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The physiological relevance of functional selectivity in dopamine signalling

International Journal of Obesity Supplements volume 4, pages S5–S8 (2014)Cite this article

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Abstract

We sought to determine the role of functionally selective dopamine (DA) signalling pathways (G protein or β-arrestin) in DA-dependent behaviours. Mice that were globally deficient for β-arrestins or mice deficient in GSK3β in D2 receptor (D2R)-expressing neurons were used to investigate the role of functional selectivity in DA-dependent behaviours such as locomotor activity and conditioned place preference (CPP). Wild-type or knockout mice were injected with drugs such as morphine and amphetamine, which are known to increase DA levels in the brain and to induce a hyper-locomotor response and CPP. Unlike β-arrestin1 (βarr1)-deficient mice, mice globally deficient for β-arrestin2 (βarr2) mount a reduced hyperlocomotor response to either morphine or amphetamine. However, mice deficient in GSK3β in D2R-expressing neurons show a significantly reduced locomotor response to only amphetamine but not morphine. Interestingly, all mice tested show a normal CPP response to either morphine or amphetamine. β-arrestin-mediated DA receptor signalling has an important role in the locomotor response, but not CPP, to drugs such as morphine and amphetamine, demonstrating a functional selectivity of DA-dependent behaviours in mice. It is likely that G-protein-dependent signalling through DA receptors mediates the CPP response.

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Acknowledgements

This work was supported by the National Institutes of Health grants RO1-MH-073853 and U-19-MH-082441. The authors thank Wendy Roberts, Xiuqin Zhang and Benjamin Phillips for maintenance of the mouse colony. GSK3β floxed mice were generously provided by Dr James Woodgett at the Samuel Lunenfeld Research Institute, Toronto, Canada.

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Authors and Affiliations

  1. Department of Cell Biology, Duke University Medical Center, Durham, NC, USA

    N M Urs & M G Caron

  2. Neurobiology, Duke University Medical Center, Durham, NC, USA

    M G Caron

  3. Medicine, Duke University Medical Center, Durham, NC, USA

    M G Caron

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  1. N M Urs
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Correspondence to M G Caron.

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Competing interests

MGC has received consulting fees from Lundbeck A/G, owns equity in in USD Acadia Pharmaceutical and has received grant support from Hoffmann LaRoche. NMU has declared no conflicts of interest.

Additional information

This article is published as part of a supplement sponsored by the Université Laval's Research Chair in Obesity in an effort to inform the public on the causes, consequences, treatments, and prevention of obesity.

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Urs, N., Caron, M. The physiological relevance of functional selectivity in dopamine signalling. Int J Obes Supp 4 (Suppl 1), S5–S8 (2014). https://doi.org/10.1038/ijosup.2014.3

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