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Delayed emergence from general anaesthesia poses a significant perioperative safety hazard. Subanaesthetic doses of ketamine not only deepen anaesthesia but also accelerate recovery from isoflurane anaesthesia; however, the mechanisms underlying this phenomenon remain elusive. Esketamine exhibits a more potent receptor affinity and fewer adverse effects than ketamine and exhibits shorter recovery times after brief periods of anaesthesia. As the paraventricular thalamus (PVT) plays a pivotal role in regulating wakefulness, we studied its role in the emergence process during combined esketamine and isoflurane anaesthesia. The righting reflex and cortical electroencephalography were used as measures of consciousness in mice during isoflurane anaesthesia with coadministration of esketamine. The expression of c-Fos was used to determine neuronal activity changes in PVT neurones after esketamine administration. The effect of esketamine combined with isoflurane anaesthesia on PVT glutamatergic (PVTGlu) neuronal activity was monitored by fibre photometry, and chemogenetic technology was used to manipulate PVTGlu neuronal activity. A low dose of esketamine (5 mg kg−1) accelerated emergence from isoflurane general anaesthesia (474 [30] s vs 544 [39] s, P =0.001). Esketamine (5 mg kg−1) increased PVT c-Fos expression (508 [198] vs 258 [87], P =0.009) and enhanced the population activity of PVTGlu neurones (0.03 [1.7]% vs 6.9 [3.4]%, P =0.002) during isoflurane anaesthesia (1.9 [5.7]% vs –5.1 [5.3]%, P =0.016) and emergence (6.1 [6.2]% vs –1.1 [5.0]%, P =0.022). Chemogenetic suppression of PVTGlu neurones abolished the arousal-promoting effects of esketamine (459 [33] s vs 596 [33] s, P <0.001). Our results suggest that esketamine promotes recovery from isoflurane anaesthesia by activating PVTGlu neurones. This mechanism could explain the rapid arousability exhibited upon treatment with a low dose of esketamine. [ABSTRACT FROM AUTHOR]

Background: Preemptive analgesia refers to the beginning of an analgesic intervention to block peripheral and central nociception before the noxious stimuli manifests. The aim of this study was to evaluate the effectiveness of preemptive regime on smooth recovery of rat undergoing somatic surgical pain model. Materials & Method: This Experiment lab based study was conducted at Khyber Medical University Peshawar for one year from January 2022 to January 2023. Thirty five female Sprague-Dawley rats were divided into five distinct research groups, with each group consisting of seven rats. Group A treated with tramadol+lidocain, while group B experienced the administration of buprenorphine+lidocain before surgery. On the other hand, group C had received only saline injections. In order to simulate a realistic minor surgical scenario, each group underwent a lower transverse skin incision right above the pubic symphysis under general anesthesia. Meanwhile, the sham groups, D and E, were treated with injections of tramadol+lidocain and buprenorphine+lidocain respectively, without surgery but following the protocol of general anesthesia. Results: The implementation of preemptive therapy with either tramadol or buprenorphine significantly shortened the time it took for recovery from the anesthesia (p <0.001), Furthermore, the time for the pedal withdrawal reflex and righting reflex return was significantly reduced compared to the saline group (p <0.001 for both measures). These improvements in recovery by preemptive groups were comparable to those observed in the sham group, with no significant differences observed (p =0.05). Conclusion: The implementation of a preemptive regime significantly reduced the recovery period and accelerated the overall recovery process in the somatic surgical pain model. [ABSTRACT FROM AUTHOR]

This study evaluated the effects of sclareol (SCL) with or without caffeine (CAF) and quercetin (QUR) using in-vivo and in-silico studies. For this, 5-day-old chicks weighing between 45 and 48 g were randomly divided into five groups and treated accordingly. The chicks were monitored to compare the occurrence, latency, and duration of sleep as well as the loss and gain of righting reflex in response to SCL-10 mg/kg, CAF-10 mg/kg, and QUR-50 mg/kg using a thiopental sodium (TS)-induced sleeping model. Data were analyzed by one-way ANOVA followed by t-Student–Newman-Keuls' as a posthoc test at 95% confidence intervals with multiple comparisons. An in-silico study was also performed to investigate the possible antidepressant mechanisms of the test and/or standard drugs with different subunits of GABAA receptors. In comparison to the SCL, CAF, and QUR individual groups, SCL+CAF+QUR significantly increased the latency while decreasing the length of sleep. The incidence of loss and gain of the righting reflex was also modulated in the combination group. SCL showed better interaction with GABAA (α2 and α5) subunits than QUR with α2, α3, and α5. All these compounds showed stronger interactions with the GABAA receptor subunits than the standard CAF. Taken together, SCL, CAF, and QUR reduced the TS-induced righting reflex and sleeping time in the combination group more than in the individual treatments. SCL may show its antidepressant effects, possibly through interactions with GABAA receptor subunits.

