title: Phosphodiesterase 4 inhibition enhances the dopamine D1 receptor/PKA/DARPP-32 signaling cascade in frontal cortex.
abstract: BACKGROUND
  Alteration of dopamine neurotransmission in the prefrontal cortex, especially hypofunction of dopamine D1 receptors, contributes to psychotic symptoms and cognitive deficit in schizophrenia. D1 receptors signal through the cAMP/PKA second messenger cascade, which is modulated by phosphodiesterase (PDE) enzymes that hydrolyze and inactivate cyclic nucleotides. Though several PDEs are expressed in cortical neurons, the PDE4 enzyme family (PDE4A-D) has been implicated in the control of cognitive function. The best studied isoform, PDE4B, interacts with a schizophrenia susceptibility factor, disrupted in schizophrenia 1 (DISC1).
  
  
  OBJECTIVE
  We explore the control of mouse frontal cortex dopamine D1 receptor signaling and associated behavior by PDE4.
  
  
  RESULTS
  Inhibition of PDE4 by rolipram induced activation of cAMP/PKA signaling in cortical slices and in vivo, leading to the phosphorylation of DARPP-32 and other postsynaptic and presynaptic PKA-substrates. Rolipram also enhanced DARPP-32 phosphorylation invoked by D1 receptor activation. Immunohistochemical studies demonstrated PDE4A, PDE4B, and PDE4D expression in DARPP-32-positive neurons in layer VI of frontal cortex, most likely in D1 receptor-positive, glutamatergic corticothalamic pyramidal neurons. Furthermore, the ability of rolipram treatment to improve the performance of mice in a sensorimotor gating test was DARPP-32-dependent.
  
  
  CONCLUSIONS
  PDE4, which is co-expressed with DARPP-32 in D1 receptor-positive cortical pyramidal neurons in layer VI, modulates the level of D1 receptor signaling and DARPP-32 phosphorylation in the frontal cortex, likely influencing cognitive function. These biochemical and behavioral actions of PDE4 inhibitors may contribute to the hypothesized antipsychotic actions of this class of compounds.
authors.affiliation: Department of Pharmacology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan.
authors.forename: Mahomi
authors.initials: M
authors.lastname: Kuroiwa
authors.forename: Gretchen L
authors.initials: GL
authors.lastname: Snyder
authors.forename: Takahide
authors.initials: T
authors.lastname: Shuto
authors.forename: Atsuo
authors.initials: A
authors.lastname: Fukuda
authors.forename: Yuchio
authors.initials: Y
authors.lastname: Yanagawa
authors.forename: David R
authors.initials: DR
authors.lastname: Benavides
authors.forename: Angus C
authors.initials: AC
authors.lastname: Nairn
authors.forename: James A
authors.initials: JA
authors.lastname: Bibb
authors.forename: Paul
authors.initials: P
authors.lastname: Greengard
authors.forename: Akinori
authors.initials: A
authors.lastname: Nishi
mesh_terms: D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000187:drug effects / Q000378:metabolism; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D017397:Prefrontal Cortex / Q000378:metabolism; D017966:Pyramidal Cells / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D020889:Rolipram / Q000494:pharmacology; D012559:Schizophrenia / Q000503:physiopathology; D055139:Sensory Gating; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D058988:Phosphodiesterase 4 Inhibitors; D017447:Receptors, Dopamine D1; D017868:Cyclic AMP-Dependent Protein Kinases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram