Antidepressant-like effects of PDE4 inhibitors mediated by the high-affinity rolipram binding state (HARBS) of the phosphodiesterase-4 enzyme (PDE4) in rats.
BACKGROUND
Phosphodiesterase-4 (PDE4) has two conformation states based on rolipram binding, the high-affinity rolipram binding state (HARBS) and the low-affinity rolipram binding state (LARBS); their functions remain to be fully explained.


OBJECTIVE
Experiments were carried out to determine the roles of the HARBS and LARBS in the mediation of antidepressant-like effects on behavior.


METHODS
Two animal models sensitive to antidepressant drugs, the forced-swim test (FST), and the differential-reinforcement-of-low-rate (DRL) 72-s operant schedule, were used to examine the antidepressant-like effects of rolipram, CDP840, and piclamilast, PDE4 inhibitors that interact differentially with the HARBS and LARBS, and MEM1018 and MEM1091, two novel PDE4 inhibitors. Drug discrimination vs rolipram and rolipram competition binding assays also were carried out.


RESULTS
In the FST, rolipram and piclamilast, both at 0.1 mg/kg, produced an antidepressant-like effect, i.e., reduced immobility and increased swimming, whereas, 1 mg/kg of CDP840 or 0.5 mg/kg of MEM1018 or MEM1091 was required to produce a similar effect. Consistent with this, only rolipram and piclamilast produced antidepressant-like effects in rats under the DRL schedule of reinforcement, as evidenced by decreased response rates and increased reinforcement rates. In addition, in rats trained to discriminate rolipram from its vehicle, only rolipram and piclamilast substituted. Finally, [(3)H]rolipram and [(3)H]piclamilast binding analysis revealed that CDP840 and the two novel PDE4 inhibitors MEM1018 and MEM1091 exhibited a lower affinity for the HARBS than did rolipram.


CONCLUSIONS
These results suggest that the HARBS of PDE4 is the primary conformation important for antidepressant-like effects on behavior.
Departments of Behavioral Medicine & Psychiatry and Neurobiology & Anatomy, West Virginia University Health Sciences Center, Morgantown, WV 26506, USA. hzhang@hsc.wvu.edu
Han-Ting
HT
Zhang
Yu
Y
Zhao
Ying
Y
Huang
Chengjun
C
Deng
Allen T
AT
Hopper
Michael
M
De Vivo
Gregory M
GM
Rose
James M
JM
O'Donnell
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001667:Binding, Competitive; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D020889:Rolipram / Q000494:pharmacology*
D000928:Antidepressive Agents; D010726:Phosphodiesterase Inhibitors; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram