively. Propensity score matching was performed to compare the vasopressor reduction effect. A total of 338 patients met the inclusion criteria, of which 23 patients underwent PMX-HP postoperatively, whereas 315 patients did not during the study period. Serum norepinephrine concentration decreased over time regardless of whether PMX-HP was applied. However, it decreased more rapidly in the PMX-HP(+) group than in the PMX-HP(-) group. There were no significant differences in demographics including age, sex, body mass index (BMI), and most underlying comorbidities between the two groups. Risk factors for in-ICU mortality were identified by comparing patient characteristics and perioperative factors between the two groups using multivariate analysis. For patients with peritonitis-induced septic shock, PMX-HP rapidly reduces the requirement of vasopressors immediately after surgery, but does not reduce in-ICU mortality. This effect could potentially accelerate recovery from shock, reduce sequelae from vasopressors, and ultimately improve quality of life after discharge.

Effects of unilateral cortical inactivation on monoamine metabolism in symmetrical forebrain areas of white outbred mice

Background: In clinical observations and animal experiments, the lateral specificity of the action of compounds that alter monoaminergic transmission has been shown. However, the mechanism of this phenomenon has not yet been studied.
 Aim: To study the effect of unilateral cortical spreading depression on monoamine metabolism in white outbred mice.
 Materials and methods: The experiments were carried out on 18 sexually mature males of white outbred mice. Functional inactivation of the cortex of one of the cerebral hemispheres was caused by unilateral epidural application of 1x1 mm filter paper moistened with 25% KCl solution. 15 minutes after exposure, the animals were decapitated. Using the HPLC method with an electrochemical detector, in the cerebral cortex, hippocampus, olfactory tubercle and striatum the contents of norepinephrine (NE), dopamine (DA), serotonin (5-HT) and their metabolites: dioxyphenylacetic (DOPAC), homovanilinic (HVA) and 5-hydroxyindolacetic (5-HIAA) acids were measured.
 Results. The inactivation of the left hemisphere (ILH) caused a bilateral decrease in the level of NE in the hippocampus, an ipsilateral increase in extracellular metabolism of DA (HVA and/or HVA/DA) in the olfactory tubercle and striatum, as well as a contralateral increase in the content of DA in the cortex and hippocampus. In addition, the ratio of DOPAC/DA in the right olfactory tubercle decreased with ILH. The inactivation of the right hemisphere (IRH) did not cause bilateral effects. With IRH on the inactivation side, the level of NE decreased in the hippocampus, and the level of HVA increased in the striatum. On the opposite (left) side in the IRH mice, the content of DA in the hippocampus increased, as well as the level of DOPAC and the ratio of DOPAC/DA in the olfactory tubercle. Only at IRH, an increase in serotonin metabolism (5-HIAA/5-HT) was detected in the right hippocampus and in the left olfactory tubercle.
 Conclusion. The monoaminergic effects of functional inactivation of the left and right hemisphere cortex in white outbred mice are not mirror-symmetrical.

Investigation of the synergistic effect of asenapine maleate with fluoxetine on ketamine induced behavioural effects and estimation of brain monoamine in rats

Asenapine maleate (ASM), a potent antipsychotic for schizophrenia, has low oral bioavailability due to Cytochrome P450-1A2 metabolism and has been linked to depression side effects. Aim of the study is to investigate the effect of Asenapine Maleate-Fluoxetine combination. By decreasing CYP1A2, FLX could boost the bioavailability and effectiveness of ASM while reducing its side effects. The increased immobility time in ASM with FLX treated group compared to disease control while rearing and ambulation activities were significantly higher in the ASM, FLX, and combination compared to the disease control group, grooming was significantly lower in the ASM-treated and in the combination compared to the disease group. The Dopamine is significantly decreased in FLX and ASM with FLX treated group, the 5-Hydroxytryptamine is higher in all other groups except disease control and the noradrenaline concentration was higher in the ASM and ASM with FLX compared to the disease control group. The ASM and FLX show synergistic action, after dose, there is substantial cataleptic activity due to dopamine receptor blockade in the nigrostriatal pathway, causing muscular stiffness. Further research is required to prevent catalepsy and excessive diabetes induction due to the combination of ASM and FLX.

A mouse model of chronic primary pain that integrates clinically relevant genetic vulnerability, stress, and minor injury.

