Current treatments for depression, including serotonin-specific reuptake inhibitors (SSRIs), are only partially effective, with a high incidence of residual symptoms, relapse, and treatment resistance. Loss of cognitive flexibility, a component of depression, is associated with dysregulation of the prefrontal cortex. Reversal learning, a form of cognitive flexibility, is impaired by chronic stress, a risk factor for depression, and the stress-induced impairment in reversal learning is sensitive to chronic SSRI treatment, and is mimicked by serotonin (5-HT) depletion. Vortioxetine, a novel, multimodal-acting antidepressant, is a 5-HT3, 5-HT7 and 5-HT1D receptor antagonist, a 5-HT1B receptor partial agonist, a 5-HT1A receptor agonist, and inhibits the 5-HT transporter. Using adult male rats, we first investigated the direct effects of vortioxetine, acting at post-synaptic 5-HT receptors, on reversal learning that was compromised by 5-HT depletion using 4-chloro-DL-phenylalanine methyl ester hydrochloride (PCPA), effectively eliminating any contribution of 5-HT reuptake blockade. PCPA induced a reversal learning impairment that was alleviated by acute or sub-chronic vortioxetine administration, suggesting that post-synaptic 5-HT receptor activation contributes to the effects of vortioxetine. We then investigated the effects of chronic dietary administration of vortioxetine on reversal learning that had been compromised in intact animals exposed to chronic intermittent cold (CIC) stress, to assess vortioxetine's total pharmacological effect. CIC stress impaired reversal learning, and chronic vortioxetine administration prevented the reversal-learning deficit. Together, these results suggest that the direct effect of vortioxetine at 5-HT receptors may contribute to positive effects on cognitive flexibility deficits, and may enhance the effect of 5-HT reuptake blockade.

BackgroundPain in the head neck area is an early symptom in oral cancer, supporting the hypothesis that cancer cells control the activities of surrounding nociceptors at the site of the tumor. Several reports implicate TRPV1 and TRPA1 in cancer pain, although there is a large gap in knowledge since the mechanisms for tumor-induced activation of these TRP receptors are unknown. Interestingly, TRP-active lipids such as linoleic acid, arachidonic acid, hydroxyoctadecadienoic acid and hydroxyeicosatetraenoic acid are significantly elevated in the saliva of oral cancer patients compared to normal patients, supporting a possible linkage between these lipids and oral cancer pain. We therefore hypothesize that oral squamous cell carcinomas release certain lipids that activate TRPV1 and/or TRPA1 on sensory neurons, contributing to the development of oral cancer pain.MethodsLipid extracts were made from conditioned media of three human oral squamous cell carcinoma (OSCC) cell lines as well as one normal human oral keratinocytes cell line. These were then injected intraplantarly into rat hindpaws to measure spontaneous nocifensive behavior, as well as thermal and mechanical allodynia. For interventional experiments, the animals were pretreated with AMG517 (TRPV1 antagonist) or HC030031 (TRPA1 antagonist) prior to extract injection.ResultsThese studies demonstrate that lipids released from the three OSCC cell lines, but not the normal cell line, were capable of producing significant spontaneous nocifensive behaviors, as well as thermal and mechanical allodynia. Notably each of the cell lines produced a different magnitude of response for each of three behavioral assays. Importantly, pre-treatment with a TRPVI antagonist blocked lipid-mediated nocifensive and thermal hypersensitivity, but not mechanical hypersensitivity. In addition, pre-treatment with a TRPA1 antagonist only reversed thermal hypersensitivity without affecting lipid-induced nocifensive behavior or mechanical allodynia.ConclusionsThese data reveal a novel mechanism for cancer pain and provide strong direction for future studies evaluating the cellular mechanism regulating the TRP-active lipids by OSCC tumors.

