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The Journal of Pharmacology and... Jul 2021The drug of abuse, -hydroxybutyric acid (GHB), is commonly co-ingested with ethanol, resulting in a high incidence of toxicity and death. Our laboratory has previously...
The drug of abuse, -hydroxybutyric acid (GHB), is commonly co-ingested with ethanol, resulting in a high incidence of toxicity and death. Our laboratory has previously reported that GHB is a substrate for the monocarboxylate transporters (MCTs), necessary for its absorption, renal clearance, and tissue distribution, including across the blood-brain barrier. Our goal was to investigate the drug-drug interaction (DDI) between GHB and ethanol and to evaluate MCT1 inhibition as a strategy to reverse toxicity. The toxicokinetics of this DDI were investigated, including brain-to-plasma concentration ratios, in the presence and absence of ethanol. The toxicodynamic parameters examined were respiratory depression (breathing frequency, tidal volume) and sedation (time of return-of-righting reflex). Ethanol was administered (2 g/kg i.v.) 5 minutes before the intravenous or oral administration of GHB, and MCT1 inhibitors AZD-3965 and AR-C155858 (5 mg/kg i.v.) were administered 60 minutes after GHB administration. Ethanol administration did not alter the toxicokinetics or respiratory depression caused by GHB after intravenous or oral administration; however, it significantly increased the sedation effect, measured by return-to-righting time. AZD-3965 or AR-C155858 significantly decreased the effects of the co-administration of GHB and ethanol on respiratory depression and sedation of this DDI and decreased brain concentrations and the brain-to-plasma concentration ratio of GHB. The results indicate that ethanol co-administered with GHB increases toxicity and that MCT1 inhibition is effective in reversing toxicity by inhibiting GHB brain uptake when given after GHB-ethanol administration. SIGNIFICANCE STATEMENT: These studies investigated the enhanced toxicity observed clinically when -hydroxybutyric acid (GHB) is co-ingested with alcohol and evaluated strategies to reverse this toxicity. The effects of the novel monocarboxylate transporter 1 (MCT1) inhibitors AR-C155858 and AZD-3965 on this drug-drug interaction have not been studied before, and these preclinical studies indicate that MCT1 inhibitors can decrease brain concentrations of GHB by inhibiting brain uptake, even when administered at times after GHB-ethanol. AZD-3965 represents a potential treatment strategy for GHB-ethanol overdoses.
Topics: Animals; Drug Interactions; Ethanol; Hydroxybutyrates; Male; Monocarboxylic Acid Transporters; Pyrimidinones; Rats; Rats, Sprague-Dawley; Respiratory Insufficiency; Symporters; Thiophenes; Uracil
PubMed: 33963018
DOI: 10.1124/jpet.121.000566 -
Journal of the Association For Research... Apr 2019Many developmental disorders of the inner ear are manifested clinically as delayed motor development and challenges in maintaining posture and balance, indicating...
Many developmental disorders of the inner ear are manifested clinically as delayed motor development and challenges in maintaining posture and balance, indicating involvement of central vestibular circuits. How the vestibular circuitry is rewired in pediatric cases is poorly understood due to lack of a suitable animal model. Based on this, our lab designed and validated a chick embryo model to study vestibular development in congenital vestibular disorders. The developing inner ear or "otocyst" on the right side of 2-day-old chick embryos (E2) was surgically rotated 180° in the anterior-posterior axis, forming the "anterior-posterior axis rotated otocyst chick" or ARO chick. The ARO chick has a reproducible pathology of a sac with truncated or missing semicircular canals. A sac is the most common inner ear defect found in children with congenital vestibular disorders. In E13 ARO chicks, the sac contained all three cristae and maculae utriculi and sacculi, but the superior crista and macula utriculi were shortened in anterior-posterior extent. Also, the number of principal cells of the tangential vestibular nucleus, a major avian vestibular nucleus, was decreased 66 % on the rotated side. After hatching, no difference was detected between ARO and normal chicks in their righting reflex times. However, unlike normal chicks, ARO hatchlings had a constant, right head tilt, and after performing the righting reflex, ARO chicks stumbled and walked with a widened base. Identifying the structure and function of abnormally developed brain regions in ARO chicks may assist in improving treatments for patients with congenital vestibular disorder.
