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Effects of (−)-OSU6162 and ACR16 on motor activity in rats, indicating a unique mechanism of dopaminergic stabilization

  • Biological Psychiatry - Original Article
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Abstract

Dopaminergic stabilizers can be defined as drugs that stimulate or inhibit dopaminergic signalling depending on the dopaminergic tone. (−)-OSU6162 and ACR16 appear to possess such a profile. They have been proposed to act as partial dopamine receptor agonists or as antagonists with preferential action on dopaminergic autoreceptors. Previous studies have shown either stimulation or inhibition of behaviour in response to (−)-OSU6162 and ACR16, which has been suggested to reflect their dual effects on dopaminergic signalling. The aims of the present work are to (1) examine the relation between behavioural response to these drugs and activity baseline, and (2) test the suggested mechanisms of action by means of close comparisons with the known partial D2-receptor agonists (−)-3-PPP and aripiprazole, and the D2 autoreceptor preferring antagonist amisulpride with respect to effects on behaviour. From the results of these experiments it can be concluded that: (1) The direction of the response to (−)-OSU6162 and ACR16 is dependent on activity baseline, which in turn, under physiological conditions, is determined primarily by test arena size of and degree of habituation to the environment. (2) The effects of (−)-OSU6162 and ACR16 cannot be explained on the basis of either partial dopamine receptor agonism or preferential dopamine autoreceptor antagonism. Nevertheless, the current data suggest at least two different D2-receptor-associated targets which mediate opposite effects on activity. This result fits in with a mechanism proposed from a recent in vitro study, according to which (−)-OSU6162 has a dual action on dopamine D2 receptors, (a) an allosteric effect causing an enhanced response to dopamine, and (b) the previously proposed orthosteric effect antagonizing the action of dopamine.

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Acknowledgments

This work was supported by Västra Götalandsregionen, Sweden, grants from the state under the LUA/ALF agreement, the Arvid Carlsson Foundation, the Swedish Lundbeck Foundation and Wilhelm och Martina Lundgrens Vetenskapsfond. We are grateful to Pfizer Inc., Sanofi-Aventis and Lilly Research Laboratories for donating drugs for these studies. We also wish to thank Kenn Johannesen for valuable technical advice.

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Authors and Affiliations

  1. Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Box 432, 405 30, Gothenburg, Sweden

    Johan P. Rung, Emilia Rung, Lisa Helgeson, Arvid Carlsson & Maria L. Carlsson

  2. Lilly Research Laboratories, Indianapolis, IN, USA

    Anette M. Johansson & Kjell Svensson

Authors
  1. Johan P. Rung
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  2. Emilia Rung
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  3. Lisa Helgeson
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  4. Anette M. Johansson
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  5. Kjell Svensson
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  6. Arvid Carlsson
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  7. Maria L. Carlsson
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Correspondence to Johan P. Rung.

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Disclosure

Arvid Carlsson and Maria Carlsson are shareholders in NeuroSearch which holds a patent for ACR16. Arvid Carlsson and Kjell Svensson are inventors of OSU6162. Kjell Svensson and Anette Johansson are employed by the pharmaceutical corporation Eli Lilly and Company.

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Rung, J.P., Rung, E., Helgeson, L. et al. Effects of (−)-OSU6162 and ACR16 on motor activity in rats, indicating a unique mechanism of dopaminergic stabilization. J Neural Transm 115, 899–908 (2008). https://doi.org/10.1007/s00702-008-0038-3

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  • DOI: https://doi.org/10.1007/s00702-008-0038-3

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