Inadvertent injection of medetomidine in the cerebromedullaris cisterna of a dog during myelographic exam.

INTRODUCTION: A mixed breed dog was anesthetized for diagnostic myelography to investigate acute onset neck pain. Instead of contrast medium, 444 µg/kg medetomidine were inadvertently injected into the cerebromedullaris cisterna owing to a human error. Severe bradycardia, undetectable peripheral pulse, respiratory arrest and loss of pupillary, palpebral and corneal reflexes were observed immediately after injection. Profound hypothermia developed and esophageal temperature, measured 20 minutes after medetomidine injection, was 33 °C. Atipamezole at 1 mg/kg im was administered, followed by a second dose of 0,5 mg/kg iv 20 minutes thereafter. In the meantime, cardiorespiratory parameters and body temperature were monitored, and supportive care that included manually assisted pulmonary ventilation, active warming, and administration of 5 µg/kg/min dopamine was initiated. The dog's clinical condition improved within one hour from the beginning of supportive care, at which time ocular reflexes and swallowing returned, spontaneous ventilation was deemed as adequate and the trachea could be extubated. The dog was discharged in good clinical conditions five days later. Human error and distraction led to a potentially life-threatening complication in the dog of this report and could have possibly been prevented with the use of checklists and with a clearer definition of roles and responsibilities of the personnel involved prior to commencing the clinical procedure. Profound cardiovascular, respiratory, and thermoregulatory depression caused by intracisternal injection of medetomidine responded to parenteral administration of its antagonist and supportive care.

INTRODUCTION: Un chien croisé a été anesthésié pour une myélographie diagnostique afin d'étudier une douleur aiguë au niveau du cou. Au lieu du produit de contraste, 444 µg/kg de médétomidine ont été injectés par inadvertance dans la citerne cérébello-médullaire en raison d'une erreur humaine. Une bradycardie sévère, un pouls périphérique indétectable, un arrêt respiratoire et une perte des réflexes pupillaire, palpébral et cornéen ont été observés immédiatement après l'injection. Une hypothermie profonde s'est développée et la température oesophagienne, mesurée 20 minutes après l'injection de médétomidine, était de 33 °C. De l'atipamézole à 1 mg/kg im a été administré, suivi d'une seconde dose de 0,5 mg / kg iv 20 minutes après. Dans l'intervalle, les paramètres cardiorespiratoires et la température corporelle ont été surveillés et des soins de soutien comprenant une ventilation assistée manuellement, un réchauffement actif et l'administration de 5 µg/kg/min de dopamine ont été initiés. L'état clinique du chien s'est amélioré dans l'heure qui a suivi le début des soins, moment où les réflexes oculaires et la déglutition sont réapparus, la ventilation spontanée a été jugée adéquate et où on a pu procéder à l'extubation. Le chien est sorti dans de bonnes conditions cliniques cinq jours plus tard. Une erreur humaine et de la distraction ont conduit à une complication potentiellement mortelle chez le chien décrit dans ce rapport et auraient pu être évitées grâce à l'utilisation de listes de contrôle et avec une définition plus claire des rôles et des responsabilités du personnel impliqué avant le début de la procédure clinique. Une profonde dépression cardiovasculaire, respiratoire et de la thermorégulation causée par l'injection intracisternale de médétomidine a répondu à l'administration parentérale de son antagoniste et à des soins de soutien.

Disentanglement of Cape fur seals (Arctocephalus pusillus pusillus) with reversible medetomidine-midazolam-butorphanol.

Anaesthesia in pinnipeds is considered a much higher risk than in most terrestrial mammals because of their frequent proximity to water and physiological and anatomical adaptations related to diving, which also influence their anaesthesia management. Anaesthetising and immobilising entangled seals does not allow for selection of animals that are at a safe distance from the water's edge. Medetomidine-midazolam-butorphanol (MMB) sedation was trialled on eight entangled Cape fur seals (CFS) (Arctocephalus pusillus pusillus) to determine if it was safe to use on animals that entered the water post-darting. The MMB was given at an estimated dose of 0.03 mg/kg, 0.2 mg/kg and 0.2 mg/kg, respectively, via remote darting. Sedation was reversed with intramuscular atipamezole (0.15 mg/kg) and naltrexone (0.4 mg/kg) to antagonise the effects of medetomidine and butorphanol, respectively. Moderate sedation was achieved in six animals. Six of the animals entered the water after being darted. There was a single mortality and a single animal that was too lightly sedated for capture. The preliminary results indicate that MMB produces suitable sedation for disentanglement of CFS. Additionally, MMB might be suitable for application to field-based biological research.

