Browsing by Subject "ketamiini"
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(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.
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(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.
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