Browsing by Subject "ketamine"

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  • Adam, Magdy; Salla, Kati; Aho, Riikka; Hänninen, Laura; Taponen, Suvi; Norring, Marianna; Raekallio, Marja; Hokkanen, Ann-Helena (2021)
    Objective To compare the sedative effects of intramuscular xylazine alone or combined with levomethadone or ketamine in calves before cautery disbudding. Study design Randomized, blinded, clinical trial. Animals A total of 28 dairy calves, aged 21 +/- 5 days and weighing 61.0 +/- 9.3 kg (mean +/- standard deviation). Methods Calves were randomly allocated to three groups: xylazine (0.1 mg kg(-1)) and levomethadone (0.05 mg kg(-1); group XL), xylazine (0.1 mg kg(-1)) and ketamine (1 mg kg(-1); group XK) and xylazine alone (0.2 mg kg(-1); group X). Local anaesthesia (procaine hydrochloride) and meloxicam were administered subcutaneously 15 minutes after sedation and 15 minutes before disbudding. The calves' responses to the administration of local anaesthesia and disbudding were recorded. Sedation was assessed at baseline and at intervals up to 240 minutes postsedation. Times of recumbency, first head lift and first standing were recorded. Drug plasma concentrations were measured. Results Data were obtained from 27 animals. All protocols resulted in sedation sufficient to administer local anaesthesia and to perform disbudding. Sedation scores significantly correlated with drug plasma concentrations (p Conclusions and clinical relevance Levomethadone or ketamine with a low dose of xylazine produced short but sufficient sedation for local anaesthesia and disbudding with minimum resistance.
  • Moliner, Rafael (Helsingin yliopisto, 2019)
    Classical and rapid-acting antidepressant drugs have been shown to reinstate juvenile-like plasticity in the adult brain, allowing mature neuronal networks to rewire in an environmentally-driven/activity-dependent process. Indeed, antidepressant drugs gradually increase expression of brain-derived neurotrophic factor (BDNF) and can rapidly activate signaling of its high-affinity receptor TRKB. However, the exact mechanism of action underlying drug-induced restoration of juvenile-like plasticity remains poorly understood. In this study we first characterized acute effects of classical and rapid-acting antidepressant drugs on the interaction between TRKB and postsynaptic density (PSD) proteins PSD-93 and PSD-95 in vitro. PSD proteins constitute the core of synaptic complexes by anchoring receptors, ion channels, adhesion proteins and various signaling molecules, and are also involved in protein transport and cell surface localization. PSD proteins have in common their role as key regulators of synaptic structure and function, although PSD-93 and PSD-95 are associated with different functions during development and have opposing effects on the state of plasticity in individual synapses and neurons. Secondly, we investigated changes in mobility of TRKB in dendritic structures in response to treatment with antidepressant drugs in vitro. We found that antidepressant drugs decrease anchoring of TRKB with PSD-93 and PSD-95, and can rapidly increase TRKB turnover in dendritic spines. Our results contribute to the mechanistic model explaining drug-induced restoration of juvenile-like neuronal plasticity, and may provide a common basis for the effects of antidepressant drugs.
  • Turunen, Heta; Raekallio, Marja; Honkavaara, Juhana; Jaakkola, Johanna; Scheinin, Mika; Männikkö, Sofia; Hautajärvi, Heidi; Bennett, Rachel; Vainio, Outi (2020)
    Objective To investigate the impact of intramuscular (IM) co-administration of the peripheral alpha(2)-adrenoceptor agonist vatinoxan (MK-467) with medetomidine and butorphanol prior to intravenous (IV) ketamine on the cardiopulmonary and anaesthetic effects in dogs, followed by atipamezole reversal. Study design Randomized, masked crossover study. Animals A total of eight purpose-bred Beagle dogs aged 3 years. Methods Each dog was instrumented and administered two treatments 2 weeks apart: medetomidine (20 mu g kg(-1)) and butorphanol (100 mu g kg(-1)) premedication with vatinoxan (500 mu g kg(-1); treatment MVB) or without vatinoxan (treatment MB) IM 20 minutes before IV ketamine (4 mg kg(-1)). Atipamezole (100 mu g kg(-1)) was administered IM 60 minutes after ketamine. Heart rate (HR), mean arterial (MAP) and central venous (CVP) pressures and cardiac output (CO) were measured; cardiac (CI) and systemic vascular resistance (SVRI) indices were calculated before and 10 minutes after MVB or MB, and 10, 25, 40, 55, 70 and 100 minutes after ketamine. Data were analysed with repeated measures analysis of covariance models. A p-value Results At most time points, HR and CI were significantly higher, and SVRI and CVP significantly lower with MVB than with MB. With both treatments, SVRI and MAP decreased after ketamine, whereas HR and CI increased. MAP was significantly lower with MVB than with MB; mild hypotension (57-59 mmHg) was recorded in two dogs with MVB prior to atipamezole administration. Sedation, induction, intubation and recovery scores were not different between treatments, but intolerance to the endotracheal tube was observed earlier with MVB. Conclusions and clinical relevance Haemodynamic performance was improved by vatinoxan co-administration with medetomidine-butorphanol, before and after ketamine administration. However, vatinoxan was associated with mild hypotension after ketamine with the dose used in this study. Vatinoxan shortened the duration of anaesthesia.