ECHOCARDIOGRAPHY AND DIRECT ARTERIAL BLOOD PRESSURE MEASUREMENT IN CAPTIVE CHIMPANZEES (PAN TROGLODYTES) DURING TWO PHASES OF AN ANESTHETIC PROTOCOL.

The effects of α-2 agonists on echocardiographic findings in great apes are not well documented, and knowledge of these effects would expand the understanding of cardiac examinations of chimpanzees under anesthesia with protocols using these drugs. Ten adult chimpanzees (Pan troglodytes), four males and six females, underwent echocardiographic examinations after anesthesia with dexmedetomidine, midazolam, and ketamine (phase 1). Four animals required isoflurane to achieve an adequate plane of anesthesia. Atipamezole was used to antagonize dexmedetomidine, and all remaining animals were placed on isoflurane (phase 2), and then a second echocardiogram was performed. Direct arterial blood pressure was monitored during the anesthetic event. Measurements and recordings were assessed for statistically significant differences between the two phases and sex. There were no significant differences between phases or sex for any two-dimensional echocardiographic measurement of systolic function, although interventricular septum thickness at end systole approached a significant decrease from phase 1 to phase 2 (P = 0.058) when sex was considered a between-subject factor. Left ventricular outflow tract (P = 0.017) and pulmonary artery (P = 0.028) velocities increased after reversal of the dexmedetomidine. Diastolic transmitral flow was consistent with grade 3 diastolic dysfunction (median early to late ventricular filling velocities (E/A) of 2.02, interquartile range [IQR], 1.53-2.13) with a nonsignificant decrease of E velocity and increase in A velocity and decreased E/A after reversal. Trace mitral and tricuspid regurgitation were common findings in the sample population. Arterial blood pressure significantly decreased between phase 1 and phase 2 (P < 0.01). All chimpanzees entered a hypotensive state (mean arterial pressure < 60 mm Hg) during phase 2. Although limited by the small number of chimpanzees, this study showed an increase in afterload, potential diastolic dysfunction, and a decrease in blood pressure after the antagonism of dexmedetomidine. Additional studies to further assess the effects of α-2 agonists in chimpanzees are warranted.

CYP2D6 phenotype explains reported yohimbine concentrations in four severe acute intoxications.

The indole alkaloid yohimbine is an alpha-2 receptor antagonist used for its sympathomimetic effects. Several cases of yohimbine intoxication have been reported and the most recent one involved four individuals taking a yohimbine-containing drug powder. All individuals developed severe intoxication symptoms and were admitted to the hospital. Even though all individuals were assumed to have taken the same dose of the drug powder, toxicology analyses revealed yohimbine blood concentrations of 249-5631 ng/mL, amounting to a 22-fold difference. The reason for this high variability remained to be elucidated. We used recently reported knowledge on the metabolism of yohimbine together with state-of-the art nonlinear mixed-effects modelling and simulation and show that a patient's cytochrome P450 2D6 (CYP2D6) phenotype can explain the large differences observed in the measured concentration after intake of the same yohimbine dose. Our findings can be used both for the identification of safe doses in therapeutic use of yohimbine and for an explanation of individual cases of overdosing.

Effects of hydrocortisone and yohimbine on selective attention to emotional cues.

