Antipsychotic medications remain the first line of treatment for individuals diagnosed with schizophrenia (SCZ). However, antipsychotic treatment is often not compliant due to dysregulation of both the central (CNS) and autonomic (ANS) nervous systems, resulting in debilitating dose-dependent side effects. Recent work suggests a new approach for treatment of SCZ that could potentially lower treatment doses and reduce side effects. Increased neuroinflammation has been shown in patients diagnosed with SCZ, particularly within the prefrontal cortex (PFC) and hippocampal (HPC) regions of the brain. Tumor necrosis factor-alpha (TNFa) is one of the key pro-inflammatory cytokines observed to be secreted during the inflammatory response. When TNFa is chronically secreted, resident CNS microglia become pro-inflammatory and toxic to the local environment. Microglial activation alongside of dopamine dysregulation thereby results in both the behavioral and neuroinflammatory aspects of SCZ. In this study, we hypothesized dietary administration of two different novel TNFamodulators (PD2024 – Experiment 1 and PD340 – Experiment 2) developed by our collaborators from P2D Bioscience, Inc. (Cincinnati, OH) would alleviate auditory sensorimotor gating deficits and reduce microglial cell activation caused by neonatal polyinosinic:polycytidylic acid (Poly I:C) treatment in rats, which is a validated rodent model of SCZ. Four groups (Experiment 1: Poly IC/PD2024, Poly IC/Control, Saline/PD2024, Saline/Control and Experiment 2: Poly IC/PD340, Poly IC/Control, Saline/PD340, Saline/Control) were intraperitoneally administered either Poly I:C (2 mg/kg) or saline (0.9% NaCl) from postnatal days 5-7. From P30-67, animals were placed on the experimental diet containing either low (10 mg/kg) or high (30 mg/kg) doses of either PD2024 or PD340, whereas the control animals remained on a normal diet. Prepulse inhibition (PPI) was used to test for auditory sensorimotor gating (behavioral abnormalities) in both adolescence (P44-46) and in adulthood (P60-66). At P67, immunohistochemistry (IHC) and confocal microscopy were used to evaluate and examine microglial cell activation using the Iba1-GFP antibody (neuroinflammatory abnormalities) in the PFC and HPC. Results revealed auditory sensorimotor gating deficits in Poly IC/Controls were alleviated in both adolescence and adulthood with either PD2024 or PD340. It was also found that both TNFa modulators significantly reduced microglial activation in the HPC, but not the PFC. The data supports our hypothesis that dietary administration of PD2024 or PD340 alleviates behavioral deficits and decreases neuroinflammation generated from the Poly I:C rodent model of SCZ. Therefore, an approach with a TNFa modulator alongside of current antipsychotic medications could treat both the behavioral and neuroinflammatory aspects of SCZ.

The prevalence of opioid use has increased in many populations including pregnant women, which has led to a substantial rise in infants born dependent on opioids due to in utero exposure. Many women use multiple substances aside from opioids during pregnancy, and their infants therefore present with a variety of symptoms. With increasing legalization and changing perception of marijuana, it has become one of the most commonly used substances during pregnancy. Few studies have evaluated concomitant use of marijuana and opioids in pregnancy despite both being implicated in adverse newborn outcomes. The primary aim of this study was to determine the association between marijuana use and pregnancy outcomes in opioid-exposed pregnancies. The secondary aim was to identify, in a sample of women already using opioids, maternal characteristics associated with marijuana use during pregnancy. A retrospective chart review was conducted from July 2011 to June 2016 of all births from 6 delivery hospitals in South-Central Appalachia to determine pregnancy and neonatal outcomes of pregnancies exposed to any form of opioid and positive urine drug screen for marijuana at the time of delivery. 2375 pregnancies met the inclusion criteria with 108 pregnancies positive for marijuana. Student t-test and Chi-Square test were used for group comparison for presence and absence of marijuana. Logistic regression was done for significant confounding variables to find aOR for marijuana exposure for neonatal abstinence syndrome diagnosis, premature birth, and low birth weight. Among opioid using women, marijuana positive women were more likely to be unmarried, nulliparous, and use tobacco and benzodiazepines. Infants born to the marijuana users were likely to be of earlier gestational age (3 days), lower birth weight, and preterm; with preterm birth and low birth weight (mean difference = 265 gms) increased two fold even after controlling for parity, marital status, tobacco and benzodiazepine use with aOR of 2.35 (1.30-4.23) and 2.02 (1.18-3.47) respectively. Ultimately, prenatal use of marijuana in opioid-exposed pregnancies carries significant risk of prematurity and low birth weight. For pregnant women continuing their American College of Obstetricians and Gynecologists recommended medical assisted treatment for opioid use disorder, providers should counsel women to abstain from marijuana during pregnancy.

