Alterations in gene regulation following inhibition of the striatum-enriched phosphodiesterase, PDE10A.
PDE10A is a member of the phosphodiesterase superfamily highly enriched within medium spiny neurons (MSN) in mammalian striatum. We have used inhibitors of PDE10A and quantitative measures of mRNA to demonstrate that PDE10A controls striatal gene expression by regulating MSN cyclic nucleotide signaling pathways. Acute treatment with PDE10A inhibitors produces rapid and transient transcription of the immediate early gene cfos in rat striatum. Although inhibition of PDE10A causes accumulation of both cAMP and cGMP, the increase in striatal cfos expression appears to depend on changes in cAMP, since the increase is present in mice deficient in nNOS which fail to increase cGMP in response to PDE10A inhibition. Consistent with its expression in a majority of striatal MSN, PDE10A inhibition significantly induces expression of both substance P and enkephalin, neuropeptide markers for the direct and indirect striatal output pathways, respectively. These findings support the hypothesis that PDE10A modulates signal transduction in both striatal output pathways and suggest that PDE10A inhibitors may offer a unique approach to the treatment of schizophrenia.
Strick
Christine A
CA
Neuroscience Research Unit, Pfizer Global Research and Development, Groton/New London Laboratories, Eastern Point Road 8220/405, Groton, CT 06340, USA. christine.a.strick@pfizer.com
James
Larry C
LC
Fox
Carol B
CB
Seeger
Thomas F
TF
Menniti
Frank S
FS
Schmidt
Christopher J
CJ
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism*; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism; D006152:Cyclic GMP / Q000235:genetics / Q000378:metabolism; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000235:genetics; D010208:Papaverine / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013373:Substance P / Q000235:genetics / Q000378:metabolism
D004745:Enkephalins; D010726:Phosphodiesterase Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D013373:Substance P; D010208:Papaverine; D000242:Cyclic AMP; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; C512064:PDE10A protein, rat; C492284:Pde10a protein, mouse; D010727:Phosphoric Diester Hydrolases; D006152:Cyclic GMP