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

• Published in: Neuropharmacology 2015-12, Vol.99, p.379-386
• Main Authors: Wilson, Jonathan M., Ogden, Ann Marie L., Loomis, Sally, Gilmour, Gary, Baucum, Anthony J., Belecky-Adams, Teri L., Merchant, Kalpana M.
• Format: Article
• Language: English
• Subjects: Animals; Basal ganglia; Benzazepines - pharmacology; Dopamine Agonists - pharmacology; Dopamine D2 Receptor Antagonists - pharmacology; Dose-Response Relationship, Drug; Haloperidol - pharmacology; Huntington's disease; Male; Mice, Inbred C57BL; Mice, Transgenic; Neostriatum - drug effects; Neostriatum - metabolism; Neostriatum - pathology; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Parkinson's disease; Phosphodiesterase Inhibitors - pharmacology; Phosphoric Diester Hydrolases - metabolism; Proto-Oncogene Proteins c-fos - metabolism; Pyrazoles - pharmacology; Quinolines - pharmacology; Random Allocation; Rats, Sprague-Dawley; Receptors, Dopamine D1 - antagonists & inhibitors; Receptors, Dopamine D1 - genetics; Receptors, Dopamine D1 - metabolism; Receptors, Dopamine D2 - metabolism; Schizophrenia
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2015.08.008

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. •MP-10 dose dependently increased c-Fos positive neurons in the rat neostriatum.•DLS showed greater activation of c-Fos than the DMS following MP-10 treatment.•MP-10-induced c-Fos was greater in D1(−) than in D1(+) in Drd1a-tdTomato mice.