Rewarding Subjective Effects of the NMDAR Antagonist Nitrous Oxide (Laughing Gas) Are Moderated by Impulsivity and Depressive Symptoms in Healthy Volunteers.

BACKGROUND: Nitrous oxide (N2O) is an anesthetic gas with both therapeutic and abuse potential. Because N2O is an NMDA receptor (NMDAR) antagonist, its effects are expected to resemble those of the prototypical NMDAR antagonist, ketamine. In this study, we examined the subjective rewarding effects of N2O using measures previously employed in studies of ketamine. We also tested for moderation of these effects by bipolar phenotype, depressive symptoms, and impulsivity. METHODS: Healthy volunteers were randomly assigned to either 50% N2O (n = 40) or medical air (n = 40). Self-reported rewarding (liking and wanting), and alcohol-like effects were assessed pre-, peri- and post inhalation. RESULTS: Effect sizes for the various rewarding/alcohol-like effects of N2O were generally similar to those reported in studies of moderate-dose ketamine. Impulsivity moderated the subjective reinforcing (liking) effects of inhaled gas, while depressive symptoms moderated motivational (wanting [more]) effects. However, depression and impulsivity had opposite directional influences, such that higher impulsivity was associated with higher N2O liking, and higher depression, with lower N2O wanting. CONCLUSION: To the extent that static (versus longitudinal) subjective rewarding effects are a reliable indicator of future problematic drug use, our findings suggests that impulsivity and depression may predispose and protect, respectively, against N2O abuse. Future studies should examine if these moderators are relevant for other NMDAR antagonists, including ketamine, and novel ketamine-like therapeutic and recreational drugs. Similarities between moderate-dose N2O and moderate-dose ketamine in the intensity of certain subjective effects suggest that N2O may, at least to some extent, serve as substitute for ketamine as a safe and easily implemented experimental tool for probing reward-related NMDAR function and dysfunction in humans.

Use of nitrous oxide in children. / Bruk av lystgass hos barn.

BACKGROUND: In July 2013, the Department of Paediatric and Adolescent Medicine at Østfold Hospital Trust introduced nitrous oxide as an option for procedural sedation of children and adolescents. MATERIAL AND METHOD: During the period 13 July 2013-25 August 2017, 311 procedures were performed with nitrous oxide in 238 patients aged 4-17 years. Age, sex, type and duration of procedure, any supplementary medications, complications and whether the procedure would previously have required general anaesthesia, were recorded in a form. The child rated the effectiveness of nitrous oxide using a graded age-appropriate 10-point pain scale, and the nurse rated it as good, moderate or none. RESULTS: The children reported a median pain score of 2/10 (interquartile range 0-4), and nurses rated effectiveness as good in 247 of 304 (81 %) cases. For 43 % of procedures, the nurse felt that general anaesthesia would have been necessary had the department not had access to nitrous oxide. Adverse effects, most often dizziness, were reported in 110 of 311 procedures (35 %). In 7 of 311 procedures (2 %), the patient experienced adverse effects that resulted in stoppage of the procedure. The procedure was completed in 286 (92 %) children. INTERPRETATION: Nitrous oxide is a useful option for children who require procedural sedation, and means that more procedures can be performed without general anaesthesia.

Exploitation of induced 2n-gametes for plant breeding.

Unreduced gamete formation derived via abnormal meiotic cell division is an important approach to polyploidy breeding. This process is considered the main driving force in spontaneous polyploids formation in nature, but the potential application of these gametes to plant breeding has not been fully exploited. An effective mechanism for their artificial induction is needed to attain greater genetic variation and enable efficient use of unreduced gametes in breeding programs. Different approaches have been employed for 2n-pollen production including interspecific hybridization, manipulation of environmental factors and treatment with nitrous oxide, trifluralin, colchicine, oryzalin and other chemicals. These chemicals can act as a stimulus to produce viable 2n pollen; however, their exact mode of action, optimum concentration and developmental stages are still not known. Identification of efficient methods of inducing 2n-gamete formation will help increase pollen germination of sterile interspecific hybrids for inter-genomic recombination and introgression breeding to develop new polyploid cultivars and increase heterozygosity among plant populations. Additionally, the application of genomic tools and identification and isolation of genes and mechanisms involved in the induction of 2n-gamete will enable increased exploitation in different plant species, which will open new avenues for plant breeding.

