Behavioral effects and mechanisms of action of (-)-OSU6162 - an atypical modulator of dopaminergic and serotonergic neurotransmission

Abstract

By causing a dual effect on locomotion depending on the baseline state of the animal, the so-called dopamine stabilizer (-)-OSU6162 stimulates inactive rodents but attenuates activity of those that are highly active. It thus displays a unique behavioral profile and shows promise in animal models putatively predicting efficacy in a variety of neurological and psychiatric disorders. It is reportedly an antagonist at D2 receptors, a partial agonist at 5-HT2A receptors, and displays high affinity for sigma-1 receptors. This thesis further investigates the behavioral profile of (-)-OSU6162 in various animal models and aims to advance the understanding of its mechanism of action. To this end, we explored the effects of (-)-OSU6162 in rat models predicting therapeutic response in disorders for which dopamine and serotonin are assumed to play a role, and also utilized assessment of locomotor activity, in vivo microdialysis, and measurement of plasma prolactin levels in the presence and absence of other dopamine-modulating compounds to delineate pre- and postsynaptic effects of the drug. Our results show (-)-OSU6162 to reduce levodopa-induced dyskinesia in a rat model of Parkinson’s disease, to counteract context-conditioned fear expressed as freezing, and to display an antidepressant-like response in the forced swim test. The compound not preventing the induction of locomotor activity produced by dopamine agonists in monoamine-depleted rats and mice argues against (-)-OSU6162 blocking postsynaptic D2 receptors – its ability to reduce the locomotion of active rats, e.g., after pretreatment with amphetamine, may instead be due to blockade of 5-HT2A or sigma-1 receptors. In contrast, (-)-OSU6162 blocks D2 autoreceptors – its stimulatory effect on locomotion in inactive animals is thus, at least partly, likely due to blockade of autoreceptors leading to enhanced extracellular levels of dopamine. In line with the well-established similarity between D2 receptors regulating prolactin release and autoreceptors, (-)-OSU6162 also blocks the former. In monoamine depleted mice but not rats, (-)-OSU6162 augmented the locomotor stimulation exerted by D1/D2 agonists – an effect that could be blocked with a 5-HT2A antagonist and partly mimicked by a 5-HT2A agonist. The antidepressant-like effect of (-)-OSU6162 remains enigmatic since it could be neither mimicked nor blocked by D2, 5-HT2A, or sigma-1 receptor antagonists. In conclusion, while (-)-OSU6162 seems to act as a D2 antagonist selectively binding to autoreceptors in both rats and mice, its 5-HT2A-mediated effects may differ between the species, warranting careful consideration regarding the translatability of effects. These results merit further clinical exploration of the possible benefit of (-)-OSU6162 in the treatment of various brain disorders.