Dissertation for Medicine Doctoral degree at Sahlgrenska Academy, Institute of Neuroscience and Physiology, Department of Pharmacology
Opponent: Kjell Svensson, Research Fellow, Eli Lilly and Company, Indianapolis, USA
Examining committee: Associate Professor Louise Adermark (chair), Associate Professor Kent Jardemark (KI) and Professor John-Olov Jansson
Chairperson of the disputation: Professor Gunnar Tobin
The so-called dopamine stabilizer (-)-OSU6162 has a dual effect on locomotion: it stimulates inactive rodents but reduces activity in highly active animals. It therefore displays a unique behavioral profile and shows promise in animal models used to study potential effects in neurological and psychiatric disorders. The compound has been reported to act on dopamine D2 receptors, serotonin 5-HT2A receptors, and sigma-1 receptors.
This thesis further investigates the behavioral profile of (-)-OSU6162 in various animal models and aims to improve the understanding of its mechanism of action. The studies explored the effects of (-)-OSU6162 in rat models relevant to disorders in which dopamine and serotonin are thought to play an important role. The thesis also used assessment of locomotor activity, in vivo microdialysis, and measurement of plasma prolactin levels, both with and without other dopamine-modulating compounds, to distinguish between different receptor-related effects of the drug.
The results show that (-)-OSU6162 reduces levodopa-induced dyskinesia in a rat model of Parkinson’s disease, counteracts context-conditioned fear expressed as freezing, and produces an antidepressant-like response in the forced swim test. The findings suggest that (-)-OSU6162 blocks specific dopamine D2 autoreceptors, which may partly explain its stimulating effect on locomotion in inactive animals. Its ability to reduce locomotion in highly active animals may instead involve effects on 5-HT2A or sigma-1 receptors. The results also indicate that some of the 5-HT2A-mediated effects of (-)-OSU6162 may differ between rats and mice.
In conclusion, (-)-OSU6162 appears to have a distinct pharmacological profile, with effects on dopamine and serotonin-related systems that may be relevant for several brain disorders. These results support further clinical studies of the possible benefit of (-)-OSU6162 in the treatment of neurological and psychiatric disorders.