Topics: Animals; Chick Embryo; Disease Models, Animal; Ear, Inner; Reflex, Vestibulo-Ocular; Vestibular Diseases
PubMed: 30564989
DOI: 10.1007/s10162-018-00705-z -
Scientific Data Aug 2021This data collection contains Magnetic Resonance Imaging (MRI) data, including structural, diffusion, stimulus-evoked, and resting-state functional MRI and behavioural...
This data collection contains Magnetic Resonance Imaging (MRI) data, including structural, diffusion, stimulus-evoked, and resting-state functional MRI and behavioural assessment results, including acute post-impact Loss-of-Righting Reflex time and acute, subacute, and longer-term Neural Severity Score, and Open Field Behaviour obtained from a mouse model of concussion. Four cohorts with 43 3-4 months old male mice in total were used: Sham (n = 14, n = 6 day 2, n = 3 day 7, n = 5 day 14), concussion day 2 (CON 2; n = 9), concussion day 7 (CON 7; n = 10), concussion day 14 (CON 14; n = 10). The data collection contains the aforementioned MRI data in compressed NIFTI format, data sheets on animal's backgrounds and behavioural outcomes and is made publicly available from a data repository. The available data are intended to facility cross-study comparisons, meta-analysis, and science reproducibility.
Topics: Animals; Brain; Brain Concussion; Disease Models, Animal; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL
PubMed: 34354090
DOI: 10.1038/s41597-021-00985-w -
Behavioural Neurology 2020Propofol is a classical anesthetic and induces consciousness loss, and gamma-aminobutyric-acid-type-A (GABA-A) receptor is its target. Righting reflex is associated with...
OBJECTIVE
Propofol is a classical anesthetic and induces consciousness loss, and gamma-aminobutyric-acid-type-A (GABA-A) receptor is its target. Righting reflex is associated with conscious response. The nucleus basalis (NB) acts as a major relay between the reticular activating system and the frontal cortex (FC). Propofol may mediate righting reflex by affecting GABA-A receptor in NB.
METHODS
Fifty male SD rats (250-350 g) were divided into parts I and II. In part I, 20 male SD rats were randomly divided into control group (CG) and NB-lesion group (NG, ibotenic acid-induced NB lesion). In part II, 30 male SD rats were treated with saline (0.9% NaCl, SG group), muscimol (a GABA-A receptor agonist, MG group), and gabazine (a GABA-A receptor antagonist, GG group) in NB, respectively. Two weeks later, the activity of the rats was measured between CG and NG groups. The rats were intravenously injected with propofol (50 mg/kg/h) to test the time of loss of righting reflex (LORR) in all rats. When LORR occurred, the rats received single administration of propofol (12 mg/kg) to measure the time of return of righting reflex (RORR). Electroencephalogram (EEG) activity of the frontal cortex (FC) was recorded.
RESULTS
The numbers of NB neurons were reduced by 44% in the NG group compared to the CG group ( < 0.05) whereas the activity of rats was reduced a little in the NG group when compared with the CG group, but the statistical difference was insignificant ( < 0.05) whereas the activity of rats was reduced a little in the NG group when compared with the CG group, but the statistical difference was insignificant ( < 0.05) whereas the activity of rats was reduced a little in the NG group when compared with the CG group, but the statistical difference was insignificant ( < 0.05) whereas the activity of rats was reduced a little in the NG group when compared with the CG group, but the statistical difference was insignificant ( < 0.05) whereas the activity of rats was reduced a little in the NG group when compared with the CG group, but the statistical difference was insignificant ( < 0.05) whereas the activity of rats was reduced a little in the NG group when compared with the CG group, but the statistical difference was insignificant (.
CONCLUSIONS
The unilateral NB lesion increased the recovery time and FC delta power, and the NB region might be involved in the emergence after propofol administration. Propofol plays a crucial role for causing conscious loss by affecting GABA-A receptor in NB.
Topics: Animals; Basal Nucleus of Meynert; Consciousness; Electroencephalography; Male; Muscimol; Propofol; Pyridazines; Rats; Rats, Sprague-Dawley; Receptors, GABA-A
PubMed: 32148565
DOI: 10.1155/2020/9370891 -
Journal of the American Association For... Nov 2023Exposure to CO₂ gas is a common rodent euthanasia method. CO₂ activates nociceptors in rats and is painful to humans at concentrations equal to or greater than 32.5%...
