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Preclinical evaluation of novel OT-analogs for the potential treatment of social behavioral deficits

C.E. Credits: P.A.C.E. CE Florida CE
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Abstract

As pharmaceutical companies have reduced or eliminated neuroscience drug development due to high costs and low approval rates, the economic and healthcare burden of CNS disorders in the United States costs an estimated $800 billion per year and rising. In the central nervous system, arginine vasopressin (AVP) and oxytocin (OT) are expressed in the social behavioral network (SBN), which includes connections important for parental bonding, peer relationships, social perception, cognition, and decision making. Within the SBN, AVP and OT are expressed in distinct cell populations and are associated with opposing roles in behavioral and physiological functions, with AVP exerting anxiogenic and depressive-like effects and OT exerting anxiolytic and anti-depressive effects. The mammalian OT-AVP receptor family is comprised of four G-protein coupled receptors: one canonical OT receptor (OTR) and three AVP receptors (V1a, V1b, and V2). Both OTR and V1aR are robustly expressed in the brain, and share ~85% structural homology, resulting in significant cross-reactivity between their ligands. Perturbations in the OT-VP system are associated with multiple psychopathologies, thus OT has received considerable interest as a therapeutic target. Currently, OT therapeutic applications are limited due to a relatively short efficacy, poor oral bioavailability, and poor blood-brain barrier penetrance. To address this, two OT variants (Pro8-OT and Val3-Pro8-OT) with a longer half-life are being compared to effects of the endogenous OT analog (Leu8-OT). This project evaluates the effects of OT analog-induced G-protein mediated signaling and effects on neuronal structure in human derived neuronal-like SH-SY5Y cells and murine primary hippocampal culture. Collectively, these data will provide key findings into how OT affects neuronal structure and function, so that these effects can better inform OT-mediated therapeutic development in humans.

Learning Objectives:

1. Describe the drug development process and timeline

2. Identify the challenges associated with neuropharmacological drug development

3. Differentiate between agonists, partial agonists and antagonists

4. Discuss how drug effects on cellular signaling and neuronal morphology may relate to physiological and sociobehavioral changes at the organismal level


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