title: Antidepressant-like profile and reduced sensitivity to rolipram in mice deficient in the PDE4D phosphodiesterase enzyme.
abstract: Pharmacological inhibition of type 4 cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase (PDE4) produces antidepressant-like effects in animals; however, it is not known which of the four PDE4 subtypes mediates these actions. In the present study, immunoblot analysis showed loss of phosphodiesterase 4D (PDE4D) expression in the cerebral cortex and hippocampus of PDE4D knockout (PDE4D-/-) mice, but unchanged PDE4A and PDE4B expression, relative to the wild type (PDE4D+/+) and heterozygous knockout (PDE4D+/-) mice. This reduced expression was accompanied by a reduction in PDE4 activity, while non-PDE4 activity was unchanged. PDE4D-/- mice exhibited decreased immobility in tail-suspension and forced-swim tests, which is indicative of an antidepressant-like effect on behavior. Desipramine and fluoxetine produced similar antidepressant-like effects in all three genotypes, even though their behavioral baselines differed markedly. By contrast, the PDE4 inhibitor rolipram only produced antidepressant-like effects in PDE4D+/+ mice. Consistent with this, rolipram potentiated isoproterenol-induced cyclic AMP formation only in the PDE4D+/+ mice. These results suggest that PDE4D is an essential mediator of the antidepressant-like effects of rolipram, and that PDE4D-regulated cyclic adenosine monophosphate signaling may play a role in the pathophysiology and pharmacotherapy of depression.
authors.affiliation: Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163, USA. hzng@utmem.edu
authors.forename: Han-Ting
authors.initials: HT
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.forename: S-L
authors.initials: SL
authors.lastname: Jin
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Frith
authors.forename: Neesha
authors.initials: N
authors.lastname: Suvarna
authors.forename: Marco
authors.initials: M
authors.lastname: Conti
authors.forename: James M
authors.initials: JM
authors.lastname: O'Donnell
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D000242:Cyclic AMP / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004347:Drug Interactions / Q000502:physiology; D004361:Drug Tolerance / Q000235:genetics*; D005838:Genotype; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D020033:Protein Isoforms / Q000172:deficiency / Q000235:genetics; D020889:Rolipram / Q000494:pharmacology*
chemical_list: D000318:Adrenergic beta-Agonists; D000928:Antidepressive Agents; D020033:Protein Isoforms; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram