Animals ; Female ; Hypoxia ; prevention & control ; Ketamine ; pharmacology ; Male ; Mice ; Mice, Inbred Strains ; Selenium ; pharmacology ; Tea

The pathogenesis and etiology of still remain unknown. Current evidence suggests that the occurrence of depression may be related to a reduced secretion of neurotransmitters, neuronal apoptosis, inflammation, intestinal flora and other factors. Although the commonly used antidepressants such as SSRIs, SNRIs, NaSSA, and SARIs produce some therapeutic effects, they fail to relieve the full spectrum of the symptoms of depression. In recent years, esketamine was found to produce a potent and a long-lasting antidepressant effect by acting on the NMDA receptors. Herein the authors review the progress in the study of the pathogenesis and drug therapies of depression, the efficacy of esketamine treatment and the underlying mechanism, and the prospect of esketamine treatment. Currently the mechanism of the antidepressant effect of esketamine remains indeterminate and its clinical application is limited, but its effect in rapidly alleviating the symptoms of depression suggests its bright prospect for clinical applications.
Antidepressive Agents ; pharmacology ; Depression ; drug therapy ; Humans ; Ketamine ; pharmacology ; Receptors, N-Methyl-D-Aspartate

The deficiency of aquaporin-4 (AQP4) has been reported to alter release of neurotransmitters in the mouse brain. However, the functional relevance of AQP4 in mediating essential components of the general anaesthetic state is unknown. The aim of the present study was to investigate the role of AQP4 in general anaesthesia in mice lacking AQP4. The hypnotic effects of propofol, ketamine, and pentobarbital in AQP4 knockout (KO) and CD1 control mice were evaluated using the behavioural endpoint of loss of righting reflex (LORR). The effects of propofol on extracellular levels of amino acids in prefrontal cortex of freely moving mice were investigated using microdialysis coupled to high performance liquid chromatography with fluorescent detection. The result showed that, after receiving ketamine or pentobarbital, LORR occurred at earlier time in KO mice than that in control animals. Intraperitoneal injection of ketamine or pentobarbital increased the duration of LORR. After the administration of propofol, the duration of LORR was significantly reduced in KO mice compared with that in controls. Propofol increased the extracellular levels of aspartate, glutamate, and GABA, but not taurine, in prefrontal cortex. There were significant differences of increase patterns of the three kinds of neurotransmitters between KO and WT mice. Notably, the duration of GABA level increase correlated with the duration of LORR in two genotypes of mice. These results provide in vivo evidence of different responses in time-dependent release of excitatory and inhibitory neurotransmitters in prefrontal cortex of the two genotypes of mice. It is suggested that changes in anaesthetic reactions in mice with AQP4 loss may be related to neurotransmitter regulation, and that normal functioning of AQP4 plays an important role in the maintenance of anaesthetic hypnosis.
Anesthetics, Intravenous ; pharmacology ; Animals ; Aquaporin 4 ; deficiency ; genetics ; Hypnotics and Sedatives ; pharmacology ; Ketamine ; pharmacology ; Mice ; Mice, Knockout ; Neurotransmitter Agents ; metabolism ; Pentobarbital ; pharmacology ; Prefrontal Cortex ; drug effects ; metabolism ; Propofol ; pharmacology

BACKGROUNDIt is a common phenomenon that children experience multiple general anesthesias in clinical practice, which raises the question whether repeated exposure to general anesthetics would interfere with the development of the central nervous system of children. The present study was designed to evaluate the effects of repeated treatment with ketamine or midazolam on postnatal dendrite development by examining the morphology of the dendritic spines of the pyramidal neurons in the hippocampal CA1 region in mice.

METHODSThe transgenic green fluorescent protein-M line (GFP-M) mice were used in this study. Ketamine (100 mg/kg), midazolam (50 mg/kg) or saline (10 ml/kg) was administered intraperitoneally once a day on consecutive days from postnatal day 8 (P8) to postnatal day 12 (P12). At postnatal day 13 (P13) and postnatal day 30 (P30), the density and length of the apical dendritic spines of the pyramidal neurons in the hippocampal CA1 region were examined under a confocal microscope.

RESULTSAt P13, for both the ketamine group and the midazolam group, the dendritic spines were found with a comparatively lower density and longer average length than in the control group. At P30, no significant difference in the density or average length of dendritic spines was found between the anesthetic group and control group.

CONCLUSIONSThis study indicated that repeated exposure to ketamine or midazolam in neonatal mice impaired dendritic spine maturation immediately afterwards, but this influence seemed to disappear during further postnatal development.