Objective: Anesthetics are of great importance in avoiding severe pain and suffering in animals and ensuring experimental progress. This study was aimed at elucidating the anesthesia score of phenobarbital sodium as a general anesthetic at different concentrations and doses in BALB/c mice, and finding the suitable anesthesia strategies for experimental surgeries. Methods: Phenobarbital sodium was administrated intraperitoneally at the doses of 75, 100, 125, 150, and 200 mg/kg and randomly in different concentrations (2%, 5%, and 10%) to female BALB/c mice. The anesthesia score was evaluated based on the stimulus index including tail-pinch, front and hind limb withdrawal, and eyelid reflexes. The speed and duration of anesthesia in different groups were recorded per the occurrence and duration of the righting reflex. Results: The anesthetic effect of phenobarbital sodium on female BALB/c mice showed an obvious dose-dependency. Respiratory suppression caused by high-dose anesthesia may lead to mouse death. Based on the anesthesia score, when the phenobarbital sodium treatment was greater than or equal to five percent or 200 mg/kg, more than 80% mice meet the anesthesia depth that surgical operation needed. The rates of achieving surgical anesthesia depth (standard-reaching rate) in mice treated with 2% sodium phenobarbital were 0% in the 75 mg/kg group, 0% in the 100 mg/kg group, 50% in the 125 mg/kg group, 66.7% in the 150 mg/kg group, and 100% in the 200 mg/kg group. The standard-reaching rate of mice treated with 5% concentration of phenobarbital sodium were: 0% in the 75 mg/kg group, 0% in the 100 mg/kg group, 83.33% in the 125 mg/kg group, 100% in the 150 mg/kg group, and 100% in the 200 mg/kg group. The standard-reaching rate of mice treated with 10% concentration of phenobarbital sodium were: 50% in the 75 mg/kg group, 66.7% in the 100 mg/kg group, 100% in the 125 mg/kg group, 100% in the 150mg/kg group, and 100% in the 200 mg/kg group. Sedation and hypnosis were induced in the low-concentration dose group, and anesthesia was induced in the highconcentration dose group. In the 5% and 125 mg/kg phenobarbital sodium groups, the mortality rate of mice was 0, the anesthesia induction time was (35.5 ± 7.92) minutes, and the anesthesia duration was (106 ± 39.59) minutes. In the 5% and 150 mg/kg phenobarbital sodium groups, the mortality rate of mice was 0, the anesthesia induction time was (34.83 ± 5.27) minutes, and the anesthesia duration was (131.7 ± 36.75) minutes. Conclusion: Phenobarbital sodium alone can provide appropriate general anesthesia in female BALB/c mice. Both the concentration and dose of phenobarbital sodium can affect the anesthetic effect. On the basis of our findings, we recommend the 5% and 125 mg/kg and 5% and 150 mg/kg concentration-dose combinations of phenobarbital sodium for anesthetizing mice according to the surgical requirement. [ABSTRACT FROM AUTHOR]

The neuronal mechanisms underlying propofol-induced modulation of consciousness are poorly understood. Neuroimaging studies suggest a potential role for non-specific thalamic nuclei in propofol-induced loss of consciousness. We investigated the contribution of the paraventricular thalamus (PVT), a midline thalamic nucleus that has been implicated in arousal control and general anaesthesia with inhaled anaesthetics, to loss and recovery of consciousness during propofol anaesthesia. Polysomnographic recordings and righting reflex test were used to determine the transitions of loss and recovery of righting reflex, used as a measure of consciousness in mice, during propofol anaesthesia in mice under conditions mimicking clinical propofol administration. PVT neuronal activities were monitored using fibre photometry and regulated using optogenetic and chemogenetic methods. Population activities of PVT glutamatergic neurones began to decrease before propofol-induced loss of consciousness and rapidly increased to a peak at the onset of recovery of consciousness. Chemogenetic inhibition of PVT calretinin-expressing (PVTCR) neurones shortened onset (from 176 [35] to 127 [26] s; P =0.001) and prolonged return (from 1568 [611] to 3126 [1616] s; P =0.002) of righting reflex. Conversely, chemogenetic activation of PVTCR neurones exerted opposite effects. Furthermore, optogenetic silencing of PVTCR neurones accelerated transitions to loss of consciousness (from 205 [35] to 158 [44] s; P =0.027) and slowed transitions to recovery of consciousness (from 230 [78] to 370 [99] s; P =0.041). During a steady period of unconsciousness maintained with continuous propofol infusion, brief optical activation of PVTCR neurones restored cortical activity and arousal with a latency of about 5 s. The paraventricular thalamus contributes to the control of consciousness transitions in propofol anaesthesia in mice. This provides a potential neuroanatomical target for controlling consciousness to reduce anaesthetic dose requirements and side effects. [ABSTRACT FROM AUTHOR]

Identifying predictors for individuals vulnerable to the adverse effects of traumatic brain injury (TBI) remains an ongoing research pursuit. This is especially important for patients with mild TBI (mTBI), whose condition is often overlooked. TBI severity in humans is determined by several criteria, including the duration of loss of consciousness (LOC): LOC < 30 min for mTBI and LOC > 30 min for moderate-to-severe TBI. However, in experimental TBI models, there is no standard guideline for assessing the severity of TBI. One commonly used metric is the loss of righting reflex (LRR), a rodent analogue of LOC. However, LRR is highly variable across studies and rodents, making strict numeric cutoffs difficult to define. Instead, LRR may best be used as predictor of symptom development and severity. This review summarizes the current knowledge on the associations between LOC and outcomes after mTBI in humans and between LRR and outcomes after experimental TBI in rodents. In clinical literature, LOC following mTBI is associated with various adverse outcome measures, such as cognitive and memory deficits; psychiatric disorders; physical symptoms; and brain abnormalities associated with the aforementioned impairments. In preclinical studies, longer LRR following TBI is associated with greater motor and sensorimotor impairments; cognitive and memory impairments; peripheral and neuropathology; and physiologic abnormalities. Because of the similarities in associations, LRR in experimental TBI models may serve as a useful proxy for LOC to contribute to the ongoing development of evidence-based personalized treatment strategies for patients sustaining head trauma. Analysis of highly symptomatic rodents may shed light on the biological underpinnings of symptom development after rodent TBI, which may translate to therapeutic targets for mTBI in humans. [ABSTRACT FROM AUTHOR]

