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作者 Li, Nanxin
書名 Neurobiological mechanism of rapid antidepressant actions of ketamine
國際標準書號 9781124807157
book jacket
說明 123 p
附註 Source: Dissertation Abstracts International, Volume: 72-10, Section: B, page: 6435
Adviser: Ronald S. Duman
Thesis (Ph.D.)--Yale University, 2011
Depression is one of the most prevalent and debilitating illnesses worldwide, affecting ∼17 percent of the population and causing enormous personal and economic burden. The impact of depression is underscored by the limitations of currently available medications, including low response rates, treatment resistance, and a time-lag of weeks to months. These data highlight a major unmet need for more efficacious and faster-acting antidepressant agents. Recent clinical studies demonstrate that a single low dose of ketamine, an antagonist of glutamate NMDA receptors, produces rapid antidepressant actions (within 2 hr) that last for up to 7 days in treatment-resistant patients. This rapid action, by a mechanism completely different from typical monoamine reuptake inhibitors, represents one of the most significant findings in the field of depression over the past 2 decades. However, the mechanisms underlying the actions of ketamine are beyond NMDA receptor blockade and largely remain unknown. One possibility is mTOR dependent synaptic protein synthesis, a synaptic plasticity event that is critical for the formation and stabilization of spine synapses and its perturbation has been implicated in many neuropsychiatric disorders. In chapter II, I demonstrate that ketamine rapidly activates mTOR signaling cascade and increases the expression of several synaptic proteins and further increases the spine density of apical dendrites of layer V pyramid neurons in prefrontal cortex. Blockade of the mTOR pathway abolishes the increased synaptic protein expression and spine density, as well as behavioral actions of ketamine in several rodent models of depression. In chapter III, I explore the effects of ketamine on depressive-like behaviors and morphological deficits induced by chronic unpredictable stress. Ketamine reverses the anhedonia-like and anxiety-like behaviors induced by CUS in a time frame comparable to its therapeutic effects in depressed patients. Ketamine also reverses decreased expression of synaptic proteins, as well as reduced spine density and electrophysiological properties of neurons in prefrontal cortex. Blockade of mTOR abolished the actions of ketamine in both behavioral models of depression and expression of synaptic proteins. Taken together, my findings demonstrate that mTOR dependent synaptic protein synthesis and spine/synapse formation is a pivotal mediator of rapid antidepressant actions of ketamine
School code: 0265
Host Item Dissertation Abstracts International 72-10B
主題 Psychology, Psychobiology
Health Sciences, Pharmacology
Psychology, Physiological
0349
0419
0989
Alt Author Yale University
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