title: Effects of phosphodiesterase 10 inhibition on striatal cyclic AMP and peripheral physiology in rats.
abstract: 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.
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Torremans
authors.forename: Abdellah
authors.initials: A
authors.lastname: Ahnaou
authors.forename: An
authors.initials: A
authors.lastname: Van Hemelrijck
authors.forename: Roel
authors.initials: R
authors.lastname: Straetemans
authors.forename: Helena
authors.initials: H
authors.lastname: Geys
authors.forename: Greet
authors.initials: G
authors.lastname: Vanhoof
authors.forename: Theo F
authors.initials: TF
authors.lastname: Meert
authors.forename: Wilhelmus H
authors.initials: WH
authors.lastname: Drinkenburg
mesh_terms: 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
chemical_list: 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