Exposure to CO₂ gas is a common rodent euthanasia method. CO₂ activates nociceptors in rats and is painful to humans at concentrations equal to or greater than 32.5% The concentration of CO₂ at which rodents become unconsciousness is inadequately defined. We used loss of righting reflex (LORR) to identify the concentration at which CO₂ caused loss of consciousness in C57Bl/6, CD1 and 129P3J mice (16 females and 16 males per strain). We used a custom built, rotating, motorized cylinder to determine LORR as CO₂ concentrations were increased. Two LORR assessment methods were used: 1) a 1-Paw assessment in which the righting reflex was considered to be present if one or more paws contacted the cylinder after rotation into dorsal recumbency and 2) a 4-Paw assessment in which the righting reflex was considered to be present only if all 4 paws contacted the cylinder. LORR test data were analyzed with Probit regression and dose response curves were plotted. 1-Paw EC values (CO₂ concentration at which LORR occurred for 95% of the population) were: C57Bl/6; 30.7%, CD1; 26.2%, 129P3J; 20.1%. The EC for C57Bl/6 was significantly higher than that of the 129P3J mice, with no significant differences between other strains. Four-Paw EC values were: C57Bl/6; 22.8%, CD1; 25.3%, 129P3J; 20.1%. Values for 129P3J mice were significantly lower than those of CD1 mice), with no significant difference between other strains. The EC varied significantly between 1-Paw and 4-Paw methods only for C57Bl/6 mice. These results suggest a potential for nociception and pain to occur in some individuals of some mouse strains during CO₂ euthanasia.
Topics: Animals; Female; Male; Mice; Carbon Dioxide; Mice, Inbred C57BL; Pain; Reflex; Reflex, Righting; Unconsciousness
PubMed: 37770194
DOI: 10.30802/AALAS-JAALAS-23-000035 -
British Journal of Anaesthesia Jul 2020We hypothesised that Calabadion 1, an acyclic cucurbit[n]uril molecular container, reverses fentanyl-induced respiratory depression and dysfunction of the CNS.
BACKGROUND
We hypothesised that Calabadion 1, an acyclic cucurbit[n]uril molecular container, reverses fentanyl-induced respiratory depression and dysfunction of the CNS.
METHODS
Experiments were conducted in male Sprague-Dawley rats. A constant-rate i.v. infusion of fentanyl (12.5 or 25 μg kg over 15 min) was administered followed by an i.v. bolus of Calabadion 1 (0.5-200 mg kg) or placebo. The primary outcome was reversal of ventilatory and respiratory depression, assessed by pneumotachography and arterial blood gas analysis, respectively. Key secondary outcomes were effects on fentanyl-induced central nervous dysfunction quantified by righting reflex, balance beam test, and electromyography (EMG).
RESULTS
Calabadion 1 reversed fentanyl-induced respiratory depression across the endpoints minute ventilation, pH, and Paco (P=0.001). Compared with placebo, Calabadion 1 dose dependently (P for trend <0.001) reversed fentanyl-induced hypoventilation {81.9 [5.1] (mean [standard error of the mean]) vs 45.5 [12.4] ml min; P<0.001}, acidosis (pH 7.43 [0.01] vs 7.28 [0.04]; P=0.005), and hypercarbia (Paco 43.4 [1.6] vs 63.4 [8.1] mm Hg; P=0.018). The effective Calabadion 1 doses required to reverse respiratory depression by 50% and 90% (ED50 and ED90) were 1.7 and 15.6 mg kg, respectively. Higher effective doses were needed for recovery of righting reflex (ED50: 9.6 mg kg; ED90: 86.1 mg kg), which was accelerated by Calabadion 1 (4.6 [0.3] vs 9.0 [0.7] min; P<0.001). Calabadion 1 also significantly accelerated recovery of full functional mobility and reversal of muscle rigidity.
CONCLUSIONS
Calabadion 1 selectively and dose dependently reversed the respiratory system and CNS side-effects of fentanyl.
Topics: Analgesics, Opioid; Animals; Disease Models, Animal; Fentanyl; Heterocyclic Compounds, 4 or More Rings; Male; Nervous System Physiological Phenomena; Rats; Rats, Sprague-Dawley; Respiratory Insufficiency; Sulfonic Acids
PubMed: 32241547
DOI: 10.1016/j.bja.2020.02.019 -
Laboratory Animals Dec 2023Anesthesia with isoflurane prior to carbon dioxide euthanasia is recommended as a refinement, but vaporizer access can be limited. An alternative to vaporizers is the...
