Phosphodiesterase 10A inhibitors: a novel approach to the treatment of the symptoms of schizophrenia.
A disruption of corticostriatal signaling is believed to underlie the psychotic symptoms of schizophrenia and also contribute to many of the cognitive deficits associated with this disorder. Phosphodiesterase (PDE)10A is a dual substrate PDE highly expressed in striatal medium spiny neurons. Biochemical and behavioral studies indicate that the inhibition of PDE10A enhances striatal output by increasing activity in the cGMP and cAMP signaling pathways. PDE10A inhibitors reduce exploratory activity and antagonize the stimulant response to both amphetamine and N-methyl-d-aspartate antagonists such as phencyclidine. Consistent with their potential as antipsychotic agents, PDE10A inhibitors are potent antagonists of conditioned avoidance responding. The presence of PDE10A in both striatal output pathways may reduce the incidence and severity of dopamine D2 receptor antagonist-like side effects, including extrapyramidal symptoms. In addition, by enhancing corticostriatal signaling, PDE10A inhibitors have the potential to improve some of the cognitive symptoms of schizophrenia.
Menniti
Frank S
FS
Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06355, USA. frank.s.menniti@pfizer.com
Chappie
Thomas A
TA
Humphrey
John M
JM
Schmidt
Christopher J
CJ
D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008954:Models, Biological; D015394:Molecular Structure; D010208:Papaverine / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D012559:Schizophrenia / Q000188:drug therapy* / Q000201:enzymology; D015398:Signal Transduction / Q000187:drug effects
D010726:Phosphodiesterase Inhibitors; D011799:Quinazolines; D010208:Papaverine; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases