Phosphodiesterase 10A inhibitor, MP-10 (PF-2545920), produces greater induction of c-Fos in dopamine D2 neurons than in D1 neurons in the neostriatum

  • Neuropharmacology. 2015 Dec;99:379-86. doi: 10.1016/j.neuropharm.2015.08.008.
Jonathan M Wilson  1 ,  Ann Marie L Ogden  2 ,  Sally Loomis  3 ,  Gary Gilmour  3 ,  Anthony J Baucum 2nd  4 ,  Teri L Belecky-Adams  5 ,  Kalpana M Merchant  5
Affiliations
  • 1. 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: [email protected].
  • 2. Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46225, USA.
  • 3. Eli Lilly and Company Ltd., Erl Wood Manor, Sunninghill Road, Windlesham, Surrey GU20 6PH, UK.
  • 4. 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.
  • 5. Department of Biology, Center for Developmental and Regenerative Biology, Indiana University-Purdue University, Indianapolis 723 West Michigan Street, Indianapolis, IN, 46202, USA.
PMID: 26256420 DOI: 10.1016/j.neuropharm.2015.08.008
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.

Keywords
Basal ganglia; Huntington's disease; Parkinson's disease; Schizophrenia.
Products