Mork, A.3; Pehrson, A.3; Montezinho, L. C. P.3; Karlsson, J. J.3; Murphy, C. T.3; Miller, S.3; Sanchez, C.5; Fischer, C. W.6; Liebenberg, N.6; Wegener, Gregers6; Bang-Andersen, B.3; Stensbol, T. B.3
1 Department of Clinical Medicine - Translational Neuropsychiatry Unit, Department of Clinical Medicine, Health, Aarhus University2 Centre for Psychiatric Research, Faculty of Health Sciences, Aarhus University, Aarhus University3 unknown4 Studienævnene på Arts - The Study of Religion Board of Studies, Studienævnene på Arts, Arts, Aarhus University5 Studienævnene på Arts - The Study of Religion Board of Studies, Studienævnene på Arts, Arts, Aarhus University6 Department of Clinical Medicine - Translational Neuropsychiatry Unit, Department of Clinical Medicine, Health, Aarhus University
Background: Lu AA21004 is a multimodal antidepressant that functions as a 5-HT3 and 5-HT7 receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and inhibitor of the 5-HT transporter in vitro. Here we investigated preclinical effects of Lu AA21004 1) on target occupancies, 2) on neurotransmitter levels in the brain, 3) in an animal model of depression and 4) on cognitive processing. Methods: Lu AA21004 occupancy at the 5-HT transporter, and 5-HT1A, 5-HT1B and 5-HT3 receptors was measured ex vivo in rat brain slices. Effects of Lu AA21004 on extracellular neurotransmitter levels [serotonin (5-HT), noradrenaline (NA), dopamine (DA), acetylcholine (ACh), histamine (Hist)] were measured by microdialysis. Antidepressant potential was assessed in the forced swim test using Flinders Sensitive Line (FSL) rats. Moreover, effects of Lu AA21004 on acquisition, consolidation and recall of contextual memory in rats were studied in the fear conditioning paradigm, and episodic memory was evaluated in the novel object recognition test. Results: Administration of Lu AA21004 (0.1-10 mg/kg, sc) demonstrated that the compound dose-dependently occupied the studied targets. Moreover, Lu AA21004 increased extracellular levels of 5-HT, NA, DA, ACh and Hist in the brain. Lu AA21004 counteracted the immobility of FSL rats in the forced swim test and enhanced memory of the rats in the cognition models. Conclusions: Lu AA21004 in vivo engages relevant targets and affects several neurotransmitter systems. Lu AA21004 shows antidepressant-like effect in a disease relevant model. Moreover, Lu AA21004 possesses procognitive-like properties. The multimodal activity profile may translate into a unique therapeutic profile.
Biological Psychiatry, 2012, Vol 71, Issue 8
serotonin monoamine antidepressant agent vortioxetine serotonin receptor neurotransmitter noradrenalin serotonin 7 receptor receptor histamine acetylcholine dopamine serotonin 1A receptor partial agonist serotonin 1B receptor cognition society psychiatry rat memory forced swim test model brain brain slice recall fear episodic memory ex vivo study processing microdialysis animal model in vitro study agonist conditioning immobilization