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ACNP 59Th Annual Meeting: Poster Session III www.nature.com/npp ABSTRACTS COLLECTION ACNP 59th Annual Meeting: Poster Session III Neuropsychopharmacology (2020) 45:278–382; https://doi.org/10.1038/s41386-020-00892-5 Sponsorship Statement: Publication of this supplement is sponsored by the ACNP. Presenting author disclosures may be found within the abstracts. Asterisks in the author lists indicate presenter of the abstract at the annual meeting. W1. Efforts to Develop and Validate Models and Endpoints understanding these endpoints and representative data will be Within the NINDS Preclinical Screening Platform for Pain presented. (PSPP) Conclusions: This presentation will describe efforts to standar- dize models and endpoints to enhance rigor and reproducibility Taleen Hanania, Mark Varney, Emer Leahy, David Budac, while evaluating potential non-opioid, non-addictive therapeutics Elizabeth Dugan, Steven Leiser, Mark Urban, Sarah Woller, for pain within the NINDS HEAL Initiative PSPP program. Smriti Iyengar* Keywords: Pain, Preclinical Models and Endpoints, Validation, Heal Initiative NINDS/NIH, Carmel, Indiana, United States Disclosure: Electrical Engineering, Delphi: Employee (Spouse), Eli Lilly: Retiree, Stock / Equity (Self) 1234567890();,: Background: The NIH Helping to End Addiction Long-term Initiative, or NIH HEAL Initiative, is a trans-agency effort to W2. The D1 Positive Allosteric Modulator, DETQ, Improves provide scientific solutions to the opioid crisis. As part of the NIH Cognition in Aged Mice and Enhance Cortical and HEAL Initiative, the National Institute of Neurological Disorders Hippocampal Acetylcholine Efflux and Stroke (NINDS) has been charged with enhancing pain management and accelerating the discovery and development Herbert Meltzer*, Lakshmi Rajagopal, Mei Huang, Kjell of new non-addictive pain therapeutics. Toward this goal, NINDS Svensson created the Preclinical Screening Platform for Pain (PSPP) with the aim of accelerating the preclinical development of non- Northwestern University, Chicago, Illinois, United States opioid, non-addictive therapeutics for pain. PSPP is working with PsychoGenics to develop and validate preclinical models and Background: Decline in memory function during normal aging is endpoints to enable the screening and profiling of assets, one of the major causes of disability. Loss of dopaminergic including small molecules, biologics, natural products, and function is one of the major causes of decline in aging. Numerous devices. studies point towards decrease in the availability of dopamine as a Methods: The PSPP aims to screen and profile candidate primary cause in the decline in memory, although it may be that therapeutics in a number of preclinical assays. Assets are downstream signaling after stimulation of D1R in cortex or evaluated in a tiered manner, starting with in vitro functional hippocampus may also contribute. Thus, a prime target for assays to rule out opioid receptor activity and to assess in vitro improving age-associated memory impairment has been a D1R abuse liability. In vivo pharmacokinetic studies are then used to agonist. However, chronic administration of orthosteric D1 measure plasma and brain exposures to guide the dose range agonists have proven to be of little value clinically or in animal and pretreatment times for the side effect profile, in vivo models when given chronically. Thus, the development of a D1 efficacy, and in vivo abuse liability studies. All experiments are positive allosteric modulator (Bruns et al) which does not blinded, both sexes are included, group sizes are determined by desensitize or show an inverted U-shaped curve is a promising power analysis, and data are reported in accordance with development. We now demonstrated that the tool D1 PAM DETQ ARRIVE guidelines is effective to restore novel object recognition and other memory Results: A key component of the PSPP is to validate new and function in aged C57Bl6 mice in which a human D1R has been existing models and endpoints. In collaboration with key opinion substituted for the mouse D1R as DETQ is only fully active at leaders in the field, NINDS and PsychoGenics have been validating the hD1r. existing preclinical models of pain in rodents for inclusion in the Methods: Methods; hD1RKI mice were tested for novel object PSPP workflow. This includes validation of models of nerve injury, recognition at various ages, and with pretreatment with DETQ and chemotherapy-induced neuropathic pain, post-operative pain, various other drugs to clarify mechanism of action. We also did a pain associated with osteoarthritis, deep muscle pain, and microdialysis study in freely moving mice to compare neuro- migraine, as well as validation of existing endpoints, of evoked transmitter release in mPFC and hippocampus (HIP), pain measures but more importantly, validating non-evoked Results: We detected a small but significant decrease in NOR, as endpoints for use in these models. For example, we aim to measured by the discriminant index (DI) at 10-11 months, a 50% understand whether endpoints such as gait, wheel running, decrease at 16-17 months, and a complete loss, by 19 months. guarding, place escape avoidance paradigm (PEAP), and electro- An acute dose of DETQ, 10 mg/kg po, restored NOR to normal encephalogram (EEG) are useful endpoints in a model of nerve levels. This was blocked by pretreatment with the D1 antagonist, injury. Another exciting feature of the program that will be SCH23390. Prolonged treatment with DETQ led to a prolonged highlighted in this presentation will be assessment of abuse recovery of NOR for three weeks at least. The GABA A agonist did liability in the context of efficacy in pain endpoints. Advances in not restore NOR in the aged mice, However, gabazine, a GABA © The Author(s), under exclusive licence to American College of Neuropsychopharmacology 2020 ACNP 59th Annual Meeting: Poster Session III 279 antagonist, blocked the effect of DETQ, while the NKCC1 inhibitor, Results: First, in a brain-wide analysis, we used light-sheet bumetanide, which restores excitatory GABA to inhibitory GABA in microscopy to identify cholinergic terminal fields and cell body scPCP mice (Kim et al, in press), also rescued NOR in the aged clusters across the brain to categorize them as either vulnerable or mice. The D1 positive allosteric modulator, DETQ, improves resilient in aged vs. young mice. Next, to determine the functional cognition and negative symptoms in aged mice as well as relevance of these identified terminal fields, ongoing studies subchronic-PCP treated mice. A single dose of Mg threonate also utilize Fos immunohistochemistry, inhibitory DREADDS, and restored NOR in aged and PCP treated mice. fluorescent biosensors coupled with behavioral assays. To Conclusions: These preliminary results are promising and determine whether resilience or vulnerability in aging arose from suggest D1PAM which is active in man may be of clinical value distinct cholinergic subpopulations defined by function or in treating age-associate memory impairment and related causes topography, we layered cell-type specific retrograde tracing of cognitive decline. The effectiveness of D1 PAM in both normal methods on to these studies. Future studies will utilize RNAseq aging and the PCP model of schizophrenia is noteworthy and for a thorough examination of gene-expression differences across suggests some common pathophysiology. The efficacy of these proposed subpopulations. bumetanide suggests depolarizing GABA may be important for Conclusions: Taken together, these studies contribute to the both aging and schizophrenia. The combination of bumetanide growing body of data highlighting the diversity of cholinergic and a D1PAM could be of clinical interest. neurons in the brain. In aging, we find differences in cholinergic Keywords: Aging, Dopamine, Gaba, Magnesium, Bumetanide terminal field and cell body health both between and within brain Disclosure: Eli Lilly: Grant (Self) regions. Better understanding the organizing principles and underlying diversity in cholinergic neurons will be critical not only for determining what factors contribute to vulnerable vs. W3. Differential Vulnerability and Resilience of Cholinergic resilient cholinergic circuits in the brain, but also how the Circuits in Aging cholinergic system facilitates higher-order processing across the brain. Mala Ananth*, David Talmage, Lorna Role Keywords: Cholinergic System, Whole-Brain Rodent Imaging, Aging National Institutes of Health, Bethesda, Maryland, United States Disclosure: Nothing to disclose. Background: Acetylcholine critically modulates cognition. Choli- W4. Altered Frontoparietal Beta Coherence Dynamics in Visual nergic input to both cortical and subcortical regions originate in Discrimination as an Early Biomarker to Predict Alzheimer’s cell bodies that reside at the base of the forebrain and the Disease brainstem. Although sparsely distributed, these cell bodies send highly branched projections to almost the entire brain with high Vinay Parikh*, Irem Asci, Evan Haley functional and topographical organization, making a strong case for the functional importance of acetylcholine in cognitive Temple University, Philadelphia, Pennsylvania, United States behaviors. It has been well-established that alterations to the cholinergic Background: Alzheimer’s disease (AD) is a progressive age-related system can lead to cognitive dysfunction. For example, loss of neurodegenerative disorder characterized by loss of synapses and cholinergic markers is a hallmark of age-related cognitive decline. neurons
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