(099) Dual Effect of a Serotonin and Dopamine Reuptake Inhibitor (IP2018), and the Search for a Depressive Rat Model with Erectile Dysfunction

Abstract

Abstract Introduction In patients with major depressive disorder, up to 68% present with comorbid sexual dysfunction, which resolves in only 5% to 30% of patients treated with antidepressants. Several groups of antidepressants negatively affect sexual function. Objective The present study investigated whether a newly developed amine transport inhibitor, IP2018, improves depression and erectile function in the same dose range. Methods The dose-dependent effect of IP2018 in two different mouse models for depression, the mouse forced swim test (mFST) and mouse tail suspension test (mTST), is reported. In male Wistar, Sprague Dawley and the depressive rats (Flinders Sensitive Line (FSL) and Flinders Resistant Line (FRL)), increases in intracavernosal pressure (ICP) and mean arterial pressure (MAP) were measured, and the ratio ICP/MAP was used as a measure of erectile function. We investigated whether IP2018 induces changes in ICP or flow and whether IP2018 facilitates suboptimal increases in ICP induced by cavernosal nerve electrical stimulation. The late IP2018 procedure was performed in the rest of the rats to evaluate their erectile function. Results We found that infusion of IP2018 dose-dependently improved mFST and was more potent than citalopram. At the same time, higher doses of IP2018 were required to obtain effect in the mTST model, and IP2018 was equipotent to citalopram. Infusion of low doses of IP2018 dose-dependently increased the number and the duration of spontaneous erections. At the highest dose of IP2018, the increases in the number and duration of spontaneous erections were similar to the effect of the lowest dose, and the increases in flow were 5 times higher. IP2018 (1-30 μM) caused small relaxations in isolated corpus cavernosum strips. FSL and FRL rats showed a diminished ICP/MAP compared to Sprague Dawley control rats. Conclusions IP2018 is more potent or has a similar effect to the well-known antidepressant drug citalopram in mouse models for depression. The potent effect of IP2018 on erectile function in anaesthetized rats suggests that IP2018 in the same dose range has positive effects on both depression and erectile function. FSL/FRL rats appear to allow the study of drug effects on both depression and sexual function in one animal model. Disclosure Yes, this is sponsored by industry/sponsor: Initiator Pharma A/S Clarification Industry funding only - investigator initiated and executed study Any of the authors act as a consultant, employee or shareholder of an industry for: Initiator Pharma A/S