Alcohol use disorders, affective disorders and their comorbidity are sexually dimorphic in humans. However, it is difficult to disentangle the interactions between subject factors influencing alcohol sensitivity in studies of humans. Herein, we combined murine models of unpredictable, chronic, mild stress (UCMS) and voluntary binge-drinking to examine for sex differences in the interactions between prior histories of excessive ethanol-drinking and stress upon ethanol-induced changes in motor behavior and subsequent drinking. In Experiment 1, female mice were insensitive to the UCMS-induced increase in ethanol-induced locomotion and ethanol intake under continuous alcohol-access. Experiment 2 revealed interactions between ethanol dose and sex (females>males), binge-drinking history (water>ethanol), and UCMS history (UCMS>controls), with no additive effect of a sequential prior history of both binge drinking and UCMS observed. We also observed an interaction between UCMS history and sex for righting recovery. UCMS history potentiated subsequent binge-drinking in water controls of both sexes and in male binge-drinking mice. Conversely, a prior binge-drinking history increased subsequent ethanol intake in females only, irrespective of prior UCMS history. In Experiment 3, a concurrent history of binge-drinking and UCMS did not alter ethanol intake, nor did it influence the ethanol dose-locomotor response function, but it did augment alcohol-induced sedation and reduced subsequent alcohol intake over that produced by binge-drinking alone. Thus, the subject factors of biological sex, prior stressor history and prior binge-drinking history interact in complex ways in mice to impact sensitivity to alcohol's motor-stimulating, -incoordinating and intoxicating effects, as well as to influence subsequent heavy drinking.

An arboreal mammal such as a squirrel can amazingly lock its head (and thus eyes) toward a fixed spot for safe landing while its body is tumbling in air after unexpectedly being thrown into air. Such an impressive ability of body motion control of squirrels has been shown in a recent YouTube video, which has amazed public with over 100 million views. In the video, a squirrel attracted to food crawled onto an ejection device and was unknowingly ejected into air by the device. During the resulting projectile flight, the squirrel managed to quickly turn its head (eyes) toward and then keeps staring at the landing spot until it safely landed on feet. Understanding the underline dynamics and how the squirrel does this behavior can inspire robotics researchers to develop bio-inspired control strategies for challenging robotic operations such as hopping/jumping robots operating in an unstructured environment. To study this problem, we implemented a 2D multibody dynamics model, which simulated the dynamic motion behavior of the main body segments of a squirrel in a vertical motion plane. The inevitable physical contact between the body segments is also modeled and simulated. Then, we introduced two motion control methods aiming at locking the body representing the head of the squirrel toward a globally fixed spot while the other body segments of the squirrel were undergoing a general 2D rotation and translation. One of the control methods is a conventional proportional-derivative (PD) controller, and the other is a reinforcement learning (RL)-based controller. Our simulation-based experiment shows that both controllers can achieve the intended control goal, quickly turning and then locking the head toward a globally fixed spot under any feasible initial motion conditions. In comparison, the RL-based method is more robust against random noise in sensor data and also more robust under unexpected initial conditions.

Identifying predictors for individuals vulnerable to the adverse effects of traumatic brain injury (TBI) remains an ongoing research pursuit. This is especially important for patients with mild TBI (mTBI), whose condition is often overlooked. TBI severity in humans is determined by several criteria, including the duration of loss of consciousness (LOC): LOC < 30 min for mTBI and LOC > 30 min for moderate-to-severe TBI. However, in experimental TBI models, there is no standard guideline for assessing the severity of TBI. One commonly used metric is the loss of righting reflex (LRR), a rodent analogue of LOC. However, LRR is highly variable across studies and rodents, making strict numeric cutoffs difficult to define. Instead, LRR may best be used as predictor of symptom development and severity. This review summarizes the current knowledge on the associations between LOC and outcomes after mTBI in humans and between LRR and outcomes after experimental TBI in rodents. In clinical literature, LOC following mTBI is associated with various adverse outcome measures, such as cognitive and memory deficits; psychiatric disorders; physical symptoms; and brain abnormalities associated with the aforementioned impairments. In preclinical studies, longer LRR following TBI is associated with greater motor and sensorimotor impairments; cognitive and memory impairments; peripheral and neuropathology; and physiologic abnormalities. Because of the similarities in associations, LRR in experimental TBI models may serve as a useful proxy for LOC to contribute to the ongoing development of evidence-based personalized treatment strategies for patients sustaining head trauma. Analysis of highly symptomatic rodents may shed light on the biological underpinnings of symptom development after rodent TBI, which may translate to therapeutic targets for mTBI in humans.

Blast traumatic brain injury (bTBI) presents a serious threat to military personnel and often results in psychiatric conditions related to limbic system dysfunction. In this study, the functional outcomes for anxiety- and depressive-like behaviors and neuronal activation were evaluated in male and female mice after exposure to an Advanced Blast Simulator (ABS) shock wave. Mice were placed in a ventrally exposed orientation inside of the ABS test section and received primary and tertiary shock wave insults of approximately 15 psi peak pressure. Evans blue staining indicated cases of blood-brain barrier breach in the superficial cerebral cortex four, but not 24 h after blast, but the severity was variable. Behavioral testing with the elevated plus maze (EPM) or elevated zero maze (EZM), sucrose preference test (SPT), and tail suspension test (TST) or forced swim test (FST) were conducted 8 days–3.5 weeks after shock wave exposure. There was a sex difference, but no injury effect, for distance travelled in the EZM where female mice travelled significantly farther than males. The SPT and FST did not indicate group differences; however, injured mice were less immobile than sham mice during the TST; possibly indicating more agitated behavior. In a separate cohort of animals, the expression of the immediate early gene, c-Fos, was detected 4 h after undergoing bTBI or sham procedures. No differences in c-Fos expression were found in the cerebral cortex, but female mice in general displayed enhanced c-Fos activation in the paraventricular nucleus of the thalamus (PVT) compared to male mice. In the amygdala, more c-Fos-positive cells were observed in injured animals compared to sham mice. The observed sex differences in the PVT and c-Fos activation in the amygdala may correlate with the reported hyperactivity of females post-injury. This study demonstrates, albeit with mild effects, behavioral and neuronal activation correlates in female rodents after blast injury that could be relevant to the incidence of increased post-traumatic stress disorder in women. [ABSTRACT FROM AUTHOR]