INTRODUCTION: Facial expressions contain important affective information, and selective attention to facial expression provides an advantage in the face of loss, stress and danger. In addition, the sympathetic nervous system and hypothalamus-pituitary-adrenal axis mediate the organism's response to loss and danger. Here, we aimed at investigating the influence of sympathetic nervous system and hypothalamus-pituitary-adrenal axis activation on selective attention to affective facial stimuli. METHODS AND MATERIALS: One hundred-and-four healthy men between 18-35 years old (mean (standard deviation) age: 24.1 (3.5) years) participated in the study. We used a randomised, double-blind, placebo-controlled design. Participants received either: (a) yohimbine, (b) hydrocortisone, (c) yohimbine and hydrocortisone or (d) placebo only and participated in a dot-probe task with sad, happy and neutral faces. We collected salivary samples to measure cortisol and alpha amylase activity in addition to measurements of blood pressure and heart rate. Salivary cortisol served as correlate of hypothalamus-pituitary-adrenal axis activation and salivary alpha amylase activity, blood pressure and heart rate as correlates of sympathetic nervous system activation. Measurements were carried out before and after drug administration. RESULTS: We did not find a main effect or interaction effect of hydrocortisone or yohimbine administration on selective attention to happy faces. However, we found an interaction of yohimbine and hydrocortisone on selective attention to sad faces. Post-hoc t-test revealed an attentional bias away from sad stimuli and towards neutral faces in the hydrocortisone-only group. DISCUSSION: Only hydrocortisone administration led to an attentional bias away from sad faces. Future studies should investigate these effects in major depression disorder, as this disorder is characterised by glucocorticoid resistance and increased processing of sad stimuli.

Antiplatelet Effect of Mirtazapine via Co-blocking of the 5-HT2A and α2-Adrenergic Receptors on Platelets.

Mirtazapine (MTZ) is a noradrenergic and specific serotonergic antidepressant. MTZ is reportedly associated with an increased risk of bleeding. However, the underlying mechanism remains unclear. In this study, we investigated the antiplatelet effect of MTZ in mice via light transmission aggregometry to elucidate the mechanism of MTZ-induced bleeding. The results of the ex vivo study showed that the oral administration of MTZ (20 or 100 mg/kg) significantly suppressed platelet aggregation mediated by the synergic interaction of 5-hydroxytryptamine (5-HT) and adrenaline. Additionally, MTZ significantly suppressed platelet aggregation, mediated by the synergic interaction of ADP and 5-HT or adrenaline. Similar results were obtained in vitro, under the condition of 5-HT- and adrenaline-induced platelet aggregation. Overall, the results suggest that MTZ exerts antiplatelet effect by co-blocking 5-HT2A and α2-adrenergic receptors on platelets and suppresses platelet aggregation mediated by ADP, increased by either 5-HT or adrenaline. Thus, a detailed monitoring of bleeding is recommended for patients taking MTZ.

CARDIORESPIRATORY EFFECTS OF DEXMEDETOMIDINE-MIDAZOLAM AND REVERSAL WITH ATIPAMEZOLE IN CAPTIVE BROWN BROCKET DEER (MAZAMA GOUAZOUBIRA).

Ketamine-free, midazolam-based protocols have successfully immobilized cervids in the past but their impact on physiological function has not yet been thoroughly investigated. Six deer received IM dexmedetomidine (30.96 ± 3.06 µg/kg) and midazolam (0.31 ± 0.03 mg/kg). Heart rates (HR), respiratory rates (f ), rectal temperature, mean arterial blood pressure (MAP), and oxygen saturation (SpO2) were recorded 25 min after drug delivery (T25) and every 5 min until T55. An arterial blood sample was collected at T40. Mean HR and temperature significantly decreased throughout sedation, but were maintained above critical values (> 60 beats/ min and 37°C, respectively). Although not statistically different, f clinically decreased during sedation. MAP remained within acceptable ranges (60-80 mmHg) and SpO2 above 95%. Mean PaO2 was normal (>80 mmHg), but a mild hypoxemia was observed on two occasions. Recovery was smooth yet prolonged, as the first head movement, attempt to stand, sternal recumbency, and standing position were recorded within 9.36 ± 3.47, 10.32 ± 1.37, 13.13 ± 2.70, and 15.34 ± 2.57 min after IM atipamezole, respectively. This protocol was effective for short-term procedures in captive brown brocket deer, and appeared to be safe on the basis of arterial blood gases and cardiorespiratory variables.

Inhibition of α2-adrenoceptor is renoprotective in 5/6 nephrectomy-induced chronic kidney injury rats.

