title: The PDE10A inhibitor MP-10 and haloperidol produce distinct gene expression profiles in the striatum and influence cataleptic behavior in rodents.
abstract: Phosphodiesterase 10A (PDE10A) has garnered attention as a potential therapeutic target for schizophrenia due to its prominent striatal expression and ability to modulate striatal signaling. The present study used the selective PDE10A inhibitor MP-10 and the dopamine D2 antagonist haloperidol to compare effects of PDE10A inhibition and dopamine D2 blockade on striatopallidal (D2) and striatonigral (D1) pathway activation. Our studies confirmed that administration of MP-10 significantly elevates expression of the immediate early genes (IEG) c-fos, egr-1, and arc in rat striatum. Furthermore, we demonstrated that MP-10 induced egr-1 expression was distributed evenly between enkephalin-containing D2-neurons and substance P-containing D1-neurons. In contrast, haloperidol (3 mg/kg) selectively activated egr-1 expression in enkephalin neurons. Co-administration of MP-10 and haloperidol (0.5 mg/kg) increased IEG expression to a greater extent than either compound alone. Similarly, in a rat catalepsy assay, administration of haloperidol (0.5 mg/kg) or MP-10 (3-30 mg/kg) did not produce cataleptic behavior when dosed alone, but co-administration of haloperidol with MP-10 (3 and 10 mg/kg) induced cataleptic behaviors. Interestingly, co-administration of haloperidol with a high dose of MP-10 (30 mg/kg) failed to produce cataleptic behavior. These findings are important for understanding the neural circuits involved in catalepsy and suggest that the behavioral effects produced by PDE10A inhibitors may be influenced by concomitant medication and the level of PDE10A inhibition achieved by the dose of the inhibitor.
authors.affiliation: Neuroscience, Merck Research Laboratories, West Point, Pennsylvania, 19486, PA, USA. Electronic address: renee_gentzel@merck.com.
authors.forename: Renee C
authors.initials: RC
authors.lastname: Gentzel
authors.affiliation: Neuroscience, Merck Research Laboratories, West Point, Pennsylvania, 19486, PA, USA.
authors.forename: Dawn
authors.initials: D
authors.lastname: Toolan
authors.affiliation: In Vivo Pharmacology, Merck Research Laboratories, West Point, Pennsylvania, 19486, PA, USA.
authors.forename: Rhonda
authors.initials: R
authors.lastname: Roberts
authors.affiliation: In Vivo Pharmacology, Merck Research Laboratories, West Point, Pennsylvania, 19486, PA, USA.
authors.forename: Amy Jo
authors.initials: AJ
authors.lastname: Koser
authors.affiliation: In Vivo Pharmacology, Merck Research Laboratories, West Point, Pennsylvania, 19486, PA, USA.
authors.forename: Monika
authors.initials: M
authors.lastname: Kandebo
authors.affiliation: In Vivo Pharmacology, Merck Research Laboratories, West Point, Pennsylvania, 19486, PA, USA.
authors.forename: James
authors.initials: J
authors.lastname: Hershey
authors.affiliation: Neuroscience, Merck Research Laboratories, West Point, Pennsylvania, 19486, PA, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
authors.affiliation: In Vivo Pharmacology, Merck Research Laboratories, West Point, Pennsylvania, 19486, PA, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Uslaner
authors.affiliation: Neuroscience, Merck Research Laboratories, West Point, Pennsylvania, 19486, PA, USA.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Smith
mesh_terms: D000818:Animals; D002375:Catalepsy / Q000139:chemically induced* / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D004745:Enkephalins / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006220:Haloperidol / Q000494:pharmacology*; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D013373:Substance P / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism
chemical_list: C545121:2-((4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy)methyl)quinoline; D003598:Cytoskeletal Proteins; C000607792:DRD2 protein, rat; D018492:Dopamine Antagonists; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D004745:Enkephalins; D009419:Nerve Tissue Proteins; D010726:Phosphodiesterase Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D011720:Pyrazoles; D011804:Quinolines; D017448:Receptors, Dopamine D2; C092069:activity regulated cytoskeletal-associated protein; D013373:Substance P; C512064:PDE10A protein, rat; D010727:Phosphoric Diester Hydrolases; D006220:Haloperidol
keywords: Catalepsy; Haloperidol; Immediate early genes; Phosphodiesterase inhibitors; Schizophrenia