As the global burden of depression continues to rise, development of more efficacious and faster-acting antidepressant treatments has remained stagnant over several decades. This has created a dire need for a newer generation of therapeutics aimed at helping a greater percentage of the patient population in a shorter period of time. Identifying which subpopulations of patients experience optimal responses to certain treatments has become of great interest, as a means of tailoring treatment strategies for more individualized clinical outcomes. In major depressive disorder, women exhibit a lifetime prevalence roughly twice that of men, and tend to display different profiles of symptomology and antidepressant response rates when compared to men, illustrating the importance of examining sex and related variables as individual differences in the pathophysiology of depression and therapeutic response. Indeed, in recent years, consideration of sex has gained interest in depression relevant preclinical research—particularly in light of the discovery that the N-methyl d-aspartate receptor (NMDAR) antagonist, ketamine, rapidly relieves depressive symptoms and suicidal ideation, even in those with treatment-resistant depression. Notably, recent work from our group and others have revealed a higher sensitivity of females to the antidepressant effects of the NMDAR antagonist ketamine. Combined with its fast-acting and relatively sustained properties, ketamine may be a particularly interesting therapeutic alternative for this sensitive population. Since its discovery, significant research efforts have been dedicated to understanding the underlying mechanisms of ketamine’s antidepressant effects by both preclinical and clinical researchers alike, with the hope of developing novel rapid-acting treatments effective in a broader range of patients. However, a comparatively small proportion of such studies have included females and/or included sex as a variable in analyses. Therefore, the aim of the current work sought to develop the current gap in understanding of how sex and hormones may contribute to the heightened sensitivity of female rats to the rapid antidepressant effects of ketamine by taking a multidisciplinary approach using behavioral, pharmacokinetic and pharmacodynamics analyses in male and female rats. We recently reported that ovarian-derived estradiol (E2) and progesterone (P4) are essential for the greater sensitivity of female rats to rapid antidepressant-like effects of ketamine compared to male rats. However, whether or not the duration of response to ketamine is modulated in a sex- and hormone-dependent manner remains unknown, in addition to the possible contribution of testosterone to such sex differences. Therefore, in the second chapter we explored this systematically by investigating the influence of testosterone, estradiol and progesterone on initiation and maintenance of hedonic response to low-dose ketamine in intact and gonadectomized male and female rats. Females, but not males, experienced a sustained increase in sucrose preference following low-dose ketamine, and did so in an E2P4-dependent manner. Whereas testosterone failed to alter male treatment response, hedonic response to low-dose ketamine was enhanced in intact males when P4 was administered concurrently with low-dose ketamine. Treatment responsiveness was associated with greater hippocampal BDNF levels in female, but not male rats 24h after ketamine administration, without activation of key downstream signaling effectors. This work provides novel evidence supporting activational roles for ovarian-, but not testicular-, derived hormones in mediating hedonic sensitivity to low-dose ketamine in female and male rats. The persistence of sex differences following gonadectomy and selective involvement of BDNF in treatment response may indicate a partial role for organizational differences in these effects. In the absence of any preclinical studies of pharmacokinetic sex differences using low-dose ketamine, it is unclear whether the effects reported in the second chapter may be the result of differences in ketamine metabolism between male and female rats, or whether functional differences in the brain are the predominant driver of behavioral sex differences. Therefore, the third chapter examined whether or not sex and hormonal status affect the metabolism of low-dose ketamine in male and female rats. Intact male rats and female rats in either diestrus (low E2, P4) or proestrus (high E2, P4) were administered low-dose ketamine, and their plasma and brains collected 5-180 minutes later to analyze levels of ketamine and its metabolites, norketamine (NK) and dehydronorketamine (DHNK). Females exhibited greater concentrations of ketamine and NK over the first 30 minutes following treatment in both the brain and plasma, largely accounted for by slower clearance rates and longer half-lives. Interestingly, despite the impact of ovarian hormones on behavioral sensitivity to ketamine, no appreciable differences in pharmacokinetic parameters existed between proestrus and diestrus female rats. Together, this work suggests that while sex differences in metabolism may influence the amount of ketamine and NK reaching target areas in the brain, the impact of circulating hormones on behavioral sensitivity is more likely an effect of actions within the brain at the time of ketamine administration. As the mechanisms underlying this sex-dependent sensitivity to ketamine’s antidepressant-like effects remain elusive, ongoing phosphoproteomics work is underway to investigate the molecular mechanisms underlying this sex-dependent sensitivity to ketamine. Preliminary results revealed striking dissimilarities in the dHPC proteome and phosphoproteome of male and female rats both at baseline, and following low-dose ketamine treatment. Notably, these differences were heavily influenced by hormonal status in female rats. While future work is needed to determine the functional significance of these findings, the collective data presented herein suggest that both biological sex and the hormonal milieu are critical modulators of ketamine’s rapid actions on drug metabolism and within the brain, and provide greater insight into potential physiological and post-translational processes underlying sex- and hormone-dependent modulation of ketamine’s therapeutic effects. / A Dissertation submitted to the Department of Biomedical Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy. / Spring Semester 2018. / April 18, 2018. / Depression, Ketamine, Sex differences / Includes bibliographical references. / Mohamed Kabbaj, Professor Directing Dissertation; Thomas Keller, University Representative; James Olcese, Committee Member; Branko Stefanovic, Committee Member; Zuoxin Wang, Committee Member.
| Identifer | oai:union.ndltd.org:fsu.edu/oai:fsu.digital.flvc.org:fsu_654752 |
| Contributors | Saland, Samantha K. (author), Kabbaj, Mohamed (professor directing dissertation), Keller, Thomas C. S. (university representative), Olcese, James (committee member), Stefanovic, Branko (committee member), Wang, Zuoxin (committee member), Florida State University (degree granting institution), College of Medicine (degree granting college), Department of Biomedical Sciences (degree granting departmentdgg) |
| Publisher | Florida State University |
| Source Sets | Florida State University |
| Language | English, English |
| Detected Language | English |
| Type | Text, text, doctoral thesis |
| Format | 1 online resource (100 pages), computer, application/pdf |
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