In the present study, we investigated the renoprotective effects of long-term treatment with yohimbine, an α2-adrenoceptor inhibitor, in a 5/6 nephrectomy-induced chronic kidney disease (CKD) rat model. Male Sprague-Dawley rats were randomly allocated into the following groups: sham-operated, 5/6-nephrectomized (5/6 Nx), 5/6 Nx + low or high dose of yohimbine (0.3 or 3.0 mg/L in drinking water, respectively), and 5/6 Nx + hydralazine (250 mg/L in drinking water). The 5/6 Nx group presented with renal dysfunction, hypertension, noradrenaline overproduction, and histopathological injuries. Blood pressure decreased in both the yohimbine- and hydralazine-treated groups. Treatment with high dose of yohimbine, but not hydralazine, apparently attenuated urinary protein excretion and noradrenaline concentration of renal venous plasma. Renal fibrosis and upregulated fibrosis-related gene expression were suppressed by high dose of yohimbine. Furthermore, yohimbine, but not hydralazine, treatment ameliorated the urinary concentration ability. These findings suggest that long-term yohimbine treatment can be a useful therapeutic option to prevent the progression of CKD.

Dexmedetomidine attenuates sevoflurane­induced neurocognitive impairment through α2­adrenoceptors.

It has been reported that sevoflurane induces neurotoxicity in the developing brain. Dexmedetomidine is an α2 adrenoceptor agonist used for the prevention of sevoflurane­induced agitation in children in clinical practice. The aim of the present study was to determine whether dexmedetomidine could prevent sevoflurane­induced neuroapoptosis, neuroinflammation, oxidative stress and neurocognitive impairment. Additionally, the involvement of α2 adrenoceptors in the neuroprotective effect of dexmedetomidine was assessed. Postnatal day (P)6 C57BL/6 male mice were randomly divided into four groups (n=6 in each group). Mice were pretreated with dexmedetomidine, either alone or together with yohimbine, an α2 adrenoceptor inhibitor, then exposed to 3% sevoflurane in 25% oxygen. Control mice either received normal saline alone or with sevoflurane exposure. Following sevoflurane exposure, the expression of cleaved caspase­3 was detected by immunohistochemistry in hippocampal tissue sections. In addition, the levels of tumor necrosis factor­α (TNF­α), interleukin (IL)­1ß, IL­6 and malondialdehyde, as well as superoxide dismutase (SOD) activity in the hippocampus were measured. At P35, the learning and memory abilities were assessed in each mouse using a Morris water maze test. Dexmedetomidine significantly decreased the expression of activated caspase­3 following sevoflurane exposure. Moreover, dexmedetomidine significantly decreased the levels of TNF­α, IL­1ß and IL­6 in the hippocampus. SOD activity also increased in a dose­dependent manner in dexmedetomidine­treated mice. MDA decreased in a dose­dependent manner in dexmedetomidine­treated mice. Lastly, sevoflurane­induced learning and memory impairment was reversed by dexmedetomidine treatment. By contrast, co­administration of yohimbine significantly attenuated the neuroprotective effects of dexmedetomidine. These findings suggested that dexmedetomidine exerted a neuroprotective effect against sevoflurane­induced apoptosis, inflammation, oxidative stress and neurocognitive impairment, which was mediated, at least in part, by α2 adrenoceptors.

Total injectable anesthesia of dogs and cats for remote location veterinary sterilization clinic.

BACKGROUND: Sterilization clinics often occur in remote places where anesthesia machines and compressed oxygen are unavailable. This study describes the use of total injectable anesthesia in dogs and cats presented for sterilization in a remote location. RESULTS: A total of 100 animals were sterilized; 26 female cats (CF), 22 male cats (CM), 28 female dogs (DF), and 24 male dogs (DM). CF were anesthetized with dexmedetomidine (20 mcg/kg), ketamine (8 mg/kg) and hydromorphone (0.1 mg/kg) IM. CM were anesthetized with dexmedetomidine (15 mcg/kg), ketamine (5 mg/kg) and hydromorphone (0.1 mg/kg) IM. Insufficient anesthesia in cats was treated with alfaxalone (1 mg/kg) IM. All cats were administered meloxicam at 0.3 mg/kg SQ. DF were anesthetized with dexmedetomidine (15 mcg/kg), ketamine (7-10 mg/kg) and hydromorphone (0.1 mg/kg) IM. DM were anesthetized with dexmedetomidine (15 mcg/kg), ketamine (5 mg/kg) and hydromorphone (0.1 mg/kg) IM. All dogs had IV catheter and endotracheal tube placed. If SpO2 < 91%, ventilation was assisted with an Ambu bag. Insufficient anesthesia in dogs was treated with alfaxalone (1 mg/kg) IV. All dogs were administered meloxicam at 0.2 mg/kg SQ. Following surgery, atipamezole (0.05-0.1 mg/kg) IM was administered to any patient that did not have voluntary movement. All patients survived and were discharged. Less than 25% of cats and male dogs required supplemental anesthesia. Fifty seven percent of female dogs required supplemental anesthesia. More than 89% of patients (in any group) required atipamezole administration. One cat recovered with agitation and hyperthermia (41.1C/ 106F). Some dogs required ventilatory assistance to remain normoxemic while anesthetized. CONCLUSION: Total injectable anesthesia can be accomplished for remote location sterilization clinics with minimal morbidity.

