Browsing by Subject "Ketamine"
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Item Molecular Mechanisms Underlying Fast-Acting Antidepressant Efficacy(2015-04-09) Szabla, Kristen Lynn; Kim, Tae-Kyung; Kavalali, Ege T.; Cobb, Melanie H.; Monteggia, LisaMajor Depressive Disorder is a devastating mental illness with a profound disease burden, particularly in the United States. Major Depressive Disorder is a heterogeneous disorder that is characterized by dysregulated mood and/or anhedonia with intense feelings of despair and sadness, agitation, self-deprecation, and suicidal ideation. Antidepressants, such as selective serotonin reuptake inhibitors, are the most common form of treatment for Major Depressive Disorder, however the precise mechanism by which these drugs work is largely unknown. Moreover, the time they take to reach clinical effect can take weeks to months, and some patients never truly respond, leaving a critical need for more rapidly acting antidepressants with sustained efficacy. In the laboratory, we have explored aspects of the neurotrophic hypothesis of depression and have made progress toward understanding the role of brain-derived neurotrophic factor in animal models. We have also made progress in understanding the role of brain-derived neurotrophic factor in cellular and molecular mechanisms which underlie fast-acting antidepressant efficacy. First, we examined whether ketamine, a novel fast acting antidepressant, functioned in a dose dependent manner to elicit its antidepressant effects. We found that only low, nonpsychomimetic doses of ketamine produce antidepressant effects, whereas high, psychomimetic doses did not produce antidepressant responses. We also demonstrated that only low dose ketamine triggered robust increases in BDNF translation, which our lab has previously shown to be required for ketamine's fast acting antidepressant effects. Next we examined the role of calcineurin in relation to our model of ketamine action, and we uncovered a parallel L-type calcium channel mediated calcium signaling pathway that dephosphorylates eukaryotic elongation factor 2 and competes with the previously identified n-methyl-d-aspartate receptor dependent signaling that activates eukaryotic elongation factor 2 kinase function. The balance between these two calcium signaling pathways determines the degree of eukaryotic elongation factor 2 phosphorylation and the extent of BDNF protein translation, which in turn gauges the efficacy of ketamine-mediated rapid antidepressant responses in preclinical mouse models. Finally, we investigated the molecular mechanisms underlying scopolamine's fast acting antidepressant effect and discovered that scopolamine mediated antidepressant effects require brain-derived neurotrophic factor transcription.Item Synaptic Mechanisms Underlying Treatment of Depression and Bipolar Disorder(2016-05-26) Gideons, Erinn Sommer; Rothenfluh, Adrian; Goldberg, Mark P.; Kavalali, Ege T.; Monteggia, LisaKetamine is a N-methyl-D-aspartate receptor (NMDAR) antagonist that elicits rapid antidepressant responses in depressed patients. However, ketamine can also produce psychotomimetic effects, which limits its widespread use. The field has been exploring the mechanism of ketamine's antidepressant action to assist in identifying drugs that may also produce the rapid effects without the potential side effects. Memantine is a NMDAR antagonist similar to ketamine in many regards but does not produce antidepressant effects in patients. Behavioral experiments in mice recapitulated clinical findings showing that ketamine but not memantine has antidepressant-like effects in two common antidepressant efficacy tests. Ketamine and memantine effectively blocked NMDAR-mediated mEPSCs in the absence of Mg2+. However, in physiological levels of extracellular Mg2+ only ketamine was able to block the NMDAR at rest. This difference between ketamine and memantine extended to intracellular signaling coupled to NMDAR at rest, in that ketamine inhibits the phosphorylation of eukaryotic elongation factor 2 (eEF2) resulting in an augmentation of subsequent protein expression of brain-derived neurotrophic factor (BDNF), that is not triggered by memantine These results demonstrate significant differences between the efficacies of ketamine and memantine on NMDA receptor mediated neurotransmission that impacts downstream intracellular signaling which is hypothesized as the trigger for rapid antidepressant responses. In a subsequent study, the therapeutic effect of lithium, a mood stabilizer and a common treatment for Bipolar Disorder (BD) is being investigated. Lithium has antidepressant and antimanic effects in patients with BD that can be recapitulated in animal models. While lithium is effective as a mood stabilizer, the mechanisms that underlie its therapeutic effect are unclear. Lithium has previously been shown to decrease the overall phosphorylation status of eEF2, which increases BDNF protein translation at the synapse. In this study, clinically effective doses of lithium were shown to result in antidepressant and antimanic-like effects in mice. We report that neither eEF2 kinase nor BDNF are necessary for the antidepressant effects of lithium. Additionally, eEF2 kinase is not required for the antimanic effects of lithium. However, BDNF appears to be necessary for lithium's antimanic actions. To begin to understand whether this requirement of BDNF in lithium's anti-manic action was due to synaptic changes we performed electrophysiological analysis on primary hippocampal neurons treated with lithium. Chronic lithium treatment caused a significant decrease in AMPAR-mEPSC amplitude, which requires both BDNF and its high affinity receptor, TrkB. Additionally, chronic lithium treatment caused a significant decrease in surface expression of the GluA1 subunit of the AMPAR. Collectively, this data demonstrates that BDNF is required for the antimanic effects of lithium, and that lithium's effects on the regulation of AMPARs are BDNF and TrkB dependent, which may underlie its behavioral effect.Item [UT Southwestern Medical Center News](2011-06-17) Ladson, LaKisha