The full mechanism of action of propofol, a commonly administered intravenous anesthetic drug in clinical practice, remains elusive. The focus of this study was the role of GABAergic neurons which are the main neuron group in the ventral pallidum (VP) closely associated with anesthetic effects in propofol anesthesia. The activity of VP GABAergic neurons following propofol anesthesia in Vgat-Cre mice was observed via detecting c-Fos immunoreactivity by immunofluorescence and western blotting. Subsequently, chemogenetic techniques were employed in Vgat-Cre mice to regulate the activity of VP GABAergic neurons. The role of VP GABAergic neurons in generating the effects of general anesthesia induced by intravenous propofol was further explored through behavioral tests of the righting reflex. The results revealed that c-Fos expression in VP GABAergic neurons in Vgat-Cre mice dramatically decreased after propofol injection. Further studies demonstrated that chemogenetic activation of VP GABAergic neurons during propofol anesthesia shortened the duration of anesthesia and promoted wakefulness. Conversely, the inhibition of VP GABAergic neurons extended the duration of anesthesia and facilitated the effects of anesthesia. The results obtained in this study suggested that regulating the activity of GABAergic neurons in the ventral pallidum altered the effect of propofol on general anesthesia. • GABAergic neurons in VP are involved in anesthesia effects of propofol. • Propofol anesthesia inhibits the activity of VP GABAergic neurons. • Activating VP GABAergic neurons attenuates anesthesia effects of propofol. • Inhibiting VP GABAergic neurons enhances anesthesia effects of propofol. [ABSTRACT FROM AUTHOR]

The deficiency of survival motor neuron (SMN) protein can result in the onset of spinal muscular atrophy (SMA), an autosomal recessive disorder characterized by a progressive loss of motor neurons and skeletal muscle atrophy. The mechanism underlying SMA pathology remains unclear. Here, we demonstrate that SMN protein regulates oxidative stress and inflammatory response in microglia. Antisense oligonucleotide, which increases SMN protein expression (SMN-ASO), attenuated SMA model mice phenotypes and suppressed the activation of microglia in the spinal cord. The expression of oxidative stress marker in microglia was decreased by SMN-ASO injection in SMA model mice. Increased reactive oxygen species production and subsequent antioxidative stress reaction was observed in SMN protein-depleted RAW264.7. Furthermore, nuclear factor kappa B (NFκB) and c-Jun amino terminal kinase (JNK) signaling, which mainly mediate the inflammatory response, are activated in SMN protein-depleted RAW264.7. Tumor necrosis factor-α (TNF-α) production is also increased in SMN protein-depleted RAW264.7. These findings suggest that SMN protein regulates oxidative stress and inflammatory response in microglia, supporting current claims that microglia can be an effective target for SMA therapy.

Objective To investigate the effect and mechanism of the anesthetic drug, desflurane, on central and peripheral clock genes in mice. Methods C57BL/6J mice were anesthetized with different concentrations (3%, 4%, 6%, 7%, 9%) of desflurane, and then the effective concentration of desflurane was determined by detecting the loss of righting reflex. Then C57BL/6J mice and Per1-/-/Per-/- mice were respectively divided into air control group and desflurane treatment group. The mice from the latter group were given 7% desflurane treatment in 2 h after the light of feeding environment was turned on, and those of the control group was exposed to air at the same time. In 2 h later, the clock genes Per1, Per2, Dbp, Bmal1, Clock and Cry1 in the hypothalamus, kidney and liver tissues were detected by RT-qPCR. Results ① Treatment of 3% desflurane resulted in no disappearance of righting reflex, while those of 4%, 6%, 7% and 9% caused the mice achieving loss of the righting reflex accounted for 16.7%, 50%, 100 % and 100%. Therefore, the effective concentration of desflurane was determined as 7%. ② Compared with the control group, treatment with 7% desflurane significantly decreased the expression of clock gene Per2 in the hypothalamus tissue in C57BL/6J mice (P < 0.01), but had no effect on the expression of the other 5 clock genes (P>0.05); It also significantly increased the expression of the clock gene Per1, while significantly decreased the expression of the clock genes Bmal1 and Dbp in the kidney tissue (P < 0.05), but there was no significant change in the expression of the other 3 clock genes (P>0.05); In the liver tissue, the expression of clock gene Per1 was significantly increased (P < 0.01), while no changes were seen in the expression of the other 5 clock genes (P>0.05). Compare with the control group, the Per1-/-/Per2-/- mice had significantly decreased the expression of Bmal1, Clock and Dbp in the hypothalamus tissue after treatment with 7% desflurane (P < 0.05); obviously reduced expression of Cry1 and Clock (P < 0.05), but no notable change in that of Bmal1 (P>0.05) in the liver and kidney tissue. Conclusion Desflurane significantly affects the circadian clock genes in mouse central and peripheral tissues, and there is a pathway independent form Per gene.