Anesthesia with isoflurane prior to carbon dioxide euthanasia is recommended as a refinement, but vaporizer access can be limited. An alternative to vaporizers is the 'drop' method, introducing a fixed volume of isoflurane into the induction chamber. Previous work suggests that isoflurane administered at a concentration of 5% via the drop method is effective but aversive to mice; lower concentrations have not been tested. We assessed mouse behavior and insensibility with induction using the drop method for isoflurane concentrations below 5%. Male Crl:CD-1 (ICR) mice ( = 27) were randomly allocated to one of three isoflurane concentrations: 1.7%, 2.7%, and 3.7%. During induction, measures of insensibility and stress-related behaviors were recorded. All mice reached a surgical plane of anesthesia, and mice exposed to higher concentrations did so more quickly; as concentrations increased from 1.7 to 2.7 and 3.7%, the time to recumbency (Least squares means ± SE: 120.5 s ± 8.1, 97.9 s ± 8.1, and 82.8 s ± 8.1, respectively), loss of righting reflex (149.1 s ± 8.5, 127.7 s ± 8.5, and 100.7 s ± 8.5, respectively), and loss of pedal withdrawal reflex (214.5 s ± 8.3, 172.2 s ± 8.3, and 146.4 s ± 8.3, respectively) all declined. Rearing was the most frequently performed stress-related behavior, and was most pronounced immediately following isoflurane administration for all treatments. Our results indicate that the drop method can be used to effectively anesthetize mice with isoflurane concentrations as low as 1.7%; future work should assess mouse aversion.
Topics: Animals; Male; Mice; Isoflurane; Anesthetics, Inhalation; Mice, Inbred ICR; Anesthesia
PubMed: 37144336
DOI: 10.1177/00236772231169550 -
British Journal of Anaesthesia Jun 2015There is limited understanding of cortical neurochemistry and cortical connectivity during ketamine anaesthesia. We conducted a systematic study to investigate the...
BACKGROUND
There is limited understanding of cortical neurochemistry and cortical connectivity during ketamine anaesthesia. We conducted a systematic study to investigate the effects of ketamine on cortical acetylcholine (ACh) and electroencephalographic coherence.
METHODS
Male Sprague-Dawley rats (n=11) were implanted with electrodes to record electroencephalogram (EEG) from frontal, parietal, and occipital cortices, and with a microdialysis guide cannula for simultaneous measurement of ACh concentrations in prefrontal cortex before, during, and after ketamine anaesthesia. Coherence and power spectral density computed from the EEG, and ACh concentrations, were compared between conscious and unconscious states. Loss of righting reflex was used as a surrogate for unconsciousness.
RESULTS
Ketamine-induced unconsciousness was associated with a global reduction of power (P=0.02) in higher gamma bandwidths (>65 Hz), a global reduction of coherence (P≤0.01) across a broad frequency range (0.5-250 Hz), and a significant increase in ACh concentrations (P=0.01) in the prefrontal cortex. Compared with the unconscious state, recovery of righting reflex was marked by a further increase in ACh concentrations (P=0.0007), global increases in power in theta (4-10 Hz; P=0.03) and low gamma frequencies (25-55 Hz; P=0.0001), and increase in power (P≤0.01) and coherence (P≤0.002) in higher gamma frequencies (65-250 Hz). Acetylcholine concentrations, coherence, and spectral properties returned to baseline levels after a prolonged recovery period.
CONCLUSIONS
Ketamine-induced unconsciousness is characterized by suppression of high-frequency gamma activity and a breakdown of cortical coherence, despite increased cholinergic tone in the cortex.
Topics: Acetylcholine; Anesthesia Recovery Period; Anesthetics, Dissociative; Animals; Behavior, Animal; Cerebral Cortex; Electrodes, Implanted; Electroencephalography; Gamma Rhythm; Ketamine; Male; Microdialysis; Rats; Rats, Sprague-Dawley; Reflex; Unconsciousness
PubMed: 25951831
DOI: 10.1093/bja/aev095 -
CNS Neuroscience & Therapeutics May 2023The circuitry mechanism associated with anesthesia-induced unconsciousness is still largely unknown. It has been reported that orexinergic neurons of the lateral...
AIMS
The circuitry mechanism associated with anesthesia-induced unconsciousness is still largely unknown. It has been reported that orexinergic neurons of the lateral hypothalamus (LHA) facilitate the emergence from anesthesia through their neuronal projections to the arousal-promoting brain areas. However, the lateral habenula (LHb), as one of the orexin downstream targets, is known for its anesthesia-promoting effect. Therefore, the current study aimed to explore whether and how the orexinergic projections from the LHA to the LHb have a regulatory effect on unconsciousness induced by general anesthesia.