Rapidly Dissolving Polymeric Microneedle Skin Patch of Naloxone for Opioid Overdose Treatment Tijani Akeemat1, Maria J. Peláez2, Prashant Dogra2,3, Ashana Puri1 1 Department of Pharmaceutical Sciences, Bill Gatton College of Pharmacy, East Tennessee State University, Johnson City, TN 37614. 2 Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, TX 77030, USA 3 Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA Worldwide opioid abuse affects over 16 million people. A major cause of death in abusers is overdosing. Naloxone (NAL) is an opioid inhibitor that reverses its respiratory depressing effect. The use of this drug is limited mostly to invasive delivery: intravenous (IV), intramuscular (IM) and subcutaneous (SC) due to its significant hepatic clearance and poor oral bioavailability (2%). These routes are painful and worse still is the need for frequent injections for patient stabilization due to the short half-life of NAL. Non-invasive intranasal forms exist but this is fraught with a couple of limitations such as nasal damage and epistaxis. The need for alternatives without these limitations is thus evident. The feasibility of the use of metal microneedles (MNs) for the transdermal delivery of NAL was demonstrated in-vitro and through in-vitro in-vivo correlation modeling in our lab. The goal of the current study was to design a rapidly dissolving polymeric MN patch with delivery and pharmacokinetic (PK) properties comparable to that seen with the commercially available NAL products, eliminating their highlighted limitations. NAL loaded rapidly dissolving polyvinyl pyrrolidone-based MN arrays (500 µm, 100 needles) were fabricated by the mold casting technique. The permeation profile of fabricated MNs over a predetermined time were assessed via an in-vitro permeation set up using porcine ear skin. Samples were analyzed via HPLC. To improve on drug flux and amount permeated, the effect of increasing MN length and density (no. of needles/unit area) were assessed by fabricating MNs 300 µm longer and those with density double that of the initial array. Factors such as drug load and polymer strength influenced the needle fabrication. Compared to passive permeation, a reduced lag time of about 15 min was observed with a significant drug flux of 15.09 ± 7.68 g/cm2/h seen in the first 1 h (pin-vitro in-vivocorrelation we were able to predict an optimized design of the patch that can reproduce the clinical PK of NAL obtained with commercial devices. Increasing needle density and/or patch area was found to be of greater significance. Overall, drug flux seen over 1 h depicts the applicability of fabricated needles in opioid overdose emergencies with delivery properties comparable to that with IM and IN delivery.

