Interaction between the antidepressant-like behavioral effects of beta adrenergic agonists and the cyclic AMP PDE inhibitor rolipram in rats.
BACKGROUND
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.
Zhang
Han-Ting
HT
Department of Pharmacology, The University of Tennessee Health Science Center, 874 Union Avenue, Memphis, TN 38163, USA. hzhang@utmem.edu
Huang
Ying
Y
Mishler
Kathleen
K
Roerig
Sandra C
SC
O'Donnell
James M
JM
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001070:Appetitive Behavior / Q000187:drug effects*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects; D002976:Clenbuterol / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004193:Discrimination Learning / Q000187:drug effects*; D004280:Dobutamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D008297:Male; D009474:Neurons / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012055:Reinforcement Schedule; D020889:Rolipram / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D000928:Antidepressive Agents; D010726:Phosphodiesterase Inhibitors; D004280:Dobutamine; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram; D002976:Clenbuterol