Animals ; Animals, Newborn ; Dendritic Spines ; drug effects ; Female ; Hippocampus ; drug effects ; Ketamine ; pharmacology ; Male ; Mice ; Microscopy, Confocal ; Midazolam ; pharmacology

OBJECTIVETo compare tonal response properties of neurons in the primary auditory cortex of Sprague-Dawley rats anesthetized with urethane and ketamine-xylazine.

METHODSForty-five female Sprague-Dawley rats (200-250 g) were randomized into two groups and anesthetized with urethane or ketamine-xylazine. Tone pips were chosen as the stimuli to obtain the action potentials of the single neurons by in vivo cell-attached recording. The features of the action potentials were extracted with Matlab software to comparatively analyze the acoustic response properties of the neurons between the two anesthetic groups.

RESULTSThe Q values and the characteristic frequencies were independent of the types of anesthetic agents, but with urethane anesthesia, the neurons tended to have higher minimum thresholds, lower spontaneous firing rates, longer response latencies, and more frequent occurrence of tuning with stronger inhibition compared to those in ketamine-xylazine group.

CONCLUSIONUrethane and ketamine might have no obvious impact on the transmission pathway of frequency tuning from the periphery to the auditory cortex, but neurons from rats with urethane anesthesia receive enhanced inhibition mediated by the interneurons or have a lower intrinsic excitability.

Anesthetics ; pharmacology ; Animals ; Audiometry, Pure-Tone ; Auditory Cortex ; drug effects ; physiology ; Female ; Ketamine ; pharmacology ; Neurons ; drug effects ; Rats ; Rats, Sprague-Dawley ; Urethane ; pharmacology

OBJECTIVETo study the psychedelic effects in healthy volunteers when given subanesthetic dose of ketamine.

METHODSThirteen male healthy volunteers aged 24-39 years were enrolled. All subjects received subanesthetic doses of ketamine using target control infusion. A stepwise series of target plasma concentrations (0, 100, 200, and 300 ng/ml) were maintained for 20 minutes each. Visual analogue scale (VAS) of mechanical pain by von Frey hair was evaluated, and then the volunteers completed a VAS rating of 13 symptom scales. Pictures were shown to them at the same time. Heart rate, mean blood pressure, and SpO2 were monitored throughout the infusion.

RESULTSDuring the process of analgesia, ketamine produced dose-related analgesic effects. With the increase of ketamine dose, some psychedelic effects became more obvious and the memory impairment became worse stepwisely.

CONCLUSIONTarget control infusion of subanesthetic doses of ketamine produce obvious psychedelic effects in healthy volunteers.

Adult ; Anesthetics, Dissociative ; administration & dosage ; adverse effects ; pharmacology ; Dose-Response Relationship, Drug ; Hallucinations ; chemically induced ; Humans ; Ketamine ; administration & dosage ; adverse effects ; pharmacology ; Male

OBJECTIVETo investigate the effect of subanaesthetic dose of ketamine on mechanical stimulus on brain regions.

METHODSTotally 13 healthy male volunteers were enrolled in this study, in whom 0 and 100 ng/ml ketamine were administrated by target controlled infusion system in pilot study. After von Frey filaments (vFFs) 300 g were used as mechanical stimuli, Visual Analogue Scale scores were evaluated. Functional magnetic resonance imaging (fMRI)was taken 1 week after pilot study at the following sequences: structure imaging + functional imaging (stimulus sequence with 300 g vFFs, ketamine sequence); stimulus sequence = 6×(20s on + 20s off), with target concentration of ketamine at 0,100 ng/ml.fMRI result was processed by SPM2 and Metlab 7.01 software package.

RESULTSPosterior cerebellum lobe and corpus callosum were inhibited at 100 ng/ml under vFFs stimulus, whereas cingulate gyrus, middle frontal gyrus, inferior parietal lobule, occipital lobe, and posterior cerebellum lobe were activated at 100 ng/ml under vFFs stimulus.

CONCLUSIONSKetamine 100 ng/ml exerts its effect on pain related brain regions. It can both activate and inhibit these brain regions, with the activating effect being the primary effect.

