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Neuronal differentiation and maturation are extended developmental processes. To determine whether neurons at different developmental stages have divergent chemosensitivities, we screened differentiating and maturing neuronal populations using a small compound library comprising FDA‐approved and investigational drugs. Using a neurotoxicity assay format, both respective neuronal population‐based screening campaigns performed robustly (Z‐factors = 0.7–0.8), although the hit rate for the differentiating neurons (2.8%) was slightly higher than for maturing neurons (1.9%). While the majority of hits were toxic to both neuronal populations, these hits predominantly represented promiscuous drugs. Other drugs were selectively neurotoxic, with receptor tyrosine kinase inhibitors disproportionally represented after confirmation. Ponatinib and amuvatinib were neuroinhibitory for differentiating and maturing neurons, respectively. Chemoinformatic analyses confirmed differences in potential drug targets that may be differentially expressed during neuronal development. Subsequent studies demonstrated neuronal expression of AXL, an amuvatinib target, in both neuronal populations. However, functional AXL activity was confirmed only in the maturing neuronal population as determined by AXL phosphorylation in response to GAS6, the cognate ligand of AXL, and concurrent STAT3Y705 phosphorylation. Differentiating neurons were unresponsive to the effects of GAS6 suggesting that the AXL‐STAT3 signaling axis was nonfunctional. Amuvatinib treatment of maturing neuronal cultures significantly reduced pAXL levels. These studies indicate that neuronal developmental states may exhibit unique chemosensitivities and that drugs may have different neuro‐inhibitory effects depending upon the developmental stage of the neuronal population. [ABSTRACT FROM AUTHOR]

The neurosteroid, 5α-pregnan-3α-ol-20-one (known as "allopregnanolone" or 3α,5α-THP), is produced in the midbrain ventral tegmental area (VTA), independent of peripheral sources of progestogens, where it has potential actions at N-methyl-D-aspartate (NMDA) and GABAA receptors to facilitate rodent sexual behavior. Progestogens can also have anti-anxiety effects, but whether these involve actions of centrally-derived 3α,5α-THP or these receptors to support reproductively-relevant behavior is not well understood. We investigated the extent to which 3α,5α-THP's actions via NMDA and/or GABAA receptors in the midbrain VTA influence reproductive behaviors. Estradiol-primed, ovariectomized/adrenalectomized (OVX/ADX) rats received midbrain VTA infusions of vehicle, an NMDA receptor blocker (MK-801; 200 ng), or a GABAA receptor blocker (bicuculline; 100 ng) followed by a second infusion of vehicle or 3α,5α-THP (100 ng). Reproductively-relevant behaviors were assessed: sexual (paced mating), anxiety-like (elevated plus maze), and social (partner preference, social interaction) behavior. Compared to vehicle, intra-VTA infusions of MK-801 exerted anxiolytic-like effects on elevated plus maze behavior and enhanced lordosis. Unlike prior observations in gonadally-intact rats, intra-VTA bicuculline had no effect on the behavior of OVX/ADX rats (likely due to a floor effect). Subsequent infusions of 3α,5α-THP reversed effects on lordosis and infusions of bicuculline inhibited 3α,5α-THP-facilitated lordosis. Thus, NMDA and GABAA receptors may act as mediators for reproductive behavioral effects of 3α,5α-THP in the midbrain VTA. [ABSTRACT FROM AUTHOR]

Ovarian cancer is the fifth leading cause of cancer death among women and the most lethal gynecologic malignancy. One of the leading causes of death in high-grade serous ovarian cancer (HGSOC) is chemoresistant disease, which may present as intrinsic or acquired resistance to therapies. Here we discuss some of the known molecular mechanisms of chemoresistance that have been exhaustively investigated in chemoresistant ovarian cancer, including drug efflux pump multidrug resistance protein 1 (MDR1), the epithelial-mesenchymal transition, DNA damage and repair capacity. We also discuss novel therapeutics that may address some of the challenges in bringing approaches that target chemoresistant processes from bench to bedside. Some of these new therapies include novel drug delivery systems, targets that may halt adaptive changes in the tumor, exploitation of tumor mutations that leave cancer cells vulnerable to irreversible damage, and novel drugs that target ribosomal biogenesis, a process that may be uniquely different in cancer versus non-cancerous cells. Each of these approaches, or a combination of them, may provide a greater number of positive outcomes for a broader population of HGSOC patients. [ABSTRACT FROM AUTHOR]

Starting college is a major life transition. This study aims to characterize patterns of substance use across a variety of substances across the first year of college and identify associated factors. We used data from the first cohort (N = 2056, 1240 females) of the “Spit for Science” sample, a study of incoming freshmen at a large urban university. Latent transition analysis was applied to alcohol, tobacco, cannabis, and other illicit drug uses measured at the beginning of the fall semester and midway through the spring semester. Covariates across multiple domains – including personality, drinking motivations and expectancy, high school delinquency, peer deviance, stressful events, and symptoms of depression and anxiety – were included to predict the patterns of substance use and transitions between patterns across the first year. At both the fall and spring semesters, we identified three subgroups of participants with patterns of substance use characterized as: (1) use of all four substances; (2) alcohol, tobacco, and cannabis use; and (3) overall low substance use. Patterns of substance use were highly stable across the first year of college: most students maintained their class membership from fall to spring, with just 7% of participants in the initial low substance users transitioning to spring alcohol, tobacco, and cannabis users. Most of the included covariates were predictive of the initial pattern of use, but covariates related to experiences across the first year of college were more predictive of the transition from the low to alcohol, tobacco, and cannabis user groups. Our results suggest that while there is an overall increase in alcohol use across all students, college students largely maintain their patterns of substance use across the first year. Risk factors experienced during the first year may be effective targets for preventing increases in substance use. [ABSTRACT FROM AUTHOR]

The neurosteroid, 5α-pregnan-3α-ol-20-one (known as "allopregnanolone" or 3α,5α-THP), is produced in the midbrain ventral tegmental area (VTA), independent of peripheral sources of progestogens, where it has potential actions at N-methyl-D-aspartate (NMDA) and GABA A receptors to facilitate rodent sexual behavior. Progestogens can also have anti-anxiety effects, but whether these involve actions of centrally-derived 3α,5α-THP or these receptors to support reproductively-relevant behavior is not well understood. We investigated the extent to which 3α,5α-THP's actions via NMDA and/or GABA A receptors in the midbrain VTA influence reproductive behaviors. Estradiol-primed, ovariectomized/adrenalectomized (OVX/ADX) rats received midbrain VTA infusions of vehicle, an NMDA receptor blocker (MK-801; 200 ng), or a GABA A receptor blocker (bicuculline; 100 ng) followed by a second infusion of vehicle or 3α,5α-THP (100 ng). Reproductively-relevant behaviors were assessed: sexual (paced mating), anxiety-like (elevated plus maze), and social (partner preference, social interaction) behavior. Compared to vehicle, intra-VTA infusions of MK-801 exerted anxiolytic-like effects on elevated plus maze behavior and enhanced lordosis. Unlike prior observations in gonadally-intact rats, intra-VTA bicuculline had no effect on the behavior of OVX/ADX rats (likely due to a floor effect). Subsequent infusions of 3α,5α-THP reversed effects on lordosis and infusions of bicuculline inhibited 3α,5α-THP-facilitated lordosis. Thus, NMDA and GABA A receptors may act as mediators for reproductive behavioral effects of 3α,5α-THP in the midbrain VTA., (Copyright © 2020 Frye, Qrareya, Llaneza and Paris.)