Studies aimed at investigating brain regions involved in arousal state control have been traditionally limited to subcortical structures. In the current study, we tested the hypothesis that inactivation of prefrontal cortex, but not two subregions within parietal cortex—somatosensory barrel field and medial/lateral parietal association cortex—would suppress arousal, as measured by an increase in anesthetic sensitivity. Male and female Sprague Dawley rats were surgically prepared for recording electroencephalogram and bilateral infusion into prefrontal cortex (N = 13), somatosensory barrel field (N = 10), or medial/lateral parietal association cortex (N = 9). After at least 10 days of post-surgical recovery, 156 μM tetrodotoxin or saline was microinjected into one of the cortical sites. Ninety minutes after injection, rats were anesthetized with 2.5% sevoflurane and the time to loss of righting reflex, a surrogate for loss of consciousness, was measured. Sevoflurane was stopped after 45 min and the time to return of righting reflex, a surrogate for return of consciousness, was measured. Tetrodotoxin-mediated inactivation of all three cortical sites decreased (p < 0.05) the time to loss of righting reflex. By contrast, only inactivation of prefrontal cortex, but not somatosensory barrel field or medial/lateral parietal association cortex, increased (p < 0.001) the time to return of righting reflex. Burst suppression ratio was not altered following inactivation of any of the cortical sites, suggesting that there was no global effect due to pharmacologic lesion. These findings demonstrate that prefrontal cortex plays a causal role in emergence from anesthesia and behavioral arousal. [ABSTRACT FROM AUTHOR]

Studies aimed at investigating brain regions involved in arousal state control have been traditionally limited to subcortical structures. In the current study, we tested the hypothesis that inactivation of prefrontal cortex, but not two subregions within parietal cortex—somatosensory barrel field and medial/lateral parietal association cortex—would suppress arousal, as measured by an increase in anesthetic sensitivity. Male and female Sprague Dawley rats were surgically prepared for recording electroencephalogram and bilateral infusion into prefrontal cortex (N = 13), somatosensory barrel field (N = 10), or medial/lateral parietal association cortex (N = 9). After at least 10 days of post-surgical recovery, 156 μM tetrodotoxin or saline was microinjected into one of the cortical sites. Ninety minutes after injection, rats were anesthetized with 2.5% sevoflurane and the time to loss of righting reflex, a surrogate for loss of consciousness, was measured. Sevoflurane was stopped after 45 min and the time to return of righting reflex, a surrogate for return of consciousness, was measured. Tetrodotoxin-mediated inactivation of all three cortical sites decreased (p < 0.05) the time to loss of righting reflex. By contrast, only inactivation of prefrontal cortex, but not somatosensory barrel field or medial/lateral parietal association cortex, increased (p < 0.001) the time to return of righting reflex. Burst suppression ratio was not altered following inactivation of any of the cortical sites, suggesting that there was no global effect due to pharmacologic lesion. These findings demonstrate that prefrontal cortex plays a causal role in emergence from anesthesia and behavioral arousal.

Crocodilians often require chemical immobilization for safe restraint and veterinary procedures, but there is a paucity of anesthetic studies for these species. The aim of this study was to compare the ability of ketamine (5 mg/kg) versus alfaxalone (5 mg/kg), in combination with dexmedetomidine (50 µg/kg) and midazolam (1 mg/kg) (KDM, ADM), to provide a loss of reflexes and safe orotracheal intubation without producing apnea in American alligators (Alligator mississippiensis). Six 22-month-old captive-hatched American alligators (4.75 ± 0.48 kg and body length of 111.1 ± 9.9 cm) were administered KDM and ADM in the lateral occipital venous sinus in a randomized, crossover design with a 72–80 h washout period between treatments. Physiologic parameters (heart rate, respiratory rate, esophageal and cloacal temperatures, end-tidal CO2) and reflexes (palpebral, cloacal, corneal, righting, withdrawal) were serially assessed throughout the anesthetic episode. Alligators were intubated, and assisted ventilation was provided to apneic animals. Intubation was safely performed within 10 min of administration of ADM and KDM. Respiratory rate was the only physiological parameter to differ between ADM and KDM. The majority (5/6, 83.3%) of alligators administered KDM maintained spontaneous ventilation (P = 0.016) and withdrawal reflexes (P = 0.031), and all alligators (6/6, 100%) given ADM became apneic and lost their withdrawal reflexes in all four limbs. Palpebral, cloacal, and righting reflexes were consistently lost in all animals with both combinations. Recovery time ranged from 5 to 35 min following administration of the reversal agents. Although KDM and ADM both permitted orotracheal intubation, KDM produced less apnea and a lighter plane of anesthesia compared to ADM. [ABSTRACT FROM AUTHOR]