A Comparison of the Efficacy and Cardiopulmonary Effects of 3 Different Sedation Protocols in Otolemur garnettii.

The Northern greater galago (Otolemur garnettii) is a prosimian primate most commonly used to study the evolutionary development of vision and somatosensation. This study aimed to investigate the efficacy and cardiopulmonary effects of 3 sedation protocols commonly used in other primate species: 1) alfaxalone (Alf; 8 mg/kg IM) 2) ketamine alone (Ket; 20 mg/kg IM) and 3) ketamine + dexmedetomidine (Ket+Dex; 4 mg/kg + 25 µg/kg IM) with reversal (atipamezole; 250 µg/kg IM). A total of 34 animals were evaluated, including 11 juveniles and 23 adults. Cardiopulmonary parameters such as indirect blood pressure, heart rate, respiratory rate, and SpO2 were measured, and blood was collected for blood gas analysis and a chemistry panel. To examine the efficacy of each sedation protocol, induction time, immobilization time, and recovery time were recorded. Subjective measures of quality and efficacy included quality of induction, pedal withdrawal reflex, palpebral reflex, muscle tension, rectal temperature, and quality of recovery. All 3 protocols successfully immobilized the animals and all animals recovered from sedation. Heart rates were highest among the Ket group and the lowest for the Ket+Dex group. On average, the Alf group was immobilized for twice as long as either the Ket or Ket+Dex groups. The Ket+Dex group had the fastest average recovery time and subjectively had the best quality of recovery. Based on these results, Ket+Dex is recommended over Alf or Ket alone for brief sedation of healthy galagos.

Mirtazapine, an α2 Antagonist-Type Antidepressant, Reverses Pain and Lack of Morphine Analgesia in Fibromyalgia-Like Mouse Models.

Treatment of fibromyalgia is an unmet medical need; however, its pathogenesis is still poorly understood. In a series of studies, we have demonstrated that some pharmacological treatments reverse generalized chronic pain but do not affect the lack of morphine analgesia in the intermittent cold stress (ICS)-induced fibromyalgia-like pain model in mice. Here we report that repeated intraperitoneal treatments with mirtazapine, which is presumed to disinhibit 5-hydroxytriptamine (5-HT) release and activate 5-HT1 receptor through mechanisms of blocking presynaptic adrenergic α2 and postsynaptic 5-HT2 and 5-HT3 receptors, completely reversed the chronic pain for more than 4 to 5 days after the cessation of treatments. The repeated mirtazapine treatments also recovered the morphine analgesia after the return of nociceptive threshold to the normal level. The microinjection of small interfering RNA (siRNA) adrenergic α2a receptor (ADRA2A) into the habenula, which showed a selective upregulation of α2 receptor gene expression after ICS, reversed the hyperalgesia but did not recover the morphine analgesia. However, both reversal of hyperalgesia and recovery of morphine analgesia were observed when siRNA ADRA2A was administered intracerebroventricularly. As the habenular is reported to be involved in the emotion/reward-related pain and hypoalgesia, these results suggest that mirtazapine could attenuate pain and/or augment hypoalgesia by blocking the habenular α2 receptor after ICS. The recovery of morphine analgesia in the ICS model, on the other hand, seems to be mediated through a blockade of α2 receptor in unidentified brain regions. SIGNIFICANCE STATEMENT: This study reports possible mechanisms underlying the complete reversal of hyperalgesia and recovery of morphine analgesia by mirtazapine, a unique antidepressant with adrenergic α2 and serotonergic receptor antagonist properties, in a type of intermittently repeated stress (ICS)-induced fibromyalgia-like pain model. Habenula, a brain region which is related to the control of emotional pain, was found to play key roles in the antihyperalgesia, whereas other brain regions appeared to be involved in the recovery of morphine analgesia in the ICS model.