Auditory cortex of the marmoset monkey - complex responses to tones and vocalizations under opiate anaesthesia in core and belt areas.

Many anaesthetics commonly used in auditory research severely depress cortical responses, particularly in the supragranular layers of the primary auditory cortex and in non-primary areas. This is particularly true when stimuli other than simple tones are presented. Although awake preparations allow better preservation of the neuronal responses, there is an inherent limitation to this approach whenever the physiological data need to be combined with histological reconstruction or anatomical tracing. Here we tested the efficacy of an opiate-based anaesthetic regime to study physiological responses in the primary auditory cortex and middle lateral belt area. Adult marmosets were anaesthetized using a combination of sufentanil (8 µg/kg/h, i.v.) and N2 O (70%). Unit activity was recorded throughout the cortical layers, in response to auditory stimuli presented binaurally. Stimuli consisted of a battery of tones presented at different intensities, as well as two marmoset calls ('Tsik' and 'Twitter'). In addition to robust monotonic and non-monotonic responses to tones, we found that the neuronal activity reflected various aspects of the calls, including 'on' and 'off' components, and temporal fluctuations. Both phasic and tonic activities, as well as excitatory and inhibitory components, were observed. Furthermore, a late component (100-250 ms post-offset) was apparent. Our results indicate that the sufentanil/N2 O combination allows better preservation of response patterns in both the core and belt auditory cortex, in comparison with anaesthetics usually employed in auditory physiology. This anaesthetic regime holds promise in enabling the physiological study of complex auditory responses in acute preparations, combined with detailed anatomical and histological investigation.

Nitrous oxide for pneumoperitoneum: no laughing matter this! A prospective single blind case controlled study.

BACKGROUND: The search for the perfect insufflating gas has been elusive. Even though Carbon dioxide (CO(2)) is the most commonly used gas, it has numerous cardiovascular, respiratory and hemodynamic side effects, which have often been taken for granted. In the current scenario of ever expanding and complex indications for Laparoscopic Surgery these changes have an increasing implication of placing the patient at risk. Nitrous Oxide (N(2)O) has now made a comeback and shown by recent studies to be as safe as CO(2) for creating pneumoperitoneum (PP). The purpose of our study is to determine whether benefits of N(2)O (PP) outweigh those of CO(2) PP in Laparoscopic Surgery. MATERIAL AND METHODS: All patients undergoing Laparoscopic Surgery over an 8 week period were divided into two groups. Data were collected prospectively for Group I {N(2)O(n = 38)} and Group II {CO(2) PP(n = 39)}. Heart rate, Mean Arterial Blood Pressure, End-Tidal CO(2), Arterial pH, Peak Airway Pressure, Minute Ventilation and O(2) Saturation were recorded before PP, 15 minutes after PP and 10 minutes after exsufflation. Intraoperative anesthetic agent and postoperative pain medication use was recorded. Pain was assessed by means of visual analog scale (VAS) at postoperative hours 2 and 4 and on day 1. Results tabulated and analyzed statistically. RESULTS: There was no statistical difference in age, sex, weight, complexity of surgery (type of procedure and duration of PP), Anesthetic risk, and duration of hospitalization between the two groups. Mean End-Tidal CO(2) increase was greater despite a greater mean intraoperative increase in Minute Ventilation in group II, Heart Rate, Arterial pH, Mean Arterial Pressure under anesthesia were significantly higher in group II. The quantum of intraoperative anesthetic agent and postoperative pain (as assessed by Visual Analog Scale) was less in group I. CONCLUSION: This is an initial study assessing the use of N(2)O for insufflation; the results of our study suggest N(2)O PP has a definitive advantage over CO(2) PP. Further multicentric randomized trials are necessary before N(2)O becomes the standard insufflating agent.

Quality of fresh-cut baby spinach grown under a floating trays system as affected by nitrogen fertilisation and innovative packaging treatments.

