, Volume 182, Issue 1, pp 104–115 | Cite as

Interaction between the antidepressant-like behavioral effects of beta adrenergic agonists and the cyclic AMP PDE inhibitor rolipram in rats

  • Han-Ting ZhangEmail author
  • Ying Huang
  • Kathleen Mishler
  • Sandra C. Roerig
  • James M. O'Donnell
Original Innvestigation



Type 4 phosphodiesterase (PDE4) is critical for hydrolysis of cAMP formed by stimulation of beta adrenergic receptors. However, it is not known if PDE4 is associated with beta adrenergic receptors in the mediation of antidepressant-like effects.


The aim of the study is to determine the relationship between PDE4 and beta adrenergic receptor-mediated cAMP signaling in mediating antidepressant-like effects.


The effects of the PDE4 inhibitor rolipram, alone or combined with dobutamine or clenbuterol, selective beta-1 and beta-2 adrenergic agonists, respectively, on behavior were examined in rats under a differential reinforcement of low rate (DRL) schedule and rats trained to discriminate rolipram from vehicle. Their effects on cAMP in primary cultures of rat cerebral cortical neurons also were determined.


Rolipram (0.01–0.3 mg/kg), dobutamine (1–30 mg/kg), and clenbuterol (0.03–0.3 mg/kg) dose-dependently produced antidepressant-like effects on DRL behavior, decreasing response rate and increasing reinforcement rate. The effects of beta adrenergic agonists were potentiated by rolipram. Isobolographic analysis revealed that rolipram enhanced the antidepressant-like effect of dobutamine additively and that of clenbuterol synergistically. Consistently, a combination of ineffective doses of rolipram (0.03 mg/kg) and dobutamine (3 mg/kg) or clenbuterol (0.03 mg/kg) completely substituted for the rolipram discrimination stimulus. Further, incubation with an ineffective concentration of clenbuterol, but not dobutamine, in the presence of a subeffective concentration of rolipram, significantly increased cAMP in cultured cortical neurons.


PDE4 plays an important role in regulating cAMP signaling by either beta-1 or beta-2 adrenergic receptors that mediate antidepressant-like actions; beta-2 adrenergic receptor-mediated cAMP signaling appears more responsive than beta-1 cAMP signaling to PDE4 inhibition.


Beta adrenergic receptors Phosphodiesterase (PDE4) Cyclic AMP Antidepressant Drug discrimination Isobole Differential reinforcement of low rate (DRL) Rolipram Dobutamine Clenbuterol 



This study was supported by research grants and an Independent Scientist Award from the National Institute of Mental Health. The authors thank Mr. Ajay K Venkatesan and Mr. Gerald K. McKinnie for their assistance with the experiments.


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Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Han-Ting Zhang
    • 1
    Email author
  • Ying Huang
    • 1
  • Kathleen Mishler
    • 1
  • Sandra C. Roerig
    • 2
  • James M. O'Donnell
    • 1
  1. 1.Department of PharmacologyThe University of Tennessee Health Science CenterMemphisUSA
  2. 2.Department of Pharmacology and TherapeuticsLouisiana State University Health Sciences CenterShreveportUSA

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