Antipsychotic profile of rolipram: efficacy in rats and reduced sensitivity in mice deficient in the phosphodiesterase-4B (PDE4B) enzyme.
BACKGROUND
Recent studies provide evidence for reduced phosphodiesterase-4B (PDE4B) as a genetic susceptibility factor as well as suggesting an association of several single nucleotide polymorphisms (SNPs) in PDE4B that are associated with an increased incidence of schizophrenia.


OBJECTIVE
The aim of the current study was to assess the activity of rolipram, a nonsubtype-selective PDE4 inhibitor, in several animal models predictive of antipsychotic-like efficacy and side-effect liability and to use PDE4B wild-type and knockout mice to begin to understand the subtypes involved in the activity of rolipram.


RESULTS
In rats, rolipram antagonized both phencyclidine hydrochloride- and D-amphetamine-induced hyperactivity and inhibited conditioned avoidance responding (CAR). In PDE4B wild-type mice, rolipram dose-dependently suppressed CAR (ED(50) = 2.4 mg/kg); however, in knockout mice, their sensitivity to rolipram at the higher doses (1.0 and 3.2 mg/kg) was reduced, resulting in a threefold shift in the ED(50) (7.3 mg/kg), suggesting PDE4B is involved, at least in part, with the activity of rolipram. Only the highest dose of rolipram (3.2 mg/kg) produced a modest but significant degree of catalepsy.


CONCLUSIONS
Rolipram has a pharmacologic profile similar to that of the atypical antipsychotics and has low extrapyramidal symptom liability. These results suggest that PDE4B mediates the antipsychotic effects of rolipram in CAR and that the PDE4B-regulated cyclic adenosine monophosphate signaling pathway may play a role in the pathophysiology and pharmacotherapy of psychosis.
Siuciak
Judith A
JA
CNS Discovery, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. judith.a.siuciak@pfizer.com
Chapin
Douglas S
DS
McCarthy
Sheryl A
SA
Martin
Ashley N
AN
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D002375:Catalepsy / Q000139:chemically induced; D003216:Conditioning, Operant / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006948:Hyperkinesis / Q000139:chemically induced / Q000188:drug therapy; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D011110:Polymorphism, Genetic; D011618:Psychotic Disorders / Q000188:drug therapy / Q000503:physiopathology; D051381:Rats; D020889:Rolipram / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D012559:Schizophrenia / Q000188:drug therapy / Q000503:physiopathology; D015398:Signal Transduction
D014150:Antipsychotic Agents; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram