Sex Differences in the Behavioral and Neuromolecular Effects of the Rapid-Acting Antidepressant Drug Ketamine in Mice

Date of Award

2019

Degree Name

Ph.D. in Biology

Department

Department of Biology

Advisor/Chair

Advisor: Pothitos Pitychoutis

Abstract

Over 350 million people currently suffer from Major Depressive Disorder (MDD). This debilitating neuropsychiatric disease is the greatest cause of disability worldwide, and available pharmacotherapeutic treatment options are largely ineffective in many depressed patients. Currently, conventional antidepressants (e.g., selective serotonin reuptake inhibitors; SSRIs and tricyclic antidepressants; TCAs) are only partially effective in managing depressive symptoms in MDD patients. Additionally, currently marketed antidepressant drugs require weeks to alleviate symptomology in depressed patients. Notably, women are twice as likely to be diagnosed with MDD as compared to men, yet until recently most clinical and preclinical studies in this field were conducted in the male sex. Ketamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist is the first rapid-acting antidepressant agent discovered that has the unique ability to relieve depressive symptoms within hours in both MDD patients and in animal models of depression. While earlier studies have determined that this drug has great promise for treating refractory depression, little is still known as to ketamine's putative sex differentiated effects and about its long-term safety. In the context of the current dissertation we explored the sex-differentiated behavioral and neuromolecular effects of antidepressant-relevant doses of ketamine following acute and repeated drug treatment in male and female mice. Specifically, we showed that behavioral responsiveness to ketamine in female mice is not accompanied by the neurochemical and synaptogenic effects that are typically observed in the male brain, and we further exposed a brain region that may be implicated in the sex-differentiated response to this drug. Moreover, we provided the first evidence that repeated ketamine dosing induced beneficial antidepressant-like effects in male mice but was associated with adverse anxiety-like and depressive-like effects in females. Taken together, the research findings pertaining to the current dissertation provide novel insights into the sex-dependent effects of the rapid-acting antidepressant drug ketamine and also suggests that the heightened sensitivity of females to this drug may put them at risk for sex-specific adverse effects following chronic treatment.

Keywords

Neurobiology, Neurosciences, Biology, Pharmacology, Ketamine, Depression, Antidepressant, Sex-differences, Female

Rights Statement

Copyright © 2019, author

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