In vivo and in vitro measurement of brain phosphodiesterase 4 in rats after antidepressant administration.
Based largely on in vitro measurements, the mechanism of several antidepressant treatments is thought to involve upregulation of 3'-5'-cyclic adenosine monophosphate (cAMP) signal transduction cascade and a corresponding increase in phosphodiesterase (PDE) 4, the enzyme that metabolizes cAMP. To assess the in vivo status of PDE4, rats were chronically treated with imipramine and then studied with: (1) in vivo positron emission tomography (PET) measurement of (R)-[(11)C]rolipram binding, (2) in vitro measurement of [(3)H]rolipram binding in brain homogenates, and (3) Western blotting for protein levels of PDE4 isoforms. Imipramine administration caused no significant change in B(max)/K(d), for both in vivo measurements with (R)-[(11)C]rolipram and in vitro measurements with [(3)H]rolipram in frontal cortex, hippocampus, and diencephalon. None of 10 isoforms of PDE4A, B, and D measured with immunoblots of frontal cortex and hippocampus showed a significant change. In summary, using relatively large brain regions for both in vivo imaging and in vitro measures of radiolabeled ligand binding and protein levels, chronic imipramine treatment via continuous mini-pump administration caused no significant change in PDE4 levels. Most, but not all, prior in vitro studies have found increased PDE4 levels after antidepressant administration. The current results raise questions about the in vivo effects of antidepressant treatment on PDE4 and on other potentially important experimental factors (e.g., continuous infusion vs. intermittent injection of antidepressant) in large brain areas. However, the results do not deny possibility of changes in discrete areas, which were not studied in the current study applying PET.
Fujita
Masahiro
M
Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA. masahiro.fujita@nih.gov
Imaizumi
Masao
M
D'Sa
Carrol
C
Zoghbi
Sami S
SS
Crescenzo
Matthew S
MS
Hong
Jinsoo
J
Musachio
John L
JL
Gee
Antony D
AD
Seidel
Jurgen
J
Green
Michael V
MV
Pike
Victor W
VW
Duman
Ronald S
RS
Innis
Robert B
RB
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism*; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage*; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000201:enzymology; D001931:Brain Mapping; D002247:Carbon Isotopes / Q000493:pharmacokinetics; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D007091:Image Processing, Computer-Assisted / Q000379:methods; D007099:Imipramine / Q000008:administration & dosage*; D066298:In Vitro Techniques; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods; D011485:Protein Binding / Q000187:drug effects; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D020889:Rolipram / Q000493:pharmacokinetics; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics
D000928:Antidepressive Agents; D002247:Carbon Isotopes; D010726:Phosphodiesterase Inhibitors; D014316:Tritium; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram; D007099:Imipramine