Heart transplant (HT) recipients are at higher risk of varicella zoster virus (VZV) reactivation. Risk factors for VZV reactivation are currently not well defined, impeding the ability to design and implement strategies to minimize the burden of this illness in this population. Automated data extraction tools were used to retrieve data from the electronic health record (EHR) of all adult HT recipients at our center between 2010 and 2016. Information from the Organ Procurement and Transplantation Network Standard Analysis and Research Files was merged with the extracted data. Potential cases were manually reviewed and adjudicated using consensus definitions. Cumulative incidence and risk factors for VZV reactivation in HT recipients were assessed by the Kaplan-Meier method and Cox modeling, respectively. In 203 HT recipients, the cumulative incidence of VZV reactivation at 8-years post-transplantation was 26.4% (95% CI: 17.8-38.0). The median time to VZV reactivation was 2.1 years (IQR, 1.5-4.1). Half (14/28) of the cases experienced post-herpetic neuralgia (PHN). Post-transplant CMV infection (HR 9.05

and hindpaw allodynia were measured for 5 hours and at 24-hour intervals until allodynia resolved. Animals remained at baseline for 24 hrs and were then given a normally subthreshold pH stimulus onto the dura. TrkB/FC, a BDNF sequestering agent, was injected into the cisterna magna 24 hours post IL-6 or animals were given intracisternal injections of BDNF to determine whether brainstem BDNF contributes to IL-6 sensitization. In both male and female rats, dural application of IL-6 produces cutaneous allodynia of similar magnitude and duration, and IL-6 primes both sexes to subsequent dural application of pH 7.0. IL-6 priming to low pH was blocked in both sexes by injection of TrkB/FC into the cisterna magna 24 hours after IL-6. IL-6 was also capable of priming rats to subsequent injection of a systemic NO donor, a stimulus known to consistently trigger attacks in humans migraineurs. These data show that dural afferents in both males and females can be primed to normally sub-threshold stimuli via prior administration of IL-6 onto the dura and that BDNF-dependent signaling within the nucleus caudalis contributes to priming in both sexes. These mechanisms may contribute to the pathophysiology of migraine headache in both males and females.

BackgroundWe created a retrospective database of solid-organ transplant (SOT) recipients using innovative data mining tools. This study describing the epidemiology of Varicella Zoster Virus (VZV) reactivation in SOT serves as a proof of concept of such techniques in clinical research.MethodsThe study design was a retrospective single-center cohort study. Using data mining tools, information was extracted from the electronic medical record and merged with data from the Scientific Registry of Transplant Recipients. First SOT from January 1, 2010–December 31, 2016 were included. Charts of subjects with ICD9/10 codes related to VZV/Herpes infections; positive VZV PCR, DFA or cultures; and recipients of acyclovir, valacyclovir or famciclovir were manually reviewed. The cumulative incidence was calculated using the Kaplan–Meier method. Cox proportional hazards models were used to identify risk factors for VZV reactivation among heart transplant (HT) recipients.ResultsA total of 1,076 SOT recipients met inclusion criteria (203 heart, 395 lung, 280 kidney, 198 liver). Forty-nine patients experienced at least one episode of VZV reactivation; median time post-transplant was 2.25 years (IQR 1.44–4.20 years). The cumulative incidence was 11.9% at 8 years post-transplant. Heart transplant (HT) recipients were at highest risk (Figure 1), with an 8-year cumulative incidence of 26.3% (Figure 2). Thirty-nine of 49 (80%) patients presented with localized disease and 4/49 (8%) with disseminated disease. In multivariable analysis (Figure 3), the risk of VZV reactivation in HT recipients after 12 months (47 patients) was associated with CMV infection before 12 months (HR [95% CI] = 4.74 [1.67–13.47]). Postherpetic neuralgia (PHN) occurred in 23/49 (47%), recurrence in 3/49 (6%), and other complications in 11/49 (22%). In univariable analysis, no risk factors for PHN were identified.Figure 1Figure 2Figure 3ConclusionHT recipients are at highest risk for VZV reactivation. CMV infection before 1 year is associated with increased risk of VZV reactivation after 1 year in HT. This information may help design clinical trials of the recombinant zoster vaccine.Disclosures All authors: No reported disclosures.