Background Serotonin 1A receptors (5-HT1A) are implicated in major depressive disorder (MDD). We previously reported higher 5-HT1A binding potential (BPF=Bavail/KD) in antidepressant naïve MDD subjects compared to controls while other studies report lower BPND(BPND=fNDBavail/KD). Discrepancies can be related to differences in study population or methodology. We sought to replicate our findings in a novel cohort and determine whether choice of reference region and outcome measure could explain discrepancies. Methods Nine new controls and 22 new not recently medicated (4 years, NRM) MDD subjects underwent positron emission tomography with [11C]WAY100635. BPF and BPND were determined using a metabolite and free fraction corrected arterial input function. BPND was also determined using cerebellar gray matter (CGM) and cerebellar white matter (CWM) reference regions as input functions. Results BPF is higher in the new NRM cohort (p=0.037) compared to new controls, which is comparable to the effect in the previous cohort (p=0.04). We combined the cohorts to examine the effects of the reference region and outcome measure. In the combined cohort, BPF is higher in the NRM compared to controls (p=0.0001). Neither BPND using CWM (p=0.86) nor VT (p=0.374) differs between groups. When CGM is used, the NRM group has lower 5HT1A BPND compared with controls (p=0.03). CGM VT is higher in NRM compared to controls (p=0.007). Conclusions Choice of reference region and outcome measure can produce different 5-HT1A findings in MDD. Higher 5-HT1A BPF in MDD was found with the method with fewest assumptions about nonspecific binding and a reference region without receptors.

E.V. is partially funded by the DSD Translational Research Network (NICHD 1R01HD068138). M.S.B. is funded by the Neuroendocrinology, Sex Differences and Reproduction training grant (NICHD 5T32HD007228). The authors have no competing interests to disclose.

Objective To determine whether follicular fluid (FF) cortisol levels affect cumulus cell (CC) lipid content during oocyte meiotic resumption and whether CCs express genes for glucocorticoid action. Design Prospective cohort study Setting Academic medical center Patients Thirty-seven non-obese women underwent ovarian stimulation for IVF Intervention(s) At oocyte retrieval, FF was aspirated from the first follicle (>16 mm in size) of each ovary and pooled CC were collected. Main Outcome Measure(s) FF cortisol and cortisone analysis was performed by liquid chromatography-tandem mass spectrometry. CCs were stained with lipid fluorescent dye BODIPY FL C16 to determine lipid content by confocal microscopy. Quantitative real-time PCR was used to detect CC gene expression of 11β-hydroxysteroid dehydrogenase (11βHSD) types 1 and 2, glucocorticoid receptor (NR3C1), lipoprotein lipase (LPL) and hormone sensitive lipase (HSL). Results Adjusting for maternal age, FF cortisol levels negatively correlated with CC lipid content and positively correlated with numbers of total and mature oocytes. CCs expressed genes for 11βHSD type 1 as the predominant 11βHSD isoform, NR3C1, LPL and HSL. Conclusion FF cortisol levels may regulate CC lipolysis during oocyte meiotic resumption and affect oocyte quality during IVF.

Racial and ethnic health disparities in reproductive medicine exist across the life span and are costly and burdensome to our healthcare system. Reduction and ultimate elimination of health disparities is a priority of the National Institutes of Health who requires reporting of race and ethnicity for all clinical research it supports. Given the increasing rates of admixture in our population, the definition and subsequent genetic significance of self-reported race and ethnicity used in health disparity research is not straightforward. Some groups have advocated using self-reported ancestry or carefully selected single-nucleotide polymorphisms, also known as ancestry informative markers, to sort individuals into populations. Despite the limitations in our current definitions of race and ethnicity in research, there are several clear examples of health inequalities in reproductive medicine extending from puberty and infertility to obstetric outcomes. We acknowledge that socioeconomic status, education, insurance status, and overall access to care likely contribute to the differences, but these factors do not fully explain the disparities. Epigenetics may provide the biologic link between these environmental factors and the transgenerational disparities that are observed. We propose an integrated view of health disparities across the life span and generations focusing on the metabolic aspects of fetal programming and the effects of environmental exposures. Interventions aimed at improving nutrition and minimizing adverse environmental exposures may act synergistically to reverse the effects of these epigenetic marks and improve the outcome of our future generations.

In adult female, but not male, Sprague Dawley rats, chronic immobilization stress (CIS) increases mossy fiber (MF) Leu-Enkephalin levels and redistributes delta-and mu-opioid receptors (DORs and MORs) in hippocampal CA3 pyramidal cells and GABAergic interneurons to promote excitation and learning processes following subsequent opioid exposure. Here, we demonstrate that CIS females, but not males, acquire conditioned place preference (CPP) to oxycodone and that CIS "primes" the hippocampal opioid system in females for oxycodone-associated learning. In CA3b, oxycodone-injected (Oxy) CIS females relative to saline-injected (Sal) CIS females exhibited an increase in the cytoplasmic and total densities of DORs in pyramidal cell dendrites so that they were similar to Sal-and Oxy-CIS males. Consistent with our earlier studies, Sal-and Oxy-CIS females but not CIS males had elevated DOR densities in MF-CA3 dendritic spines, which we have previously shown are important for opioid-mediated long-term potentiation. In the dentate gyrus, Oxy-CIS females had more DOR-labeled interneurons than Sal-CIS females. Moreover, Sal-and Oxy-CIS females compared to both groups of CIS males had elevated levels of DORs and MORs in GABAergic interneuron dendrites, suggesting capacity for greater synthesis or storage of these receptors in circuits important for opioid-mediated disinhibition.However, more plasmalemmal MORs were on large parvalbumin-containing dendrites of Oxy-CIS males compared to Sal-CIS males, suggesting a limited ability for increased granule cell disinhibition. These results suggest that low levels of DORs in MF-CA3 synapses and hilar GABAergic interneurons may contribute to the attenuation of oxycodone CPP in males exposed to CIS. K E Y W O R D S conditioned place preference, delta-opioid receptor, drug addiction, GABAergic interneurons, Leu-enkephalin, mossy fiber-CA3 synapses, mu-opioid receptor S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section at the end of the article. How to cite this article: Reich B, Zhou Y, Goldstein E, et al. Chronic immobilization stress primes the hippocampal opioid system for oxycodone-associated learning in female but not male rats. Synapse. 2019;73:e22088. https://doi.