  • Sun, Weilun; Suzuki, Kunimichi; Toptunov, Dmytro; Stoyanov, Stoyan; Yuzaki, Michisuke; Khiroug, Leonard; Dilyatev, Alexander (2019)
    Two-photon imaging of fluorescently labeled microglia in vivo provides a direct approach to measure motility of microglial processes as a readout of microglial function that is crucial in the context of neurodegenerative diseases, as well as to understand the neuroinflammatory response to implanted substrates and brain-computer interfaces. In this longitudinal study, we quantified surveilling and photodamage-directed microglial processes motility in both acute and chronic cranial window preparations and compared the motility under isoflurane and ketamine anesthesia to an awake condition in the same animal. The isoflurane anesthesia increased the length of surveilling microglial processes in both acute and chronic preparations, while ketamine increased the number of microglial branches in acute preparation only. In chronic (but not acute) preparation, the extension of microglial processes toward the laser-ablated microglial cell was faster under isoflurane (but not ketamine) anesthesia than in awake mice, indicating distinct effects of anesthetics and of preparation type. These data reveal potentiating effects of isoflurane on microglial response to damage, and provide a framework for comparison and optimal selection of experimental conditions for quantitative analysis of microglial function using two-photon microscopy in vivo.
  • Lilius, T.; Kangas, E.; Niemi, M.; Rauhala, P.; Kalso, E. (2018)
    Background: Ketamine attenuates morphine tolerance by antagonising N-methyl-D-aspartate receptors. However, a pharmacokinetic interaction between morphine and ketamine has also been suggested. The interaction between oxycodone and ketamine is unclear. We studied the effects of ketamine and norketamine on the attenuation of morphine and oxycodone tolerance focusing on both the pharmacodynamic and pharmacokinetic interactions. Methods: Morphine 9.6 mg day(-1) or oxycodone 3.6 mg day(-1) was delivered to SpragueeDawley rats by subcutaneous pumps. Once tolerance had developed, the rats received subcutaneous injections of ketamine or norketamine. Tail-flick, hot-plate, and rotarod tests were performed. Drug concentrations were measured with high-performance liquid chromatographyetandem mass spectrometry. Results: Anti-nociceptive tolerance to morphine and oxycodone developed similarly by Day 6. Acute ketamine 10 mg kg(-1) and norketamine 30 mg kg(-1) attenuated morphine tolerance for 120 and 150 min, respectively, whereas in oxycodonetolerant rats the effect lasted only 60 min. Both ketamine and norketamine increased the brain and serum concentrations of morphine, and inhibited its metabolism to morphine-3-glucuronide, whereas oxycodone concentrations were not changed. Morphine, but not oxycodone, pretreatment increased the brain and serum concentrations of ketamine and norketamine. Ketamine, but not norketamine, significantly impaired the motor coordination. Conclusions: Ketamine and norketamine attenuated morphine tolerance more effectively than oxycodone tolerance. Ketamine and norketamine increased morphine, but not oxycodone brain concentrations, which may partly explain this difference. Norketamine is effective in attenuating morphine tolerance with minor effects on motor coordination. These results warrant pharmacokinetic studies in patients who are co-treated with ketamine and opioids.