Bidirectional pharmacological perturbations of the noradrenergic system differentially affect tactile detection.

The brain neuromodulatory systems heavily influence behavioral and cognitive processes. Previous work has shown that norepinephrine (NE), a classic neuromodulator mainly derived from the locus coeruleus (LC), enhances neuronal responses to sensory stimuli. However, the role of the LC-NE system in modulating perceptual task performance is not well understood. In addition, systemic perturbation of NE signaling has often been proposed to specifically target the LC in functional studies, yet the assumption that localized (specific) and systemic (nonspecific) perturbations of LC-NE have the same behavioral impact remains largely untested. In this study, we trained mice to perform a head-fixed, quantitative tactile detection task, and administered an α2 adrenergic receptor agonist or antagonist to pharmacologically down- or up-regulate LC-NE activity, respectively. We addressed the outstanding question of how bidirectional perturbations of LC-NE activity affect tactile detection, and tested whether localized and systemic drug treatments exert the same behavioral effects. We found that both localized and systemic suppression of LC-NE impaired tactile detection by reducing motivation. Surprisingly, while locally activating LC-NE enabled mice to perform in a near-optimal regime, systemic activation impaired behavior by promoting impulsivity. Our results demonstrate that localized silencing and activation of LC-NE differentially affect tactile detection, and that localized and systemic NE activation induce distinct behavioral changes.

Different Reactions of Zebra Finches and Bengalese Finches to a Three-Component Mixture of Anesthetics.

Kawai et al. (2011) recently introduced a mixture of three anesthetic agents (here called MMB) that has an effect similar to ketamine/xylazine in mice, which might allow more effective reaction to changes in the animal condition, as an antagonist is available, and which can be used without license for handling narcotic drugs. Using Kawai's study as a baseline, we tested whether this anesthesia and its antagonist can also be used in avian studies. In the present study, we used two species, the zebra finch and the Bengalese finch, of the avian family Estrildidae. In zebra finches, anesthesia effects similar to the use of ketamine/xylazine and to those obtained in mice can be reached by the use of MMB if a higher dose is applied. MMB leads to more variable anesthesia, but has the advantage of a longer time window of deep anesthesia. An antagonist to one component of MMB reduced the awaking time, but was not as effective as in mice. For Bengalese finches, MMB cannot be generally recommended because of difficult handling and high mortality rate when used without antagonist, but could be used for perfusions instead of pentobarbital.

Tissue Residue Levels of the Tranquilizer Combination of Butorphanol, Azaperone, and Medetomidine, and the Antagonists, Naltrexone, Atipamezole, and Tolazoline, in Black Bears (Ursus americanus) Postimmobilization.

The tranquilizer combination of butorphanol, azaperone, and medetomidine (BAM) has shown good efficacy for immobilization of wildlife, including black bears (Ursus americanus). BAM is antagonized with a combination of naltrexone and atipamezole. We immobilized 19 adult captive wild caught black bears and, except for three bears that were euthanized immediately, bears were recovered with naltrexone and atipamezole. Tissue residues (≥0.01 ppm) for the tranquilizers butorphanol, azaperone, and medetomidine were detected in liver and muscle of all three bears euthanized on day 0 postinjection (PI). Azaperone was not detected after 1 d PI. Residue for medetomidine was detected in two bears: in the liver 3 d PI and in the kidney 6 d PI. Butorphanol was reported in three bears: in fat 5 d PI, in kidney 6 d PI, and, surprisingly, in kidney, muscle, and fat 7 d PI. No tissue residues were detected in the three bears euthanized at 8 d PI. Tissue residues for the antagonists, naltrexone and atipamezole, were detected in bears euthanized 2 and 6 d PI, but not in tissues from animals euthanized at 7 or 8 d PI.

COMPARISON OF SUBCUTANEOUS ADMINISTRATION OF ALFAXALONE-MIDAZOLAM-DEXMEDETOMIDINE WITH KETAMINE-MIDAZOLAM-DEXMEDETOMIDINE FOR CHEMICAL RESTRAINT IN JUVENILE BLUE POISON DART FROGS (DENDROBATES TINCTORIUS AZUREUS).

