Effects of phosphodiesterase 10 inhibition on striatal cyclic AMP and peripheral physiology in rats.
Phosphodiesterases (PDEs) form a family of enzymes involved in the hydrolysis of cyclic adenosine and guanosine monophosphate (cAMP and cGMP). PDE10A is a member of this family that is almost exclusively expressed in the striatum. Increasing cAMP/cGMP levels via inhibition of PDE10A is under consideration as a novel therapeutic avenue in the discovery of antipsychotics. Papaverine has been used as a pharmacological tool to establish the possible clinical use of PDE10A inhibitors as antipsychotics. Papaverine is known to increase cAMP levels in striatum and to decrease blood pressure, body temperature and locomotor activity after systemic administration. In this study, the effects of papaverine are compared to those of a more specific PDE10A inhibitor MP10. Papaverine raised striatal cAMP levels with hypothermia, hypoactivity and decreased cardiovascular responses. The more selective MP10 had significantly less effects on body temperature and cardiovascular functions, but reduced locomotor activity to a similar extend as papaverine.
Torremans
An
A
Johnson & Johnson Pharmaceutical Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium.
Ahnaou
Abdellah
A
Van Hemelrijck
An
A
Straetemans
Roel
R
Geys
Helena
H
Vanhoof
Greet
G
Meert
Theo F
TF
Drinkenburg
Wilhelmus H
WH
D000818:Animals; D019540:Area Under Curve; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D017551:Microdialysis / Q000379:methods; D009043:Motor Activity / Q000187:drug effects; D010208:Papaverine / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010829:Physiological Phenomena / Q000187:drug effects*; D011720:Pyrazoles / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013686:Telemetry / Q000379:methods; D013997:Time Factors
C545121:2-((4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy)methyl)quinoline; D010726:Phosphodiesterase Inhibitors; D011720:Pyrazoles; D011804:Quinolines; D010208:Papaverine; D000242:Cyclic AMP