METHODS
We applied optogenetic, chemogenetic, or pharmacological approaches to regulate the orexinergic pathway. Fiber photometry was used to assess neuronal activity. Loss or recovery of the righting reflex was used to evaluate the induction or emergence time of general anesthesia. The burst-suppression ratio and electroencephalography spectra were used to measure the anesthetic depth.
RESULTS
We found that activation of the orexinergic pathway promoted emergence and reduced anesthetic depth during sevoflurane anesthesia. Surprisingly, the arousal-promoting effect of the orexinergic pathway was mediated by excitation of glutamate decarboxylase (GAD2)-expressing neurons, but not glutamatergic neurons in the LHb.
CONCLUSION
The orexinergic pathway facilitates emergence from sevoflurane anesthesia, and this effect was mediated by OxR2 in GAD2-expressing GABA neurons.
Topics: Humans; Sevoflurane; Habenula; GABAergic Neurons; Anesthetics, Inhalation; Anesthesia, General; Unconsciousness
PubMed: 36740262
DOI: 10.1111/cns.14106 -
Brain : a Journal of Neurology Feb 2021Vestibular dysfunction, causing dizziness and imbalance, is a common yet poorly understood feature in patients with TBI. Damage to the inner ear, nerve, brainstem,...
Vestibular dysfunction, causing dizziness and imbalance, is a common yet poorly understood feature in patients with TBI. Damage to the inner ear, nerve, brainstem, cerebellum and cerebral hemispheres may all affect vestibular functioning, hence, a multi-level assessment-from reflex to perception-is required. In a previous report, postural instability was the commonest neurological feature in ambulating acute patients with TBI. During ward assessment, we also frequently observe a loss of vertigo sensation in patients with acute TBI, common inner ear conditions and a related vigorous vestibular-ocular reflex nystagmus, suggesting a 'vestibular agnosia'. Patients with vestibular agnosia were also more unbalanced; however, the link between vestibular agnosia and imbalance was confounded by the presence of inner ear conditions. We investigated the brain mechanisms of imbalance in acute TBI, its link with vestibular agnosia, and potential clinical impact, by prospective laboratory assessment of vestibular function, from reflex to perception, in patients with preserved peripheral vestibular function. Assessment included: vestibular reflex function, vestibular perception by participants' report of their passive yaw rotations in the dark, objective balance via posturography, subjective symptoms via questionnaires, and structural neuroimaging. We prospectively screened 918 acute admissions, assessed 146 and recruited 37. Compared to 37 matched controls, patients showed elevated vestibular-perceptual thresholds (patients 12.92°/s versus 3.87°/s) but normal vestibular-ocular reflex thresholds (patients 2.52°/s versus 1.78°/s). Patients with elevated vestibular-perceptual thresholds [3 standard deviations (SD) above controls' average], were designated as having vestibular agnosia, and displayed worse posturography than non-vestibular-agnosia patients, despite no difference in vestibular symptom scores. Only in patients with impaired postural control (3 SD above controls' mean), whole brain diffusion tensor voxel-wise analysis showed elevated mean diffusivity (and trend lower fractional anisotropy) in the inferior longitudinal fasciculus in the right temporal lobe that correlated with vestibular agnosia severity. Thus, impaired balance and vestibular agnosia are co-localized to the inferior longitudinal fasciculus in the right temporal lobe. Finally, a clinical audit showed a sevenfold reduction in clinician recognition of a common peripheral vestibular condition (benign paroxysmal positional vertigo) in acute patients with clinically apparent vestibular agnosia. That vestibular agnosia patients show worse balance, but without increased dizziness symptoms, explains why clinicians may miss treatable vestibular diagnoses in these patients. In conclusion, vestibular agnosia mediates imbalance in traumatic brain injury both directly via white matter tract damage in the right temporal lobe, and indirectly via reduced clinical recognition of common, treatable vestibular diagnoses.
Topics: Adolescent; Adult; Aged; Agnosia; Brain Injuries, Traumatic; Dizziness; Female; Humans; Male; Middle Aged; Postural Balance; Reflex, Righting; Vestibule, Labyrinth; White Matter; Young Adult
PubMed: 33367536
DOI: 10.1093/brain/awaa386