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

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Abstract

Rationale

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.

Objective

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

Methods

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.

Results

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.

Conclusions

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.

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Acknowledgements

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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Authors and Affiliations

  1. Department of Pharmacology, The University of Tennessee Health Science Center, 874 Union Avenue, Memphis, TN, 38163, USA

    Han-Ting Zhang, Ying Huang, Kathleen Mishler & James M. O'Donnell

  2. Department of Pharmacology and Therapeutics, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA, 71130, USA

    Sandra C. Roerig

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  1. Han-Ting Zhang
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  2. Ying Huang
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  3. Kathleen Mishler
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  4. Sandra C. Roerig
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Correspondence to Han-Ting Zhang.

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Zhang, HT., Huang, Y., Mishler, K. et al. Interaction between the antidepressant-like behavioral effects of beta adrenergic agonists and the cyclic AMP PDE inhibitor rolipram in rats. Psychopharmacology 182, 104–115 (2005). https://doi.org/10.1007/s00213-005-0055-y

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