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S(−)DP-5,6-ADTN as an in vivo dopamine receptor ligand: Relation between displacement by dopamine agonists and their pharmacological effects

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Summary

The use of (−)DP-5,6-ADTN as a non-radio-actively labeled ligand for an in vivo DA receptor assay is described and compared with racemic DP-5,6-ADTN, previously used for that purpose. The effects of four DA agonists (NPA, bromocriptine, DP-7-OH-ATN and 3-PPP) on the specific (−)DP-5,6-ADTN binding are related to their potencies to decrease striatal HVA concentrations and to induce stereotypy in rats. NPA and DP-7-OH-ATN caused a maximal decrease in HVA levels, when only a fraction of the receptors were occupied, while the occurrence of stereotypy was associated with a high receptor occupation, reflecting the higher affinity of these agonists for presynaptic than for postsynaptic receptors. Bromocriptine did not show this effect, as the dose-response relationships for HVA decrease, for induction of stereotypy and for the decrease in specific (−)DP-5,6-ADTN binding were all virtually equal to each other. While NPA and bromocriptine behaved as full postsynaptic agonists, in that maximal stereotyped behavior was observed after high doses, DP-7-OH-ATN was found to be a partial postsynaptic agonist, as it did not induce maximal stereotypy at a maximal receptor occupation. Racemic 3-PPP only caused a state of hypoactivity, but did neither affect specific (−)DP-5,6-ADTN binding nor striatal HVA levels. Our results are discussed in view of theories on the relation between receptor occupation and pharmacological effects and it is concluded that the in vivo receptor binding method using (−)DP-5,6-ADTN is a very useful tool for such investigations.

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Author notes

  1. Matthijs G. P. Feenstra

    Present address: The Netherlands Institute for Brain Research, Meibergdreef 33, NL-1105 AZ, Amsterdam, The Netherlands

  2. Mark H. Lewis

    Present address: Department of Psychiatry, UMDNJ-SOM, 401 Haddon Camden, 08103, New Jersey, NJ, USA

Authors and Affiliations

  1. Medicinal Chemistry Unit, Department of Pharmacy, State University Groningen, Ant. Deusinglaan 2, NL-9713 AW, Groningen, The Netherlands

    Hans Rollema, Matthijs G. P. Feenstra & Cor J. Grol

  2. Biological Sciences Research Center, University of North Carolina School of Medicine, 27514, Chapel Hill, NC, USA

    Mark H. Lewis, Laura Staples & Richard B. Mailman

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  1. Hans Rollema
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  2. Matthijs G. P. Feenstra
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  3. Cor J. Grol
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  4. Mark H. Lewis
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  5. Laura Staples
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  6. Richard B. Mailman
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Rollema, H., Feenstra, M.G.P., Grol, C.J. et al. S(−)DP-5,6-ADTN as an in vivo dopamine receptor ligand: Relation between displacement by dopamine agonists and their pharmacological effects. Naunyn-Schmiedeberg's Arch. Pharmacol. 332, 338–345 (1986). https://doi.org/10.1007/BF00500084

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  • DOI: https://doi.org/10.1007/BF00500084

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