Chronic primary pain conditions (CPPCs) affect over 100 million Americans, predominantly women. They remain ineffectively treated, in large part because of a lack of valid animal models with translational relevance. Here, we characterized a CPPC mouse model that integrated clinically relevant genetic (catechol-O-methyltransferase; COMT knockdown) and environmental (stress and injury) factors. Compared with wild-type mice, Comt+/- mice undergoing repeated swim stress and molar extraction surgery intervention exhibited pronounced multisite body pain and depressive-like behavior lasting >3 months. Comt+/- mice undergoing the intervention also exhibited enhanced activity of primary afferent nociceptors innervating hindpaw and low back sites and increased plasma concentrations of norepinephrine and pro-inflammatory cytokines interleukin-6 (IL-6) and IL-17A. The pain and depressive-like behavior were of greater magnitude and longer duration (≥12 months) in females versus males. Furthermore, increases in anxiety-like behavior and IL-6 were female-specific. The effect of COMT genotype × stress interactions on pain, IL-6, and IL-17A was validated in a cohort of 549 patients with CPPCs, demonstrating clinical relevance. Last, we assessed the predictive validity of the model for analgesic screening and found that it successfully predicted the lack of efficacy of minocycline and the CB2 agonist GW842166X, which were effective in spared nerve injury and complete Freund's adjuvant models, respectively, but failed in clinical trials. Yet, pain in the CPPC model was alleviated by the beta-3 adrenergic antagonist SR59230A. Thus, the CPPC mouse model reliably recapitulates clinically and biologically relevant features of CPPCs and may be implemented to test underlying mechanisms and find new therapeutics.

Phasic locus coeruleus activity enhances trace fear conditioning by increasing dopamine release in the hippocampus.

Locus coeruleus (LC) projections to the hippocampus play a critical role in learning and memory. However, the precise timing of LC-hippocampus communication during learning and which LC-derived neurotransmitters are important for memory formation in the hippocampus are currently unknown. Although the LC is typically thought to modulate neural activity via the release of norepinephrine, several recent studies have suggested that it may also release dopamine into the hippocampus and other cortical regions. In some cases, it appears that dopamine release from LC into the hippocampus may be more important for memory than norepinephrine. Here, we extend these data by characterizing the phasic responses of the LC and its projections to the dorsal hippocampus during trace fear conditioning in mice. We find that the LC and its projections to the hippocampus respond to task-relevant stimuli and that amplifying these responses with optogenetic stimulation can enhance long-term memory formation. We also demonstrate that LC activity increases both norepinephrine and dopamine content in the dorsal hippocampus and that the timing of hippocampal dopamine release during trace fear conditioning is similar to the timing of LC activity. Finally, we show that hippocampal dopamine is important for trace fear memory formation, while norepinephrine is not.

Phasic locus coeruleus activity enhances trace fear conditioning by increasing dopamine release in the hippocampus

Locus coeruleus (LC) projections to the hippocampus play a critical role in learning and memory. However, the precise timing of LC-hippocampus communication during learning and which LC-derived neurotransmitters are important for memory formation in the hippocampus are currently unknown. Although the LC is typically thought to modulate neural activity via the release of norepinephrine, several recent studies have suggested that it may also release dopamine into the hippocampus and other cortical regions. In some cases, it appears that dopamine release from LC into the hippocampus may be more important for memory than norepinephrine. Here, we extend these data by characterizing the phasic responses of the LC and its projections to the dorsal hippocampus during trace fear conditioning in mice. We find that the LC and its projections to the hippocampus respond to task-relevant stimuli and that amplifying these responses with optogenetic stimulation can enhance long-term memory formation. We also demonstrate that LC activity increases both norepinephrine and dopamine content in the dorsal hippocampus and that the timing of hippocampal dopamine release during trace fear conditioning is similar to the timing of LC activity. Finally, we show that hippocampal dopamine is important for trace fear memory formation, while norepinephrine is not.