BACKGROUND: Alternative techniques for cultivation of leafy vegetables such as a floating tray system and unconventional gas mixtures for post-harvest active modified atmosphere packaging (MAP) could be of interest in the minimally processed vegetable industry. RESULTS: The combined effect of three pre-harvest fertilisation doses (8, 12 or 16 mmol N L(-1)) and three post-harvest MAP conditions (passive, super-atmospheric or N2O-enriched) on the main quality attributes of fresh-cut baby spinach leaves throughout 10 days at 5 degrees C was studied. After 8 days of shelf life, spinach leaves fertilised with 8 and 16 mmol N L(-1) and stored under N2O-enriched MAP showed the lowest microbial growth, with good sensory quality. Such combined treatments also preserved the total antioxidant capacity sampled at harvest (8 g ascorbic acid equivalent antioxidant capacity kg(-1) f.w.). A decrease of 10-20% in total vitamin C content regardless of N fertilisation and packaging treatment was found during shelf life. Total phenolics content at harvest was 2 g gallic acid equivalents kg(-1) f.w., which was slightly decreased or preserved during shelf life while total chlorophylls were preserved for all treatments assayed around 550 mg kg(-1) f.w. CONCLUSION: No clear effect of fertilisation doses was observed during post-harvest storage on overall quality of fresh-cut baby spinach leaves, while N2O-enriched atmospheres seems to be a promising alternative to passive MAP for extending shelf life.

Enhancement of suggestibility and imaginative ability with nitrous oxide.

RATIONALE: Imaginative suggestibility, a trait closely related to hypnotic suggestibility, is modifiable under some circumstances. Nitrous oxide (laughing gas) is commonly used for sedation in dentistry and is reported to be more effective when combined with appropriate suggestions. OBJECTIVE: The aim of this study was to determine whether nitrous oxide inhalation alters imaginative suggestibility and imagery vividness. METHODS: Thirty participants were tested twice in a within-subjects design, once during inhalation of 25% nitrous oxide and once during inhalation of air plus oxygen. Before the study, participants' expectancies regarding the effects of nitrous oxide were assessed. Participants were blinded to drug administration. During each session, participants were verbally administered detailed measures of imagination and suggestibility: the Sheehan-Betts Quality of Mental Imagery scale and the Stanford Hypnotic Susceptibility Scale Form C, minus the hypnotic induction. RESULTS: Imaginative suggestibility and imaginative ability (imagery vividness) were both elevated in the nitrous oxide condition. This effect was unrelated to participants' expectations regarding the effects of the drug. CONCLUSIONS: Nitrous oxide increased imaginative suggestibility and imaginative ability. Possible explanations of these findings are discussed with respect to the effects of N-methyl-d-aspartate antagonists and to other pharmacological effects upon suggestibility and imagination.

The excitatory and inhibitory effects of nitrous oxide on spinal neuronal responses to noxious stimulation.

BACKGROUND: Because of the logistical obstacles to measurement under hyperbaric conditions, the effect of nitrous oxide (N2O) alone on spinal neuronal responses has not been tested. We hypothesized that, like other inhaled anesthetics, N2O would depress spinal neuronal responses to noxious stimulation. METHODS: The lumbar spinal cord was exposed in rats anesthetized with isoflurane. Mechanically ventilated rats were placed into a hyperbaric chamber and needle electrodes were inserted into the hindpaws. Isoflurane administration was discontinued and anesthesia converted to N2O by pressurizing the chamber with N2O. A microelectrode was inserted into the lumbar cord using computer-controlled motors and a hydraulic microdrive. Neuronal responses to electrical stimulation of the hindpaw were sought at 1.5, 2, and 2.5 atm N2O (0.8-1.3 minimum alveolar concentration). RESULTS: Increasing N2O partial pressures variably affected neuronal responses to a 2 s 100-Hz electrical stimulus. Neuronal depth and neuronal response were correlated, with superficial neurons tending to be facilitated, while deeper neurons were depressed; (overall responses were 1331 +/- 408, 1594 +/- 383, and 1578 +/- 500 impulses/min at 1.5, 2, and 2.5 atm N2O, respectively; mean, standard error). N2O did not affect neuronal responses to a repetitive "windup" stimulus. Infusion of the N-methyl-d-aspartate blocker MK-801 into separate rats increased the neuronal response to the 100-Hz stimulus (from 781 +/- 216 to 1352 +/- 269 impulses/min, P < 0.05). CONCLUSIONS: N2O facilitated superficial spinal neuronal responses to noxious stimulation while depressing deeper neurons. These results suggest that anesthetic partial pressures of N2O have divergent effects on spinal neuronal responses to noxious stimulation, the specific responses depending on the depth of the spinal neurons.

Corresponding minimum alveolar concentrations of isoflurane and isoflurane/nitrous oxide have divergent effects on thalamic nociceptive signalling.

BACKGROUND: Suppression of nociceptive signalling in the thalamus is considered to contribute significantly to the anaesthetic state. Assuming additivity of anaesthetic mixtures, our study assessed the effects of corresponding minimum alveolar concentrations (MACs) of isoflurane and isoflurane/nitrous oxide on thalamic nociceptive signalling. METHODS: Nociceptive response activity (elicited by controlled radiant heat stimuli applied to cutaneous receptive fields) of single thalamic neurons was compared in rats anaesthetized at approximately 1.1 and approximately 1.4 MAC isoflurane with that at approximately 1.1 and approximately 1.4 MAC isoflurane/nitrous oxide. RESULTS: Under baseline anaesthesia ( approximately 0.9 MAC isoflurane), noxious stimulation elicited excitatory responses in all neurons (n = 19). These responses were uniformly suppressed at approximately 1.1 and approximately 1.4 MAC isoflurane. In contrast, at approximately 1.1 and approximately 1.4 MAC isoflurane/nitrous oxide, excitatory responses no different to baseline were still present in 64 and 37% of the neurons, respectively. CONCLUSIONS: These data demonstrate a pronounced nitrous oxide-induced response variability. It appears that, with respect to thalamic transfer of nociceptive information, the interaction of isoflurane and nitrous oxide may not be compatible with the concept of additivity and that the antinociceptive potency of nitrous oxide is considerably less than previously reported.

A method for recording single unit activity in lumbar spinal cord in rats anesthetized with nitrous oxide in a hyperbaric chamber.

The limited potency of nitrous oxide mandates the use of a hyperbaric chamber to produce anesthesia. Use of a hyperbaric chamber complicates anesthetic delivery, ventilation, and electrophysiological recording. We constructed a hyperbaric acrylic-aluminum chamber allowing recording of single unit activity in spinal cord of rats anesthetized only with N(2)O. Large aluminum plates secured to each other by rods that span the length of the chamber close each end of the chamber. The 122 cm long, 33 cm wide chamber housed ventilator, intravenous infusion pumps, recording headstage, including hydraulic microdrive and stepper motors (controlled by external computers). Electrical pass-throughs in the plates permitted electrical current or signals to enter or leave the chamber. In rats anesthetized only with N(2)O we recorded extracellular action potentials with a high signal-to-noise ratio. We also recorded electroencephalographic activity. This technique is well-suited to study actions of weak anesthetics such as N(2)O and Xe at working pressures of 4-5 atm or greater. The safety of such pressures depends on the wall thickness and chamber diameter.

A study of the role of serotonin in the anxiolytic effect of nitrous oxide in rodents.

RATIONALE: In earlier studies, we have shown that nitrous oxide (N2O)-induced behavioral effects in rats and mice are mediated by benzodiazepine receptors. OBJECTIVES: This two-part study was conducted in order to investigate the possible role of serotonin (5-HT) in the behavioral effects of N2O by clarifying its effects on regional brain concentrations of 5-HT and assessing the influence of 5-HT antagonist and reuptake inhibiting drugs on the anxiolytic-like behavioral effect of N2O. METHODS: In experiment A, male, 150-200 g Sprague-Dawley rats were killed following a 15-min exposure to room air or 70% N2O. The frontal cortex, hippocampus, corpus striatum and hypothalamus were dissected out and analyzed by HPLC with electrochemical detection for content of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA); dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) were also measured. In experiment B, male 18-22 g NIH Swiss mice were pretreated with the 5-HT2 antagonist cinanserin, the 5-HT3 antagonist LY-278,584, the 5-HT reuptake inhibitor fluoxetine or saline and tested in the light/dark exploration test under 70% N2O 30 min after pretreatment. RESULTS: In experiment A, N2O produced differential effects on 5-HT neurons in distinct brain areas. There was increased 5-HT turnover in the hypothalamus, decreased turnover in the frontal cortex but no changes in either hippocampus or corpus striatum. By comparison, dopamine turnover in these brain regions was unaltered by N2O exposure. In experiment B, pretreatment with neither cinanserin, LY-278,584 nor fluoxetine had any appreciable effect on the N2O-induced increase in time spent in the light compartment. Only cinanserin significantly reduced the N2O-induced increase in transitions. CONCLUSIONS: While neurochemical results suggest an effect of N2O on brain 5-HT function, there was no effect of 5-HT2 or 5-HT3 antagonists or 5-HT reuptake inhibitor on N2O-induced anxiolytic-like behavior.

Induction of tetraploid derivatives of maize inbred lines by nitrous oxide gas treatment.

Maize (Zea mays L.) is a model organism for various genetic and physiological studies. Induction of autotetraploid lines from elite inbred lines is valuable for investigating gene dosage effects on the molecular level. We applied nitrous oxide gas at the time of fertilization (30-36 h after pollination) for 20 h on maize inbred line Oh43. The nitrous oxide gas treatment between pressures of 600-1000 kPa proved to be effective in inducing tetraploids. The treatment also significantly increased the rates of germless and shriveled kernels. Twelve inbred lines were treated with nitrous oxide gas for 20 h at either 800 or 900 kPa pressures, 30 or 36 h after pollination. Although tetraploid or tetraploid class aneuploid plants from 9 of 12 inbreds tested were successfully generated, only six genotypes produced progenies. The successful tetraploid inbred lines were from the A188, B73, H99, Oh43, Stock 6, and W22 genetic backgrounds. Aneuploids, plants with broken chromosomes and chimeras, were also found among the treated materials.

Contrasting anesthetic sensitivities of T-type Ca2+ channels of reticular thalamic neurons and recombinant Ca(v)3.3 channels.

Reticular thalamocortical neurons express a slowly inactivating T-type Ca(2+) current that is quite similar to that recorded from recombinant Ca(v)3.3b (alpha1Ib) channels. These neurons also express abundant Ca(v)3.3 mRNA, suggesting that it underlies the native current. Here, we test this hypothesis by comparing the anesthetic sensitivities of recombinant Ca(v)3.3b channels stably expressed in HEK 293 cells to native T channels in reticular thalamic neurons (nRT) from brain slices of young rats. Barbiturates completely blocked both Ca(v)3.3 and nRT currents, with pentobarbital being about twice more potent in blocking Ca(v)3.3 currents. Isoflurane had about the same potency in blocking Ca(v)3.3 and nRT currents, but enflurane, etomidate, propofol, and ethanol exhibited 2-4 fold higher potency in blocking nRT vs Ca(v)3.3 currents. Nitrous oxide (N(2)O; laughing gas) blocked completely nRT currents with IC(50) of 20%, but did not significantly affect Ca(v)3.3 currents at four-fold higher concentrations. In addition, we observed that in lower concentration, N(2)O reversibly increased nRT but not Ca(v)3.3 currents. In conclusion, contrasting anesthetic sensitivities of Ca(v)3.3 and nRT T-type Ca(2+) channels strongly suggest that different molecular structures of Ca(2+) channels give rise to slowly inactivating T-type Ca(2+) currents. Furthermore, effects of volatile anesthetics and ethanol on slowly inactivating T-type Ca(2+) channel variants may contribute to the clinical effects of these agents.

Unconscious auditory priming during surgery with propofol and nitrous oxide anaesthesia: a replication.