To evaluate the effect of dexmedetomidine on alfaxalone immobilization in snakes. Nonblinded, crossover study. A total of eight mature common garter snakes (Thamnophis sirtalis). Snakes were administered each of three treatments intracoelomically: alfaxalone (30 mg kg–1; treatment A), alfaxalone (30 mg kg–1) combined with dexmedetomidine (0.05 mg kg–1; treatment AD0.05); and alfaxalone (30 mg kg–1) combined with dexmedetomidine (0.10 mg kg–1; treatment AD0.10). A minimum of 10 days elapsed between experimental trials. Times to loss of righting reflex (LRR) and return of righting reflex (RRR) were recorded. Heart rate (HR) was recorded every 5 minutes throughout the period of LRR and averaged for each snake. Times to LRR and RRR, and mean HR in snakes that achieved LRR were reported. LRR occurred in eight (100%), five (63%) and three (38%) snakes in treatments A, AD0.05 and AD0.10, respectively. For all treatments, time to LRR ranged 3–20 minutes. Median (range) times to RRR were 39 (30–46), 89 (62–128) and 77 (30–185) minutes for treatments A, AD0.05 and AD0.10, respectively. In animals where righting reflex was lost, mean HR was lower in all dexmedetomidine treatments compared with treatment A. In this pilot study, alfaxalone resulted in reliable immobilization, whereas dexmedetomidine and alfaxalone combinations resulted in highly variable durations of immobilization with low HR in immobilized animals. For snakes that achieved LRR, the addition of dexmedetomidine (0.05 mg kg–1) to alfaxalone appeared to extend the period of immobilization compared with alfaxalone alone. [ABSTRACT FROM AUTHOR]

Aims: General anesthesia has been applied in surgery for more than 170 years, and there is little doubt that GABAA receptors have an important role as anesthetic molecular targets, but its neural mechanisms remain unclear. Increasing researchers have shown that dopaminergic pathways in the brain are crucial for sleep and wake. General anesthesia‐induced unconsciousness and natural sleep share some neural correlates. However, the role of GABAA receptors in ventral periaqueductal gray (vPAG) dopamine (DA) neurons in the isoflurane‐induced unconsciousness has yet to be identified. Methods: In the present study, we used calcium fiber photometry recording to explore that the activity of ventral periaqueductal gray (vPAG) neurons. Then, rats were unilaterally microinjected with 6‐hydroxydopamine into the vPAG area to determine the role of vPAG‐DA neurons in isoflurane‐induced‐anesthesia. Furthermore, thirty SD rats were divided into three groups: a GABAAR agonist‐muscimol group, a GABAAR antagonist‐gabazine group, and a control group. Finally, whole‐cell patch clamp was used to examine the effects of isoflurane and GABAA receptor agonist/antagonist on vPAG‐DA neurons. Results: The vPAG neurons were markedly inhibited during isoflurane anesthesia induction and that these neurons were activated during emergence from isoflurane anesthesia. Lesion to the vPAG‐DA neurons shortened the induction time and prolonged the emergence time while increasing δ power in isoflurane anesthesia. Intracerebral injection of the GABAA receptor agonist (muscimol) into the vPAG accelerated the induction of anesthesia and delayed recovery from isoflurane anesthesia, with a decrease of δ power and an augment of β power. Injection of GABAA receptor antagonist gabazine generated the opposite effects. Isoflurane enhanced GABAergic transmission, and GABAA receptor agonist partly increased isoflurane‐induced inhibition of vPAG‐DA neurons, while GABAA receptor antagonist evidently attenuated GABAergic transmission. Conclusion: Our results suggest that vPAG‐DA neurons are involved in isoflurane anesthesia through activation of the GABAA receptor. [ABSTRACT FROM AUTHOR]

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This study evaluated the effects of sclareol (SCL) with or without caffeine (CAF) and quercetin (QUR) using in-vivo and in-silico studies. For this, 5-day-old chicks weighing between 45 and 48 g were randomly divided into five groups and treated accordingly. The chicks were monitored to compare the occurrence, latency, and duration of sleep as well as the loss and gain of righting reflex in response to SCL-10 mg/kg, CAF-10 mg/kg, and QUR-50 mg/kg using a thiopental sodium (TS)-induced sleeping model. Data were analyzed by one-way ANOVA followed by t -Student–Newman-Keuls' as a posthoc test at 95% confidence intervals with multiple comparisons. An in-silico study was also performed to investigate the possible antidepressant mechanisms of the test and/or standard drugs with different subunits of GABA A receptors. In comparison to the SCL, CAF, and QUR individual groups, SCL+CAF+QUR significantly increased the latency while decreasing the length of sleep. The incidence of loss and gain of the righting reflex was also modulated in the combination group. SCL showed better interaction with GABA A (α 2 and α 5) subunits than QUR with α 2 , α 3 , and α 5. All these compounds showed stronger interactions with the GABA A receptor subunits than the standard CAF. Taken together, SCL, CAF, and QUR reduced the TS-induced righting reflex and sleeping time in the combination group more than in the individual treatments. SCL may show its antidepressant effects, possibly through interactions with GABA A receptor subunits. [Display omitted] • Antidepressive effect of sclareol, possibly GABAergic transmission. • Synergistic antidepressive modulation with quercetin and caffeine. • GABA A α 2 and α 5 -mediated antidepressant activity of sclareol. [ABSTRACT FROM AUTHOR]