Schizophrenia (SZ) is a neurological disorder that presents with paranoia, hallucinations, and negative affect. A neurobiological hallmark of SZ is increased dopamine D2 receptor sensitivity. Antipsychotics that treat SZ have demonstrated limited efficacy as well as harmful and sometimes fatal side effects. Additionally, nicotine abuse is greatly increased in individuals diagnosed with SZ compared to the normal population. Treatment of this comorbidity is important, because cigarette smoking diminishes the quality of life in individuals with SZ and shortens their lifespan. The adenosine system is a potential novel target for SZ treatment. Adenosine A2a receptors form a heteromeric complex with dopamine D2 receptors that is mutually inhibitory, meaning each receptor exhibits lower sensitivity to its agonist after the opposing receptor agonist is bound. This study investigated the efficacy of an adenosine A2a agonist, CGS 21680, in alleviating the rewarding aspects of nicotine in the neonatal quinpirole rodent model of SZ. Rats were treated neonatally from postnatal (P)day 1 through 21 with the dopamine D2/D3 agonist quinpirole, raised to P41, and tested on conditioned place preference (CPP). CPP is a behavioral measure of the rewarding properties of a drug through temporal pairing of a drug with a distinct environmental context. Rats were given a drug free pre-conditioning preference test, and then conditioned to saline or nicotine (0.6 mg/kg base) from P43-51. Groups receiving CGS 21680 (0.03 or 0.09 mg/kg) were given the agonist 15 min before nicotine was administered. A drug-free post-conditioning test was administered on P52 to determine preference. The following day, brain tissue was analyzed for brain-derived neurotrophic factor (BDNF) and glial cell-lined neurotrophic factor (GDNF). BDNF is a ubiquitous neurotrophic factor involved in synaptic growth throughout the brain, whereas GDNF is important in dopamine plasticity. Results revealed that neonatal quinpirole enhanced nicotine CPP, replicating previous work, and both doses of CGS 21680 alleviated this enhancement. Nicotine resulted in a CPP in controls, and both doses of CGS 21680 also alleviated this preference. Therefore, CGS 21680 alleviated the rewarding aspects of nicotine. BDNF analyses in the nucleus accumbens (Nacc), a brain area that mediates drug reward, revealed that BDNF closely followed the behavioral results: CGS 21680 alleviated the enhancement in Nacc BDNF in neonatal quinpirole-treated animals, and eliminated the increase in Nacc BDNF produced by nicotine in controls. GDNF analyses revealed that neonatal quinpirole animals conditioned to nicotine resulted in an increase of GDNF in the NAacc, but this was eliminated by CGS 21680. This project revealed that an adenosine agonist with antispsychotic properties may have utility towards decreasing the rewarding aspects of nicotine and its accompanying neural plasticity changes in a model of SZ.

Over 16 million people in the US suffer from major depressive disorder (MDD) each year. Approximately 1/3rd of MDD patients (~5 million) obtain only partial remission or no benefit after trials with multiple drugs or drug combinations. Recently, Ordway and colleagues have reportedelevated levels of DNA oxidation and upregulated gene expression of the base excision repair enzyme poly(ADP-ribose) polymerase-1 (PARP1) in postmortem brain from donors who had MDD at the time of death, as compared to age-matched psychiatrically normal control donors. This study was designed to test whether an inhibitor of PARP, 3-aminobenzamide (3-AB), may be effective to alleviate depressive-like behaviors in a rodent model of treatment-resistant depression. Male rats were ip administered lipopolysaccharide (LPS;100ug/kg) daily for 28 days, and administered a chronic unpredictable stressor on each day. All rats were also administered saline, 3-AB (40 mg/kg), or the serotonin-reuptake inhibitor (SSRI) fluoxetine (trade name: Prozac; 10 mg/kg) on each day, approximately 30 min after LPS treatment. During the 28 day period of LPS treatment, animals were behaviorally tested 5 times on sucrose preference (a test of anhedonia). At the end of the 28 day period, rats were behaviorally tested on a test of acute stress, the Porsolt swim test. Results revealed that 3-AB alleviated anhedonia and the response to acute stress in the Porsolt swim test superior to the fluoxetine group, demonstrating the utility of a PARP inhibitor to alleviate depressive-like behavior in this model. In addition, fluoxetine produced a loss of weight which recovered over days, but not to control levels, and 3-AB did not produce this effect. This study shows that PARP inhibitors may be effective in treatment-resistant depression.

Mental health is an ever-growing crisis among adolescents and young adults, with suicide as second leading cause of death and the number of those negatively affected continually on the rise. Transitions are one of the major stressors prevalent among these age groups, placing individuals at risk for mental health deficits. This quantitative voluntary response comparative study assesses the transitional mental health of pre-nursing students and students in the nursing program at East Tennessee State University. Emailed to all with a declared major of pre-nursing or nursing, this study measured mental health using evidenced based assessment tools. The PHQ-9 for depression and the GAD-7 for anxiety, along with additional demographic information and mental health service usage questions, was sent to and completed by participants. A total of n = 173 responses were received. Of these responses n = 99 or 57.2 percent were nursing students, a participation rate of 9.6 percent, and n = 74 or 42.8 percent were pre-nursing students. The research revealed that depression and anxiety scores were above the cutoff for moderate depression and anxiety in both groups, as well as identified a deficit in availability of mental health resources, with over 10 percent of students unable to access counseling or psychiatric services. Contraindicatory to literature, which predicted improving mental health in the progression through university studies, this study reveals a variable and even worsening trajectory of mental health as students transition into the nursing program and progressed through college.