  • Molari, Joonas (Helsingin yliopisto, 2018)
    Currently, there is an undeniable need for more effective treatments of depression. The efficacy of traditional antidepressant drugs becomes apparent after multiple weeks of treatment. New advancements in depression treatments have been made, as glutamatergic NMDA-receptor antagonist ketamine is seen to ameliorate symptoms rapidly, even only hours after drug administration. Understanding ketamine’s mechanism of action as an antidepressant could enable the development of more effective antidepressant drugs. The critical molecular level component in ketamine’s antidepressant effect is considered to be the activation of TrkB tyrosine receptor kinase B, which subsequently leads to the initiation of signaling pathways, which regulate synaptic plasticity. So far, it has not been examined; whether there is a difference in ketamine’s antidepressant effect based on the dosing-time of day. The aim of the present study was to find out if there is a variation between ketamine’s effect on synaptic plasticity and the circadian phase in which the drug is administered. Ketamine’s (200 or 50 mg/kg, i.p.) effects were studied in C57BL/6J–mice during light phase (mouse’s inactive phase) and dark phase (mouse’s active phase) of the day. The phase of the day didn’t affect the activity of TrkB signaling in its related parts (pTrkBTyr816, pGSK3βSer9, p-p70S6KTyr421/Ser424 and p-p44/42MAPKThr202/Tyr204) in prefrontal cortex samples which were analysed in Western blot assay. Ketamine increased dose-dependently the phosphorylation of GSK3βSer9 and p70S6KTyr421/Ser424 as well as decreased p-p44/42MAPKThr202/Tyr204 at 30 minutes after drug administration in both phases of the day. Ketamine (200 mg/kg, i.p.) also lowered the glucose concentration measured from the trunk blood. To examine the effect of hypoglycemia on the activity of TrkB signaling another experiment was conducted. The hypoglycemia induced by insulin detemir (6 IU/kg, i.p.) didn’t affect any measured protein phosphorylation at 60 minutes after drug administration. The results of this study support the notion of ketamine’s rapid and dosedependent induction of neuroplasticity. The possible role of hypoglycemia in ketamine's neuropharmacology should be investigated in future studies.
  • Viisanen, Hanna; Lilius, Tuomas O.; Sagalajev, Boriss; Rauhala, Pekka; Kalso, Eija; Pertovaara, Antti (2020)
    Descending facilitatory circuitry that involves the rostroventromedial medulla (RVM) exerts a significant role in the development of antinociceptive tolerance and hyperalgesia following chronic morphine treatment. The role of the RVM in the development of antinociceptive tolerance to oxycodone, another clinically used strong opioid. is not yet known. Ketamine, an N-methyl-o-aspartate (NMDA) receptor antagonist, attenuates opioid antinociceptive tolerance, but its effect on RVM cell discharge in opioid-tolerant animals is not known. Here, we compared chronic effects of morphine and oxycodone on the discharge properties of RVM cells and attempted to attenuate chronic treatment-induced changes with ketamine. Parallel recordings of RVM cell discharge and limb withdrawal response were performed under light pentobarbital anesthesia in male rats following sustained systemic treatment with morphine or oxycodone at equianalgesic doses. Ongoing activity and the response to noxious heat and pinch were determined in pronociceptive RVM ON-cells and antinociceptive OFF-cells on the sixth treatment day. Proportions of RVM cell types were not changed. Chronic oxycodone induced antinociceptive tolerance both in limb withdrawal and RVM cell activity. Chronic morphine induced antinociceptive tolerance in limb withdrawal that was accompanied by pronociceptive heat response changes in RVM ON- and OFF-cells. A behaviorally subantinociceptive dose of acute ketamine reversed antinociceptive tolerance both to morphine and oxycodone in limb withdrawal and reversed the chronic morphine-induced pronociceptive discharge changes in RVM cells. The results indicate that an NMDA receptor-dependent descending pronociceptive circuitry involving the RVM has an important role in behavioral antinociceptive tolerance to morphine but not oxycodone. NEW & NOTEWORTHY Morphine and oxycodone are two clinically used strong opioids. Chronic treatment with oxycodone as well as morphine can lead to analgesic tolerance and paradoxical hyperalgesia. Here we show that an N-methyl-n-aspartate receptor-dependent pronociceptive change in discharge properties of rostroventromedial medullary neurons controlling spinal nociception has an important role in antinociceptive tolerance to morphine but not oxycodone. Interestingly, chronic oxycodone did not induce pronociceptive changes in the rostroventromedial medulla.
