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Phenotypic studies on dopamine receptor subtype and associated signal transduction mutants: insights and challenges from 10 years at the psychopharmacology–molecular biology interface

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Abstract

Background

Mutants with targeted gene deletion (‘knockout’) or insertion (transgenic) of D1, D2, D3, D4 and D5 dopamine (DA) receptor subtypes are complemented by an increasing variety of double knockout and transgenic-‘knockout’ models, together with knockout of critical components of DA receptor signalling cascades such as Gαolf[Gγ7], adenylyl cyclase type 5, PKA [RIIβ] and DARPP-32. However, it is increasingly recognised that these molecular techniques have a number of inherent limitations. Furthermore, there are poorly understood methodological factors that contribute to inconsistent phenotypic findings between laboratories.

Objective

This review seeks to document the impact of DA receptor subtype and related transduction mutants on our understanding of the behavioural roles of these entities, primarily at the level of unconditioned psychomotor behaviour.

Methods

It includes ethologically based and orofacial movement studies in our own laboratories, since these are the only studies to systematically compare each of the D1, D2, D3, D4 and D5 receptor and DARPP-32 signal transduction ‘knockouts’.

Discussion

There is a particular emphasis on identifying methodological factors that might influence phenotypic effects and account for inconsistencies. The findings are offered empirically to (1) specify the extent of phenotypic diversity among individual DA receptor subtypes and transduction components and (2) indicate relationships between D1, D2, D3, D4 and D5 receptor subtype proteins, associated Gαi/Gαs/Gαolf[Gγ7]–adenylyl cyclase type 5–PKA [RIIβ]–DARPP-32 signalling cascades and behaviour. The findings are also offered heuristically as a base for such phenotypic comparisons at additional levels of behaviour so that a yet more complete phenotypic profile might emerge.

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Acknowledgements

The authors' studies would be impossible without the generous collaboration of our colleagues in molecular biology who have kindly made their mutants available to us; we are indebted to: Emiliana Borrelli, John Drago, Allen Fienberg, Sara Fuchs, David Grandy, Paul Greengard, Malcolm Low, Marcelo Rubinstein and David Sibley. Additionally, we thank Jerry Clifford, Fergal McNamara ,Ashling Mulcahy and Rachel Nally for assistance in preparing this review. The authors' studies are supported by Science Foundation Ireland, Enterprise Ireland and the Stanley Medical Research Institute, and were carried out in the Institute of Biopharmaceutical Sciences under the Higher Education Authority's Programme for Research in Third Level Institutions, Ireland; a Nihon University research grant, research grants from the Sato Fund and the Dental Research Centre, the Promotion and Mutual Aid Corporation for Private Schools of Japan, a grant for promotion of multidisciplinary research projects and grants-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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  1. Department of Clinical Pharmacology and Institute, Royal College of Surgeons in Ireland, St. Stephen's Green, Dublin 2, Ireland

    John L. Waddington, Colm O'Tuathaigh & Gerard O'Sullivan

  2. Department of Pharmacology and Dental Research Centre, Nihon University School of Dentistry, Tokyo, 101, Japan

    Katsunori Tomiyama & Noriaki Koshikawa

  3. Department of Biochemistry and Institute of Biopharmaceutical Sciences, Royal College of Surgeons in Ireland, Dublin 2, Ireland

    David T. Croke

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  1. John L. Waddington
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Correspondence to John L. Waddington.

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Waddington, J.L., O'Tuathaigh, C., O'Sullivan, G. et al. Phenotypic studies on dopamine receptor subtype and associated signal transduction mutants: insights and challenges from 10 years at the psychopharmacology–molecular biology interface. Psychopharmacology 181, 611–638 (2005). https://doi.org/10.1007/s00213-005-0058-8

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