Adolescent alcohol exposure is associated with lasting behavioral changes in humans and in mice. Prior work from our laboratory and others have demonstrated that C57BL/6J and DBA/2J mice differ in sensitivity to some effects of acute alcohol exposure during adolescence and adulthood. However, it is unknown if these strains differ in cognitive, anxiety-related, and addiction-related long-term consequences of adolescent intermittent alcohol exposure. This study examined the impact of a previously validated adolescent alcohol exposure paradigm (2–3 g/kg, i.p., every other day PND 30–44) in C57BL/6J and DBA/2J male and female mice on adult fear conditioning, anxiety-related behavior (elevated plus maze), and addiction-related phenotypes including nicotine sensitivity (hypothermia and locomotor depression) and alcohol sensitivity (loss of righting reflex; LORR). Both shared and strain-specific long-term consequences of adolescent alcohol exposure were found. Most notably, we found a strain-specific alcohol-induced increase in sensitivity to nicotine's hypothermic effects during adulthood in the DBA/2J strain but not in the C57BL/6J strain. Conversely, both strains demonstrated a robust increased latency to LORR during adulthood after adolescent alcohol exposure. Thus, we observed strain-dependent cross-sensitization to nicotine and strain-independent tolerance to alcohol due to adolescent alcohol exposure. Several strain and sex differences independent of adolescent alcohol treatment were also observed. These include increased sensitivity to nicotine-induced hypothermia in the C57BL/6J strain relative to the DBA/2J strain, in addition to DBA/2J mice showing more anxiety-like behaviors in the elevated plus maze relative to the C57BL/6J strain. Overall, these results suggest that adolescent alcohol exposure results in altered adult sensitivity to nicotine and alcohol with some phenotypes mediated by genetic background. • Adolescent alcohol exposure is associated with lasting behavioral changes. • Adolescent alcohol exposure increased adult sensitivity to nicotine. • Adolescent alcohol exposure altered adult tolerance to alcohol. • Adolescent alcohol exposure effects interacted with genetic background. [ABSTRACT FROM AUTHOR]

Abstract Background Volatile anesthetics increase levels of the neurotransmitter nitric oxide (NO) and the secondary messenger molecule cyclic guanosine monophosphate (cGMP) in the brain. NO activates the enzyme guanylyl cyclase (GC) to produce cGMP. We hypothesized that the NO-GC-cGMP pathway contributes to anesthesia-induced unconsciousness. Methods Sevoflurane-induced loss and return of righting reflex (LORR and RORR, respectively) were studied in wild-type mice (WT) and in mice congenitally deficient in the GC-1α subunit (GC-1−/− mice). Spatial distributions of GC-1α and the GC-2α subunit in the brain were visualized by in situ hybridization. Brain cGMP levels were measured in WT and GC-1−/− mice after inhaling oxygen with or without 1.2% sevoflurane for 20 min. Results Higher concentrations of sevoflurane were required to induce LORR in GC-1−/− mice than in WT mice (1.5 ± 0.1 vs. 1.1 ± 0.2%, respectively, n = 14 and 14, P

In adults, vasopressin exerts an anxiogenic effect, but less is known about the perinatal period. As a sign of distress, rat pups emit ultrasonic vocalizations when they are separated from their mothers, known as maternal separation-induced ultrasonic vocalization (MS-USV). Previously, reduced MS-USV was reported in 7–8-day-old genetically vasopressin-deficient Brattleboro rats. Here, we aimed to examine the contributing vasopressin receptor (VR) subtypes using Wistar pups. MS-USV was recorded for 10 min, 30 min after vasopressin (V) 1aR, V1bR or V2R antagonist treatment (SR49059, SSR149415, SR121463B; 3, 10 and 30 mg/kg, intraperitoneal). Sedation was studied by the righting reflex and negative geotaxis, and finally, the stress hormone levels were measured by radioimmunoassay. The vasopressin-deficient pups showed decreased MS-USV and adrenocorticotropin levels even after a saline injection, with unchanged corticosterone levels. Thirty mg/kg of V1aR-antagonist increased the corticosterone levels. All V1bR antagonist doses decreased the MS-USV and adrenocorticotropin, while 10 + 10 mg/kg of V1aR and V1bR antagonists decreased MS-USV without influencing the stress hormones. Three mg/kg of V2R antagonist enhanced MS-USV, while 30 mg/kg increased the stress hormone levels. We confirmed that vasopressin deficiency already caused anxiolytic effects in pups. V1bRs are the most important player in connection with their adrenocorticotropin (ACTH)-regulatory role, but a combination of V1aR and V1bR antagonists might be also beneficial through other mechanisms, reducing the possibility of side effects. In contrast, antagonizing the V2Rs may be stressful due to an induction of imbalance in saltwater homeostasis.

Abstract Alcohol use disorders, affective disorders and their comorbidity are sexually dimorphic in humans. However, it is difficult to disentangle the interactions between subject factors influencing alcohol sensitivity in studies of humans. Herein, we combined murine models of unpredictable, chronic, mild stress (UCMS) and voluntary binge-drinking to examine for sex differences in the interactions between prior histories of excessive ethanol-drinking and stress upon ethanol-induced changes in motor behavior and subsequent drinking. In Experiment 1, female mice were insensitive to the UCMS-induced increase in ethanol-induced locomotion and ethanol intake under continuous alcohol-access. Experiment 2 revealed interactions between ethanol dose and sex (females > males), binge-drinking history (water > ethanol), and UCMS history (UCMS > controls), with no additive effect of a sequential prior history of both binge drinking and UCMS observed. We also observed an interaction between UCMS history and sex for righting recovery. UCMS history potentiated subsequent binge-drinking in water controls of both sexes and in male binge-drinking mice. Conversely, a prior binge-drinking history increased subsequent ethanol intake in females only, irrespective of prior UCMS history. In Experiment 3, a concurrent history of binge-drinking and UCMS did not alter ethanol intake, nor did it influence the ethanol dose-locomotor response function, but it did augment alcohol-induced sedation and reduced subsequent alcohol intake over that produced by binge-drinking alone. Thus, the subject factors of biological sex, prior stressor history and prior binge-drinking history interact in complex ways in mice to impact sensitivity to alcohol's motor-stimulating, -incoordinating and intoxicating effects, as well as to influence subsequent heavy drinking. Highlights • Moderate sex differences exist regarding the effects of unpredictable stress on alcohol behavioral sensitivity. • Sex differences exist regarding the effects of prior binge-drinking on alcohol behavioral sensitivity and intake. • Irrespective of prior stress or drinking history, females exhibit less behavioral sensitivity to alcohol than males. • Combined histories of stress and binge-drinking upon alcohol behavioral sensitivity are neither additive nor synergistic. [ABSTRACT FROM AUTHOR]