BACKGROUND: Priming during anaesthesia has been hard to replicate and the conditions under which it occurs remain poorly understood. We replicated and extended a recent study to determine whether intraoperative priming during propofol and nitrous oxide anaesthesia is a reliable phenomenon, whether it occurs due to awareness during word presentation and whether it is suppressed by a dose of fentanyl at induction. METHODS: Words were played through headphones during surgery to 62 patients receiving propofol and nitrous oxide anaesthesia. Thirty-two patients received fentanyl 1.5 microg kg(-1) at induction and 30 received no fentanyl. Neuromuscular blocking drugs were not used. Depth of anaesthesia was measured using the bispectral index (BIS). Anaesthetic variables were recorded at 1 min intervals during word presentation. On recovery, implicit and explicit memory were assessed using an auditory word-stem completion test and a yes-no word-recognition test, respectively. RESULTS: BIS, blood pressure, end-tidal carbon dioxide and heart rate during word presentation did not differ between the study groups. The infusion rate of propofol and the patients' ventilatory frequency were significantly higher in the group not receiving fentanyl. No patient had unprompted explicit recall of surgery, although there was above-zero performance in six patients on the yes-no recognition task (P<0.05). There was no physiological evidence of awareness during anaesthesia (median mean-BIS=38 in the no-fentanyl group and 42 in the fentanyl group). There was evidence for priming (mean priming score=0.09, P<0.05 in the no-fentanyl study group; mean priming score=0.07, P<0.05 in the fentanyl group) even when patients with momentary light anaesthesia (maximum recorded BIS> or =60) and/or positive recognition scores were excluded from the analysis. CONCLUSIONS: Existing knowledge can be primed by information presented during propofol and nitrous oxide anaesthesia. This priming is evidence of unconscious information processing and not the result of moments of awareness.

Variable effects of nitrous oxide at multiple levels of the central nervous system in goats.

The direct and indirect effects of nitrous oxide (N2O) on the nociceptive responses of lumbar dorsal horn neurons, and the indirect effects on midbrain reticular formation (MRF) neurons and thalamic neurons were determined in goats anaesthetized with isoflurane. The technique used enabled the differential delivery of N2O to either the torso or the cerebral circulation, thus allowing assessment of the direct spinal and indirect brain effects of N2O. Systemic delivery of N2O appeared to have divergent effects, facilitating (4/11) or depressing (7/11) the responses of dorsal horn neurons. Such divergent effects were also observed when N2O was differentially delivered to the circulation in the torso (i.e. the spinal cord). Likewise, MRF and thalamic responses to noxious stimulation were variably affected by administration of N2O to the torso, with some cells facilitated (7/13 MRF neurons, 3/8 thalamic neurons) and others depressed (6/13 MRF neurons, 5/8 thalamic neurons). It appears that N2O has variable effects on the caprine CNS. The facilitatory action of N2O might partially explain why it is a relatively weak anaesthetic.

Xenon inhalation increases norepinephrine release from the anterior and posterior hypothalamus in rats.

PURPOSE: To investigate the effect of xenon (Xe) and nitrous oxide (N(2)O) on norepinephrinergic neuronal activity in the rat medial preoptic area (mPOA) and posterior hypothalamus (PH) using microdialysis. METHODS: Sixty male Wistar rats were equally allocated to two groups: mPOA and PH. A microdialysis probe was implanted into the mPOA or the PH. In both groups, each animal was exposed to one of the following inhalations: 25% oxygen (control, n=6), 30% Xe (n=6), 60% Xe (n=6), 30% N(2)O (n=6) or 60% N(2)O (n=6). Norepinephrine concentration in the perfused artificial cerebrospinal fluid was measured by high pressure liquid chromatography at ten-minute intervals. After plotting the time-norepinephrine concentration curve, the area under the curve (AUC) in each group was calculated. RESULTS: In the mPOA, 30 and 60% Xe, but only 60% N(2)O significantly increased norepinephrine release. The AUC in the 30% Xe, 60% Xe or 60% N(2)O group was 160 +/- 9 (P <0.05), 288 +/- 42 (P <0.01) or 237 +/- 46 pg x min/sample (P <0.01), respectively, compared to that in the control group: 77 +/- 14 pg x min/sample. In the PH, only 60% Xe significantly increased norepinephrine release compared to control (AUC: 191 +/- 38 vs. 71 +/- 1 pg x min/sample, P <0.01). CONCLUSION: The present data suggest that Xe stimulates norepinephrinergic neurons more potently than N(2)O; 1.2 times more in the mPOA and 2.5 times more in the PH. This stimulant effect may contribute to the hypnotic and sympathotonic effects of Xe in rats.