Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5813807 | Neuropharmacology | 2015 | 31 Pages |
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 30Â 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 3Â 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 2Â 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 (2Â mg/kg, IP) and SKF82858 (3Â mg/kg, IP). In the Drd1a-tdTomato mice, MP-10 (3 or 10Â 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
MP-10DLSMSNGPCRDMScGMPPDEcAMPG protein-coupled receptorsBACdorsolateral striatumdorsomedial striatumCyclic adenosine monophosphateOral administrationSprague DawleySchizophreniagamma-aminobutyric acidHuntington's diseaseParkinson's diseaseanalysis of varianceANOVAintraperitoneal administrationbasal gangliaPhosphodiesterasecyclic guanosine monophosphatemedium spiny neuronbacterial artificial chromosomeGABA
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Authors
Jonathan M. Wilson, Ann Marie L. Ogden, Sally Loomis, Gary Gilmour, Anthony J. II, Teri L. Belecky-Adams, Kalpana M. Merchant,