Blue poison dart frogs (Dendrobates tinctorius azureus) are commonly maintained in zoological institutions and are becoming popular in the pet trade industry. Sedation or light anesthesia is required for safe and effective handling of this species. In this study, the sedative effects of subcutaneously administered alfaxalone-midazolam-dexmedetomidine (AMD) (20, 40, 5 mg/kg, respectively) and ketamine-midazolam-dexmedetomidine (KMD) (100, 40, 5 mg/kg, respectively) were compared in a prospective, randomized, blinded, crossover study in juvenile blue poison dart frogs (n = 10). Both protocols were partially reversed 45 min after administration of either protocol with subcutaneously administered flumazenil (0.05 mg/kg) and atipamezole (50 mg/kg). Heart rate, pulmonic respiratory rate, various reflexes, and behavioral parameters were monitored after drug administration. Both protocols resulted in rapid loss of righting reflex [median (range): AMD, 5 min (5-5 min); KMD, 5 min (5-10 min)]. Time to complete recovery was similar with both protocols (mean ± SD: AMD, 97.5 ± 11.4 min; KMD, 96.5 ± 25.4 min). The AMD protocol resulted in pulmonic respiratory depression, whereas no significant difference in heart rate was found between the two protocols. All frogs were observed eating within 24 hr of chemical restraint. Gastric prolapses occurred in four frogs (AMD 3, KMD 1) that were easily reduced with a cotton-tip application. No other adverse reactions were observed. The results of this study provide two different subcutaneous chemical restraint protocols in juvenile blue poison dart frogs.

THE EFFECTS OF PROCEDURE DURATION AND ATIPAMEZOLE ADMINISTRATION ON HYPERKALEMIA IN TIGERS (PANTHERA TIGRIS) AND LIONS (PANTHERA LEO) ANESTHETIZED WITH α-2 AGONISTS.

A retrospective analysis of 40 extended (>2 hr) anesthetic events in eight lions (Panthera leo) and 32 tigers (Panthera tigris) was performed using a hierarchical linear growth curve model to assess the effects of anesthetic time, α-2 adrenoreceptor agonist dosages, administration of atipamezole, and biochemical parameters on rising plasma K+ concentrations. Hyperkalemia was first noted at a mean time of 187 min (range: 131-226 min), with time under anesthesia as a statistically significant predictor of K+ concentration (P < 0.0001). A significant two-way interaction between time and atipamezole administration (P = 0.0082) for rising K+ concentrations was demonstrated, indicating that administration of atipamezole can mitigate the rise in K+ concentrations. Administration of atipamezole beyond 150 min of anesthetic time was less effective in reducing K+ concentrations than if administered earlier. Electrocardiographic abnormalities were noted in eight animals, including three hyperkalemic individuals. Lions developed significantly greater plasma K+ concentrations than tigers (P = 0.0009) during anesthesia. No biochemical parameter was identified as a significant indicator of which individuals will develop hyperkalemia. Clinicians anesthetizing any large nondomestic felid should monitor electrolytes regularly during anesthetic events; consider early, partial- to full-dose reversal of α-2 agonists; and be prepared to correct potentially life-threatening electrocardiographic abnormalities resulting from hyperkalemia.

Enhanced noradrenergic activity by yohimbine and differential fear conditioning in patients with major depression with and without adverse childhood experiences.

Major depressive disorder (MDD) has been associated with changes in the biological stress systems, including the locus coeruleus-noradrenergic system. Accumulated evidence suggests an upregulation of central alpha2-receptors, leading to decreased noradrenergic activity on a central level in MDD patients. Adverse childhood experiences (ACE) such as physical or sexual abuse might contribute to those changes. Furthermore, noradrenaline can affect cognitive processes, e.g. learning and memory. Cognitive dysfunctions constitute an important symptom of MDD. We aimed to investigate the relationship of alpha2-receptor dysregulation with learning processes in MDD by conducting a differential fear conditioning paradigm after double-blind administration of the alpha2-receptor antagonist yohimbine versus placebo. To investigate the role of ACE systematically, we included four groups of healthy participants and MDD patients with and without ACE (MDD-/ACE-: N = 44, MDD-/ACE+: N = 26, MDD+/ACE-: N = 24, MDD+/ACE+: N = 24; without antidepressant medication). We found increased noradrenergic activity after yohimbine administration across groups as measured by alpha-amylase and blood pressure. Overall, fear responses were higher after yohimbine as indicated by skin conductance responses and fear-potentiated startle responses. While we found no significant MDD effect, ACE had significant impact on the ability to discriminate between both conditioned stimuli (CS+ predicting an aversive stimulus, CS- predicting none), depending on drug condition. After yohimbine, CS discrimination decreased in individuals without ACE, but not in individuals with ACE. Differences in the response to yohimbine might be explained by aberrant alpha2-receptor regulation in individuals with ACE. Impaired discrimination of threat and safety signals might contribute to enhanced vulnerability following ACE.

