title: Phosphodiesterase 10A inhibitor, MP-10 (PF-2545920), produces greater induction of c-Fos in dopamine D2 neurons than in D1 neurons in the neostriatum.
abstract: Studies described here tested the hypothesis that phosphodiesterase 10A inhibition by a selective antagonist, MP-10, activates the dopamine D2 receptor expressing medium spiny neurons to a greater extent than the D1 receptor expressing neurons. We used regional pattern of c-Fos induction in the neostriatal subregions of rodents and direct assessment of D1-positive and -negative neurons in the DRd1a-tdTomato mice for the purpose. MP-10 (1, 3, 10 or 30 mg/kg, PO) dose-dependently increased c-Fos immunopositive nuclei in all regions of neostriatum. However, the effect was statistically greater in the dorsolateral striatum, a region known to be activated preferentially by the D2 antagonism, than the D1-activated dorsomedial striatum. The D2 antagonist, haloperidol (0.3, 1, or 3 mg/kg, PO) produced an identical, regional pattern of c-Fos induction favoring the dorsolateral striatum of the rat. In contrast, the D1 agonist, SKF82958 (0.5, 1, or 2 mg/kg, PO), induced greater expression of c-Fos in the dorsomedial striatum. The C57Bl/6 mouse also showed regionally preferential c-Fos activation by haloperidol (2 mg/kg, IP) and SKF82858 (3 mg/kg, IP). In the Drd1a-tdTomato mice, MP-10 (3 or 10 mg/kg, IP) increased c-Fos immunoreactivity in both types of neurons, the induction was greater in the D1-negative neurons. Taken together, both the regional pattern of c-Fos induction in the striatal sub-regions and the greater induction of c-Fos in the D1-negative neurons indicate that PDE10A inhibition produces a small but significantly greater activation of the D2-containing striatopallidal pathway.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46225, USA; Department of Biology, Center for Developmental and Regenerative Biology, Indiana University-Purdue University, Indianapolis 723 West Michigan Street, Indianapolis, IN, 46202, USA. Electronic address: wilsonjo@lilly.com.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Wilson
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46225, USA.
authors.forename: Ann Marie L
authors.initials: AM
authors.lastname: Ogden
authors.affiliation: Eli Lilly and Company Ltd., Erl Wood Manor, Sunninghill Road, Windlesham, Surrey GU20 6PH, UK.
authors.forename: Sally
authors.initials: S
authors.lastname: Loomis
authors.affiliation: Eli Lilly and Company Ltd., Erl Wood Manor, Sunninghill Road, Windlesham, Surrey GU20 6PH, UK.
authors.forename: Gary
authors.initials: G
authors.lastname: Gilmour
authors.affiliation: Department of Biology, Center for Developmental and Regenerative Biology, Indiana University-Purdue University, Indianapolis 723 West Michigan Street, Indianapolis, IN, 46202, USA; Stark Neurosciences Research Institute, Indiana University-Purdue University, Indianapolis 723 West Michigan Street, Indianapolis, IN, 46202, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Baucum
authors.affiliation: Department of Biology, Center for Developmental and Regenerative Biology, Indiana University-Purdue University, Indianapolis 723 West Michigan Street, Indianapolis, IN, 46202, USA.
authors.forename: Teri L
authors.initials: TL
authors.lastname: Belecky-Adams
authors.affiliation: Department of Biology, Center for Developmental and Regenerative Biology, Indiana University-Purdue University, Indianapolis 723 West Michigan Street, Indianapolis, IN, 46202, USA.
authors.forename: Kalpana M
authors.initials: KM
authors.lastname: Merchant
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; 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*; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*
chemical_list: C545121:2-((4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy)methyl)quinoline; D001552:Benzazepines; D018491:Dopamine Agonists; D065127:Dopamine D2 Receptor Antagonists; D010726:Phosphodiesterase Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D011720:Pyrazoles; D011804:Quinolines; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C071262:SK&F 82958; C512064:PDE10A protein, rat; C492284:Pde10a protein, mouse; D010727:Phosphoric Diester Hydrolases; D006220:Haloperidol
keywords: Basal ganglia; Huntington's disease; Parkinson's disease; Schizophrenia