Adult ; Analgesics ; administration & dosage ; pharmacology ; Brain ; drug effects ; physiopathology ; Humans ; Ketamine ; administration & dosage ; pharmacology ; Magnetic Resonance Imaging ; Male ; Pain ; physiopathology ; Pilot Projects

This study was designed to determine the effects of ketamine on contractions induced by norepinephrine (NE), K+ or histamine (Hist) and on agonist-induced calcium mobilization, in rabbit thoracic aorta with or without endothelium. Contractile responses to NE, K+ or Hist were markedly attenuated by prior exposure to ketamine. Subsequent addition of ketamine to the rabbit aorta undergoing an isometric contraction induced by NE, K+ or Hist also decreased the contractile responses in a calcium ion concentration-dependent manner. Preincubation with ketamine produced a concentration-dependent inhibition of contractile responses elicited by the addition of calcium ion (1.6 mM) to a Ca(++)-free depolarizing solution. However, the phasic contraction produced by NE with 2mM lanthanum pretreatment, which is release of intracellular calcium, was also inhibited by ketamine. Moreover, the tonic contraction produced by NE after depletion of the agonist-releasable pool of intracellular calcium, which is thought to be due to calcium influx, was depressed by ketamine. These data suggest that ketamine relaxes NE-contracted rings of rabbit thoracic aorta by decreasing calcium entry and by producing an extracellular calcium-independent relaxant effect.
Animal ; Aorta, Thoracic ; Calcium/pharmacology ; Dose-Response Relationship, Drug ; Female ; Histamine/pharmacology ; Isometric Contraction/drug effects ; Ketamine/*pharmacology ; Male ; Muscle Contraction/*drug effects ; Muscle, Smooth, Vascular/*drug effects ; Norepinephrine/pharmacology ; Rabbits ; Support, Non-U.S. Gov't

The purpose of this study was to verify whether small intestinal peristalsis could be observed and quantitatively assessed using pulsed-Doppler ultrasound. Pulsed-Doppler ultrasound was used to evaluate small intestinal peristalsis after a meal in ten normal dogs and ten sedated dogs. The small intestinal peristalses were measured 0, 1, 3, 6, 9, 12, and 24 hours after a 24-hour fast and after feeding. The number of small intestinal peristalsis were 0.133/min, 0.100/min, 0.033/min, 0.167/min, 0.070/min, 0.067/min, and 0.100/min in the fasted dogs, and 1.667/ min, 0.933/min, 1.133/min, 1.234/min, 1.933/min, 1.533/ min, and 0.533/min in fed dogs, respectively. In the dogs sedated with xylazine HCl, the number of small intestinal peristalsis was significantly reduced (p<0.01). However, in the dogs treated with ketamine HCl and acepromazine, the number of small intestinal peristalsis remained unchanged. Therefore, it can be concluded that pulsed-Doppler ultrasound allows graphic visualization of the intestinal movements, which can be subjected to qualitative and quantitative analysis, and may be suitable for a non-invasive study of small intestinal motility.
Acepromazine/pharmacology ; Animals ; Dogs ; Dopamine Antagonists/pharmacology ; Excitatory Amino Acid Antagonists/pharmacology ; *Gastrointestinal Motility/drug effects ; Intestine, Small/drug effects/*physiology/ultrasonography ; Ketamine/pharmacology ; Peristalsis/drug effects/*physiology ; Ultrasonography, Doppler, Pulsed/methods/*veterinary

OBJECTIVE: To investigate the effects of intravenous anesthetics on LPS-induced inflammatory responses of primary cultures of rat glial cells in vitro. METHODS: The primary cultures of rat glial cells were stimulated with lipopolysaccharide( LPS) to produce inflammatory responses. Glial cells were divided into 8 groups (n=4): blank control (Group C), LPS(Group L), 100micromol/L ketamine with LPS(Group K1), 1000micromol/L ketamine with LPS (Group K2), 30micromol/L propofol with LPS (Group P1), 300micromol/L propofol with LPS (Group P2), 3micromol/L midazolane with LPS (Group M1), and 30micromol/L midazolane with LPS (Group M2). TNF-alpha released into the culture media was measured by radioimmunity assay. RESULTS: Compared with the blank control Group C, LPS-induced TNF-alpha productions in Group L, K1, K2, P1, P2, M1 and M2 increased significantly. The levels of TNF-alpha in Group K1 and K2 were significantly lower than those in Group L (P<0.05), but TNF-alpha productions in Group P1, P2, M1 and M2 were not significantly different as compared with that in Group L. CONCLUSION Ketamine can reduce LPS-induced TNF-alpha production of glial cells, thereby inhabiting some of the inflammatory responses. Propofol and midazolam have no effect on the production of TNF-alpha from LPS-stimulated glial cells.
Anesthetics, Intravenous ; pharmacology ; Animals ; Cells, Cultured ; Female ; Glial Fibrillary Acidic Protein ; biosynthesis ; Immunohistochemistry ; Ketamine ; pharmacology ; Lipopolysaccharides ; pharmacology ; Neuroglia ; cytology ; drug effects ; metabolism ; Propofol ; pharmacology ; Rats ; Rats, Wistar ; Tumor Necrosis Factor-alpha ; biosynthesis