Effects of atipamezole dosage and timing of administration on recovery time and quality in cats following injectable anaesthesia incorporating ketamine.

OBJECTIVES: The aim of this study was to establish the optimum dosage and timing of administration of atipamezole in cats undergoing general anaesthesia incorporating ketamine to provide the shortest recovery possible without unacceptably compromising recovery quality. METHODS: In total, 128 healthy male cats (age range 2-108 months, weight range 0.56-5.22 kg) admitted for castration were randomly allocated to groups of 32. Anaesthesia was induced with 60 mg/m2 ketamine, 180 µg/m2 buprenorphine, 3 mg/m2 midazolam and 600 µg/m2 medetomidine intramuscularly (IM). Cats received 600 µg/m2 (groups 1ATI20 and 1ATI40) or 1.5 mg/m2 (groups 2.5ATI20 and 2.5ATI40) atipamezole IM either 20 (groups 1ATI20 and 2.5ATI20) or 40 mins (groups 1ATI40 and 2.5ATI40) after the 'quad'. Preparation time, surgical time, auricular temperature, times to sternal recumbency and first standing, and recovery quality score were recorded. Data were analysed using ANOVA, Kruskal-Wallis, Mann-Whitney U-tests and χ2 tests. Statistical significance was deemed to be P ⩽0.05. RESULTS: Groups did not differ significantly in preparation or surgical time. Auricular temperature decreased significantly over time (P <0.01) but did not differ between atipamezole treatment groups. Time to sternal recumbency in group 2.5ATI20 (52.9 ± 22.3 mins) was faster than group 1ATI20 (65.7 ± 24.7 mins) (P ⩽0.05), but there were no significant differences between other groups. Time to first standing and recovery quality scores did not differ significantly between groups. Minimal adverse effects were seen. CONCLUSIONS AND RELEVANCE: Atipamezole administration after 20 mins did not reduce recovery time but neither was recovery quality adversely affected compared with when it was administered after 40 mins, following datasheet recommendations with concurrent ketamine administration. The results of this study also suggest that an atipamezole:medetomidine dose ratio of 2.5:1 is more effective than 1:1 in reducing recovery time, regardless of timing of administration, although this only reached statistical significance for time to sternal recumbency when atipamezole was administered after 20 mins.

Effects of precondition α2-adrenoceptor agents on memory- and anxiety-related processes in the transient cerebral ischemic rats.

Neurological evidence for the neuroprotective function of α2-adrenoceptors in the cerebral ischemia is inconsistent. It is not examined how pretreatment with a single dose of α2-adrenoceptor agents can affect motor function and anxiety- and memory-related responses in the cerebral ischemic animals. The transient forebrain ischemia model was provided, using a bilateral common carotid arterial occlusion (two-vessel occlusion, 2VO) in male Wistar rats. The 2VO rats impaired motor functions in the Rota-rod and wire grip tests and also decreased the step-through latency and the percentage of time spent on the open arms (%OAT), the percentage of entries into the open arms (%OAE) as well as locomotion in the elevated plus maze (EPM), indicating a memory deficit and anxiety-like behavior. Intraperitoneal single administration of yohimbine (0, 0.001, 0.01, and 0.1 mg/kg) before the 2VO did not alter these parameters while the higher and middle doses of clonidine (0.01 and 0.1 mg/kg) prevented the memory deficit and hypo-locomotion and its middle dose abrogated Rota-rod dysfunction and anxiety-like response. Meanwhile, both drugs did not influence on the measured behaviors in the sham groups by themselves. Moreover, yohimbine (0.001 mg/kg) abolished the beneficial effects of clonidine (0.01 and 0.1 mg/kg) on motor function in the Rota-rod and memory retention and also at its middle dose on the %OAT and locomotion in the 2VO rats. Our findings show a neuroprotective role for clonidine in motor function and memory- and anxiety-related behaviors of 2VO rats and the importance of α2-adrenoceptors in these processes.