Psychopharmacology

, Volume 141, Issue 1, pp 83–92 | Cite as

Short- and long-term heterologous sensitization of adenylate cyclase by D4 dopamine receptors

  • Val J. Watts
  • Minh N. Vu
  • Brenda L. Wiens
  • Vera Jovanovic
  • Hubert H. M. Van Tol
  • Kim A. Neve
ORIGINAL INVESTIGATION

Abstract

The D4 dopamine receptor, a member of the D2-like dopamine receptor family, may be important in the etiology and treatment of schizophrenia. The present study was designed to examine the effects of dopamine agonist exposure on adenylate cyclase activity in HEK293 cells stably expressing recombinant-D4 receptors. Two hour pretreatment with dopamine receptor agonists resulted in heterologous sensitization of forskolin-stimulated cyclic AMP accumulation in intact cells expressing the D4.2, D4.4, or D4.7 dopamine receptor variant. The potency and efficacy of dopamine for sensitization of cyclic AMP accumulation was comparable at all D4 receptor variants. D4 dopamine receptor-mediated sensitization was blocked by the D4 antagonist, clozapine, and prevented by overnight pretreatment with pertussis toxin, implying a role for Gi/Go proteins in heterologous sensitization. Further, long-term (18 h) agonist exposure resulted in a greater degree of sensitization of forskolin-stimulated cyclic AMP accumulation in both intact cells and membrane preparations of cells expressing the D4 receptor, compared to 2 h agonist exposure, without altering the density of the receptors. In addition, long-term agonist exposure decreased the abundance of G without altering the abundance of G, whereas short-term agonist treatment had no effect on the immunoreactivity of either G protein. In summary, long-term agonist-induced sensitization of adenylate cyclase by the D4 receptor may involve mechanisms that do not contribute to short-term sensitization.

Key words Dopamine D4 receptor Adenylate cyclase Heterologous sensitization 

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Copyright information

© Springer-Verlag Berlin Heidelberg 1999

Authors and Affiliations

  • Val J. Watts
    • 1
  • Minh N. Vu
    • 1
  • Brenda L. Wiens
    • 1
  • Vera Jovanovic
    • 2
  • Hubert H. M. Van Tol
    • 2
  • Kim A. Neve
    • 1
  1. 1.Department of Behavioral Neuroscience, Oregon Health Sciences University, Portland, OR 97201, USAUS
  2. 2.Laboratory for Molecular Neurobiology, Clarke Institute of Psychiatry, Toronto, Canada ON M5T 1R8CA

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