Inhibition of the striatum-enriched phosphodiesterase PDE10A: a novel approach to the treatment of psychosis.
Phosphodiesterase 10A (PDE10A) is a recently identified cyclic nucleotide phosphodiesterase expressed primarily in dopaminoreceptive medium spiny neurons of the striatum. We report that papaverine is a potent, specific inhibitor of PDE10A and use this compound to explore the role of PDE10A in regulating striatal function. Papaverine administration produces an increase in striatal tissue levels of cGMP and an increase in extracellular cAMP measured by microdialysis. These cyclic nucleotide changes are accompanied by increases in the phosphorylation of CREB and ERK, downstream markers of neuronal activation. In rats, papaverine potentiates haloperidol-induced catalepsy, consistent with the hypothesis that inhibition of PDE10A can increase striatal output and prompting a further evaluation of papaverine in models predictive of antipsychotic activity. Papaverine is found to inhibit conditioned avoidance responding in rats and mice and to inhibit PCP- and amphetamine-stimulated locomotor activity in rats. The effects of papaverine on striatal cGMP and CREB and ERK phosphorylation, as well as on conditioned avoidance responding, were absent in PDE10A knockout mice, indicating that the effects of the compound are the result of PDE10A inhibition. These results indicate that PDE10A regulates the activation of striatal medium spiny neurons through effects on cAMP- and cGMP-dependent signaling cascades. Furthermore, the present results demonstrate that papaverine has efficacy in behavioral models predictive of antipsychotic activity. Thus, inhibition of PDE10A may represent a novel approach to the treatment of psychosis.
Siuciak
Judith A
JA
CNS Discovery, MS 8220-4142, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA.
Chapin
Douglas S
DS
Harms
John F
JF
Lebel
Lorraine A
LA
McCarthy
Sheryl A
SA
Chambers
Leslie
L
Shrikhande
Alka
A
Wong
Stephen
S
Menniti
Frank S
FS
Schmidt
Christopher J
CJ
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003342:Corpus Striatum / Q000201:enzymology* / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D049229:Dendritic Spines / Q000187:drug effects / Q000502:physiology; D003913:Dextroamphetamine / Q000494:pharmacology; D004357:Drug Synergism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D010208:Papaverine / Q000494:pharmacology*; D010622:Phencyclidine / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000502:physiology*; D010766:Phosphorylation; D051381:Rats
D014150:Antipsychotic Agents; D000697:Central Nervous System Stimulants; D017362:Cyclic AMP Response Element-Binding Protein; D018691:Excitatory Amino Acid Antagonists; D010726:Phosphodiesterase Inhibitors; D010208:Papaverine; D000242:Cyclic AMP; D048049:Extracellular Signal-Regulated MAP Kinases; C512064:PDE10A protein, rat; D010727:Phosphoric Diester Hydrolases; D006152:Cyclic GMP; D010622:Phencyclidine; D006220:Haloperidol; D003913:Dextroamphetamine