Association of Fetal Catecholamines With Neonatal Hypoglycemia

Perinatal stress and fetal growth restriction increase the risk of neonatal hypoglycemia. The underlying pathomechanism is poorly understood. In a sheep model, elevated catecholamine concentrations were found to suppress intrauterine insulin secretion, followed by hyperresponsive insulin secretion once the adrenergic stimulus subsided. To determine whether neonates with risk factors for hypoglycemia have higher catecholamine concentrations in umbilical cord blood (UCB) and/or amniotic fluid (AF) and whether catecholamines are correlated with postnatal glycemia. In a prospective cohort study of 328 neonates at a tertiary perinatal center from September 2020 through May 2022 in which AF and UCB were collected immediately during and after delivery, catecholamines and metanephrines were analyzed using liquid chromatography with tandem mass spectrometry. Participants received postnatal blood glucose (BG) screenings. Risk factor for neonatal hypoglycemia. Comparison of catecholamine and metanephrine concentrations between at-risk neonates and control participants, and correlation of concentrations of catecholamines and metanephrines with the number and severity of postnatal hypoglycemic episodes. In this study of 328 neonates (234 in the risk group: median [IQR] gestational age, 270 [261-277] days; and 94 in the control group: median [IQR] gestational age, 273 [270-278] days), growth-restricted neonates showed increased UCB median (IQR) concentrations of norepinephrine (21.10 [9.15-42.33] vs 10.88 [5.78-18.03] nmol/L; P < .001), metanephrine (0.37 [0.13-1.36] vs 0.12 [0.08-0.28] nmol/L; P < .001), and 3-methoxytyramine (0.149 [0.098-0.208] vs 0.091 [0.063-0.149] nmol/L; P = .001). Neonates with perinatal stress had increased UCB median (IQR) concentrations of norepinephrine (22.55 [8.99-131.66] vs 10.88 [5.78-18.03] nmol/L; P = .001), normetanephrine (1.75 [1.16-4.93] vs 1.25 [0.86-2.56] nmol/L; P = .004), and 3-methoxytyramine (0.120 [0.085-0.228] vs 0.091 [0.063-0.149] nmol/L; P = .008) (P < .0083 was considered statistically significant). Concentrations of UCB norepinephrine, metanephrine, and 3-methoxytyramine were negatively correlated with AF C-peptide concentration (rs = -0.212, P = .005; rs = -0.182, P = .016; and rs = -0.183, P = .016, respectively [P < .017 was considered statistically significant]). Concentrations of UCB norepinephrine, metanephrine, and 3-methoxytyramine were positively correlated with the number of hypoglycemic episodes (BG concentration of 30-45 mg/dL) (rs = 0.146, P = .01; rs = 0.151, P = .009; and rs = 0.180, P = .002, respectively). Concentrations of UCB metanephrine and 3-methoxytyramine were negatively correlated with the lowest measured BG concentration (rs = -0.149, P = .01; and rs = -0.153, P = .008, respectively). Neonates at risk for hypoglycemia displayed increased catecholamine and metanephrine concentrations that were correlated with postnatal hypoglycemic episodes and lower BG levels; these results are consistent with findings in a sheep model that fetal catecholamines are associated with neonatal β-cell physiology and that perinatal stress or growth restriction is associated with subsequent neonatal hyperinsulinemic hypoglycemia. Improving the pathomechanistic understanding of neonatal hypoglycemia may help to guide management of newborns at risk for hypoglycemia.

DOPAMINE AND NOREPINEPHRINE CONTENT IN THE CEREBRAL CORTEX OF BALB/C NUDE MICE WITH MULTIPLE PRIMARY MALIGNANT TUMOURS

The increase in patients with multiple primary malignant tumors (MPMT) determines the need to study their pathogenesis. An important role in the functioning of brain neurons belongs to norepinephrine (NA) and dopamine (DA), which can contribute to tumor development in immunodeficient mice of both sexes.&#x0D; The purpose of our work was a comparative analysis of dopamine and norepinephrine content in the cerebral cortex of immunodeficient mice of both sexes during isolated and combined growth (MPMT model) of experimental tumors.&#x0D; Materials and Methods. 56 BALB/c Nude mice were divided into 7 groups: 4 groups of females (intact, mice with standard subcutaneous inoculation of B16/F10 melanoma or Lewis lung carcinoma (LLC), mice with MPMT model – subcutaneous injection of a tumor cell suspension); 3 groups of males (the same groups as for females, except LLC). ELISA technique was used to detect NA and DA content.&#x0D; Results. In the cerebral cortex of intact females, DA level was higher (3.7 times) and NA level was lower (1.8 times) when compared to males. In all types of tumor growth, monoamine level decrease was observed in animals of both sexes. In females, DA decrease was 57.2 % and 65.8 % with isolated B16/F10 melanoma growth and LLC, and with MPMT it reached 70 %. In males, DA decreased significantly only with MPMT – by 37.6 %. NA in females decreased in case of LLC and MPMT by 26.2 % and 28.1 %, respectively. In males, NA decreased with B16/F10 melanoma and MPMT by 53.3 % and 43 % respectively (p&lt;0.0001 in all cases). In females, there was a more than twofold increase in the ratio of stress-implementing NA and stress-limiting DA (NA/DA) levels, while in males there was a decrease in this index. This was consistent with the large tumor sizes (2–3 times larger) in case of MPMT in females.&#x0D; Conclusion. The results indicate the participation of brain neurotransmitters in the development of multiple primary malignant tumors in BALB/c Nude mice of both sexes and lower stress resistance in females.