Offshore renewables are expanding, yet more information is required to understand their possible impacts on the environment. Little is known about the effects of Electromagnetic Fields (EMF) from subsea power cables on marine life. This study simulated an EMF of 500 μT, as modelled for an export cable over a rocky shore, where the industry standard cable burial would not be possible. Righting reflex, refractive index of haemolymph/coelomic fluid, and total haemocyte/coelomocyte counts were measured for four coastal invertebrates (Asterias rubens , Echinus esculentus , Necora puber , and Littorina littorea). No significant differences were found in either behavioural or physiological responses. This was the first study to investigate EMF exposure on righting reflex, and the first ever EMF study on edible sea urchins and periwinkles, and only one of a couple for common starfish and velvet crabs. It therefore, provides valuable data for environmental impact assessments, marine spatial planning, and commercial fisheries. [Display omitted] • First Electromagnetic Field (EMF) study on Littorina littorea and Echinus esculentus • EMF also tested on Asterias rubens and commercially important Necora puber. • EMF on righting reflex studied for first time, which was not significantly affected • Refractive index of haemolymph/coelomic fluid not significantly affected by EMF • Total haemocyte/coelomocyte cell counts not significantly affected by EMF [ABSTRACT FROM AUTHOR]

It has been reported that central dopaminergic system is implicated in the mechanism underlying general anesthesia. Whether dopamine (DA) neurons in midbrain ventral periaqueductal gray (vPAG) are involved in general anesthesia and how general anesthetics affect these neurons remain sparsely documented. To determine the role of vPAG DA neurons in propofol-induced anesthesia, we performed microinjection of 6-hydroxydopamine (6-OHDA) into vPAG to damage DA neurons and investigated the alteration in somatosensory electroencephalogram (EEG), as well as the induction and recovery time of propofol anesthesia. Subsequently, we examined the effect of propofol on the electrophysiological activity of DA neurons in vPAG using whole-cell patch clamp. Two weeks after 6-OHDA microinfusion, DA neurons in the vPAG were markedly reduced by 63.6% in the 6-OHDA-treated rats compared with vehicle rats. This lesion significantly shortened the induction time (7.15 ± 3.97 s vs. 11.18 ± 2.83 s, P < 0.05) and prolonged the recovery time of propofol anesthesia (780.26 ± 150.86 s vs. 590.68 ± 107.97 s, P < 0.05). Meanwhile, EEG in somatosensory cortex revealed that delta power (0-4 Hz) was significantly higher in 6-OHDA-treated rats than vehicle rats. In the electrophysiological experiment, propofol decreased the frequency of spontaneous excitatory postsynaptic currents rather than the amplitude and decay time. In addition, propofol preferentially increased the frequency and prolonged the decay time of spontaneous inhibitory postsynaptic currents without affecting the amplitude. Significance: Propofol can promote presynaptic GABA release, inhibit presynaptic glutamate release and increase postsynaptic GABAA receptor sensitivity, which eventually inhibits the activity of vPAG DA neurons and thereby influences the state of consciousness. [ABSTRACT FROM AUTHOR]

• The components of anesthesia muscle relaxation, unconsciousness, and immobility were examined by grip strength, righting reflex, and the loss of motor response in mice. • The change in each behavior induced by pentobarbital was roughly consistent with that in EEG and EMG power. • A low dose of the indirect GABA receptor agonist gabaculine alone did not affect these components, but it enhanced all components induced by pentobarbital. • This suggests that pentobarbital-induced components of anesthesia are mediated by GABAergic neurons. • Moreover, muscle relaxation or immobility induced by the agent might be partially involved in NMDA receptor antagonism or glycinergic neuron activation, respectively. Pentobarbital-induced anesthesia is believed to be mediated by enhancement of the inhibitory action of γ-aminobutyric acid (GABA)ergic neurons in the central nervous system. However, it is unclear whether all components of anesthesia induced by pentobarbital, such as muscle relaxation, unconsciousness, and immobility in response to noxious stimuli, are mediated only through GABAergic neurons. Thus, we examined whether the indirect GABA and glycine receptor agonists gabaculine and sarcosine, respectively, the neuronal nicotinic acetylcholine receptor antagonist mecamylamine, or the N-methyl- d -aspartate receptor channel blocker MK-801 could enhance pentobarbital-induced components of anesthesia. Muscle relaxation, unconsciousness, and immobility were evaluated by grip strength, the righting reflex, and loss of movement in response to nociceptive tail clamping, respectively, in mice. Pentobarbital reduced grip strength, impaired the righting reflex, and induced immobility in a dose-dependent manner. The change in each behavior induced by pentobarbital was roughly consistent with that in electroencephalographic power. A low dose of gabaculine, which significantly increased endogenous GABA levels in the central nervous system but had no effect on behaviors alone, potentiated muscle relaxation, unconsciousness, and immobility induced by low pentobarbital doses. A low dose of MK-801 augmented only the masked muscle-relaxing effects of pentobarbital among these components. Sarcosine enhanced only pentobarbital-induced immobility. Conversely, mecamylamine had no effect on any behavior. These findings suggest that each component of anesthesia induced by pentobarbital is mediated through GABAergic neurons and that pentobarbital-induced muscle relaxation and immobility may partially be associated with N-methyl- d -aspartate receptor antagonism and glycinergic neuron activation, respectively. [ABSTRACT FROM AUTHOR]