Browsing by Subject "Antidepressive Agents"
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Item Exploring Mechanisms of Depression-Related Behavior and Rapid Antidepressant Action(2011-12-12) Autry, Anita Ellen; Monteggia, LisaMajor Depressive Disorder is a serious mental disorder with a profound disease burden, particularly in the United States. Intriguingly, this disease is almost twice as prevalent in females compared to males. Presently, antidepressant treatment for patients with Major Depressive Disorder requires chronic use and first-line treatment is often ineffective. The neurotrophic hypothesis of depression suggests that a) neurotrophins, in particular brain-derived neurotrophic factor, are necessary for maintaining normal mood states and that b) increases in neurotrophin signaling mediate therapeutic effects of clinical antidepressants. In the laboratory, we have explored aspects of the neurotrophic hypothesis of depression and made progress toward understanding the role of brain-derived neurotrophic factor in depression-related animal models as well as its role in the cellular mechanisms underlying antidepressant efficacy. First, we examined whether loss of brain-derived neurotrophic factor in forebrain neurons impacted susceptibility to chronic stress, an animal model of depression, in a gender-specific manner. Next we examined the contribution of dorsal raphe nucleus brain-derived neurotrophic factor signaling on traditional antidepressant efficacy. Finally, we uncovered a novel role for brain-derived neurotrophic factor in mediating effects of rapid antidepressant efficacy. In the course of my studies, we have found that brain-derived neurotrophic factor expression may be more important for protecting females from negative behavioral effects of chronic stress; that brain-derived neurotrophic factor receptor activation in dorsal raphe is essential for traditional antidepressant efficacy; and finally that brain-derived neurotrophic factor is required for the action of novel rapid antidepressant ketamine.Item An In Vitro Characterization of the Raphe Nucleus and the Effects of SSRIs on Synaptic Neurotransmission(2010-05-14) Ashimi, Sunbola Shefiat; Monteggia, LisaAntidepressants are traditionally used in the treatment of depression. While these drugs rapidly inhibit the reuptake of neurotransmitters in the synaptic terminal by blocking the serotonin and norepinephrine transporters, clinical efficacy can take several weeks. This phenomenon implies that antidepressants not only target neurotransmitter transporters, but have secondary down-stream effects that are important in the treatment of depression. Interestingly, depressed patients respond differently to similar antidepressant therapies, suggesting that although depression is due to a distrubance in the serotonergic neural system, alleviating depression involves more than enhancing synaptic sertonin concentration. Attention must be given to postsynaptic targets and how elevated serotonin modulates these pathways. Some studies have sought to investigate the mechanism of this delay in antidepressant responses,however, few have investigated the influence antidepressants have on synaptic neurotransmission. Dysfunction in synaptic neurotransmission can have profound affects on the functionality of the nervous system. The goal of this thesis is to evaluate the influence of antidepressants on synaptic neurotransmission. To study this question from a mechanistic standpoint, a primary neuronal co-culture system of serotonergic raphe and hippocampal neurons, was developed. The use of the co-culture neuronal system was devised to recapitulate the raphe/hippocampal pathway, an important serotonergic pathway implicated in the pathophysiology of depression, and provide a foundation in which to study how antidepressants alter synaptic function. The most widely prescribed antidepressants are those that target sertonergic systems, and so selective serotonin reuptake inhibitors were used, with the intention that alterations in synpatic function would elucidate the pathomechanism of depression treatment. The use of raphe and hippocampal neurons provide a unique oppurtunity to manipilate the presynaptic selective serotonin reuptake inhibitor target; the serotonin transporters, have a postysnptic receptors to activate, as well as have an endogenous supply of serotonin. Employing electrophysiological techniques, we found that selective serotonin reuptake inhibitors effect synaptic function by modulation of N-methyl-D-aspartic acid receptors through serotonin 1 A heteroreceptors. Understanding how selective serotonin reuptake inhibitors effect synaptic function will offer a more in depth knowledge base regarding the pathophysiology of the delayed onset of antidepressant action in clinical depression.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 [Southwestern News](2004-08-17) Hansard, Donna StephItem [Southwestern News](2002-12-12) Harrell, AnnItem 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](2012-03-08) Wormser, DeborahItem [UT Southwestern Medical Center News](2011-04-21) Ladson, LaKishaItem [UT Southwestern Medical Center News](2011-06-17) Ladson, LaKishaItem [UT Southwestern Medical Center News](2008-08-28) McKenzie, AlineItem [UT Southwestern Medical Center News](2009-05-13) Ladson, LaKisha