Behavioral and physiological responses of horses to ground-based adaptive horsemanship lessons for veterans with post-traumatic stress disorder (PTSD)

Little literature exists on horses in adaptive horsemanship (AH) despite concerns about their well-being. The study objective was to evaluate behavioral and physiological responses of horses to ground-based AH lessons for veterans with post-traumatic stress disorder (PTSD). Lessons were expected to alter horses’ hormone concentrations, behavior, and muscle activity. Geldings were assigned to AH (n=6; 20.3 ± 1.9 yrs., mean ± SE) or control (CON; stall in arena, n=6; 13.8 ± 1.7 yrs.) conditions for 8-week sessions based on current occupation (AH = equine-assisted services; CON = recreational riding). Plasma cortisol, epinephrine, norepinephrine, and oxytocin concentrations from samples at 0 (start of lesson), 3, 5, 25, and 30 (end) min were determined using assays validated in horses. Surface electromyography (sEMG) (masseter and brachiocephalic; Noraxon, Scottsdale, AZ, USA) and video were recorded continuously. Average rectified values (ARV) and median frequency (MF) were calculated (100 ms) after sEMG data were normalized, rectified, and filtered. The number, number of unique, and duration of stress related behaviors (ethogram) were recorded by three trained (ĸ ≥ 0.7) observers. Data were analyzed with repeated measures ANOVAs (significance P ≤ 0.05) with fixed effects of treatment, time point, week, and their interactions as appropriate and random effect of horse. CON horses had elevated cortisol concentrations (P = 0.0023) at 25 and 30 min. AH horses displayed fewer (P ≤ 0.0491) stress related and unique behaviors. CON horses were described as more (P < 0.0001) anxious, nervous, and stressed than AH horses (calm, comfortable, patient, and relaxed) in qualitative behavior analysis (22 observers). AH horses were less stressed than CON horses.

Large nesting expression in deer mice remains stable under conditions of visual deprivation despite heightened limbic involvement: Perspectives on compulsive-like behavior.

Visual stimuli and limbic activation varyingly influence obsessive-compulsive symptom expression and so impact treatment outcomes. Some symptom phenotypes, for example, covert repugnant thoughts, are likely less sensitive to sensory stimuli compared to symptoms with an extrinsic focus, that is, symptoms related to contamination, safety, and "just-right-perceptions." Toward an improved understanding of the neurocognitive underpinnings of obsessive-compulsive psychobiology, work in naturalistic animal model systems is useful. Here, we explored the impact of visual feedback and limbic processes on 24 normal (NNB) and large (LNB) nesting deer mice, respectively (as far as possible, equally distributed between sexes). Briefly, after behavioral classification into either the NNB or LNB cohorts, mice of each cohort were separated into two groups each and assessed for nesting expression under either standard light conditions or conditions of complete visual deprivation (VD). Nesting outcomes were assessed in terms of size and neatness. After nesting assessment completion, mice were euthanized, and samples of frontal-cortical and hippocampal tissues were collected to determine serotonin and noradrenaline concentrations. Our results show that LNB, as opposed to NNB, represents an inflexible and excessive behavioral phenotype that is not dependent on visually guided action-outcome processing, and that it associates with increased frontal-cortical and hippocampal noradrenaline concentrations, irrespective of lighting condition. Collectively, the current results are informing of the neurocognitive underpinnings of nesting behavior. It also provides a valuable foundation for continued investigations into the noradrenergic mechanisms that may influence the development and promulgation of excessive, rigid, and inflexible behaviors.