  • Uusitalo, Salla (Helsingin yliopisto, 2020)
    Salvinorin A is a dissociative hallucinogen found in the plant Salvia divinorum. Unlike other hallucinogens it is a selective kappa-opioid receptor antagonist with no affinity to serotonin receptor 5-HT-2A. Modern case studies suggest low, regularly used salvinorin A doses might have antidepressant properties. In animal studies salvinorin A causes both pro- and antidepressant behaviour. Other hallucinogens, such as classical psychedelics psilocybin and LSD, show great promise as rapid acting antidepressants in multiple clinical trials focusing on treatment resistant depression. The most well-known rapid acting antidepressant drug ketamine belongs to the same group of dissociative hallucinogens as Salvinorin A. The use of subanesthetic ketamine has become an integral part of treatment resistant patient care in Finnish healthcare. Ketamine as well as chronic treatment with traditional antidepressants induce plasticity via BDNF-TrkB signaling. The antidepressant mechanism of classical psychedelics is mostly unknown, but they have been shown to promote neuroplasticity by increasing the expression of immediate-early genes and spinogenesis in cortical neurons. The experimental part of this master’s thesis examines the acute effects of salvinorin A on the signaling pathways associated with antidepressant response in C57BL/6 mice. To better characterize the effects of salvinorin A an open field test of 100 min was carried out in addition to phosphorylation studies. Single high dose (5-10 mg/kg) of salvinorin A causes a robust reduction in locomotor activity almost immediately after i.p. administration in mice. However it does not affect the phosphorylation of proteins associated with antidepressant response, nor does it affect BDNF m:RNA expression in mouse prefrontal cortex. According to previous studies, the therapeutic effects of salvinorin A might be present only at low doses or in regular microdosing.
  • Annala, Iina (Helsingin yliopisto, 2021)
    Subanesthetic-dose ketamine, an N-methyl-D-aspartate receptor (NMDAR) blocker, exerts rapid antidepressant effects that sustain long after its elimination from the body. The precise mechanism remains unknown, but regulation of TrkB (tropomyosin receptor kinase B), ERK (extracellular-regulated kinase 1 and 2), GSK3β (glycogen synthase kinase 3β) and mTOR (mammalian target of rapamycin) signaling within the prefrontal cortex (PFC) have been deemed important for its antidepressant-like effects in rodents. In addition, activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) is thought to be an important step in its mechanism. Nitrous oxide (N2O), another NMDAR antagonist and a putative rapid-acting antidepressant, regulates the same molecular pathways as ketamine in the rodent PFC. The fast pharmacokinetics of N2O have been exploited to show that markers of neuronal excitation, including phosphorylation of ERK, are upregulated in the PFC during its acute pharmacological effects (NMDAR blockade), while regulation of TrkB, GSK3β and P70S6K emerges only upon N2O withdrawal. In the first part of this study, we investigated the N2O-induced biochemical changes associated with neuronal excitation and BDNF-TrkB signaling in the PFC and further, the requirement for AMPAR activation in inducing them. We focused on the effects seen after the acute pharmacological effects of N2O. N2O (65% for 20 min) was administered to adult male C57BL/6 mice with or without pretreatment with AMPAR antagonist (NBQX, 10 mg/kg) and PFC samples were collected 15 minutes after stopping N2O delivery. Within this time N2O is expected to be completely eliminated. The brain samples were analyzed using western blot, enzyme-linked immunosorbent assay and quantitative reverse transcription PCR. We observed that N2O increased levels of phosphorylated TrkB, GSK3β and P70S6K, and these effects were not attenuated by NBQX pretreatment. At the same time, we observed a decrease in the levels of phosphorylated ERK, which was attenuated in mice that received NBQX prior to N2O. Tissue levels of BDNF protein or messenger RNA (exon IV) were not different between control and experimental groups. These results indicate that the mechanism of N2O is associated with TrkB and ERK signaling that are regulated independently of each other. It appears that AMPAR activation is not required for TrkB signaling, although it might play a role in ERK signaling. Further, N2O-induced TrkB phosphorylation in the PFC is not associated with changes in total levels of BDNF. In the second part of the study, we aimed to search for new ketamine-like NMDAR blockers with antidepressant potential. Ketamine was used as a query compound for in silico substructure search to find commercial ketamine analogs. The retrieved ketamine analogs were filtered by their computed ADMET properties and then further screened virtually by docking them to the pore region of NMDAR complex (protein data bank code: 4TLM), around the predicted binding site of ketamine. Finally, we sought to study if selected ketamine analogs could elicit ketamine-like effects on TrkB and ERK signaling in mouse primary cortical neurons. However, we did not proceed to test the analogs since ketamine (positive control) did not show any effects on TrkB or ERK phosphorylation in our culture. Overall, this study advances the understanding of the mechanism of N2O, possibly giving new insight of the antidepressant mechanisms of NMDAR-blocking agents more generally. Additionally, we found promising ketamine analogs that await experimental testing.