Behavioral and neurochemical characterization of mice deficient in the phosphodiesterase-4B (PDE4B) enzyme.
BACKGROUND
Phosphodiesterases (PDEs) belonging to the PDE4 family control intracellular concentrations of cyclic adenosine monophosphate (cAMP) by catalyzing its hydrolysis. Four separate PDE4 genes (PDE4A, PDE4B, PDE4C, and PDE4D) have been identified. PDE4 has been reported to be involved in various central nervous system (CNS) functions including depression, memory, and schizophrenia, although the specific subtype mediating these effects remains unclear.


OBJECTIVE
To investigate the role of PDE4B in the CNS, PDE4B wild-type and knockout mice (C57BL/6N background) were assessed in a variety of well-characterized behavioral tasks, and their brains were assayed for monoamine content.


RESULTS
Knockout mice showed a significant reduction in prepulse inhibition. Spontaneous locomotor activity was decreased (16%) in knockout mice. Furthermore, when challenged with amphetamine, both groups of mice responded similarly to a low dose of d-amphetamine (1.0 mg/kg), but knockout mice showed an enhanced response to a higher dose (1.78 mg/kg). Decreases in baseline levels of monoamines and their metabolites within the striatum of knockout mice were also observed. PDE4B knockout mice showed a modest decrease in immobility time in the forced swim test that approached significance. In several other tests, including the elevated plus maze, hot plate, passive avoidance, and Morris water maze, wild-type and knockout mice performed similarly.


CONCLUSIONS
The present studies demonstrate decreased striatal DA and 5-HT activity in the PDE4B knockout mice associated with decreased prepulse inhibition, decreased baseline motor activity, and an exaggerated locomotor response to amphetamine. These data further support a role for PDE4B in psychiatric diseases and striatal function.
CNS Discovery Research, Pfizer Global Research & Development, Groton, CT, 06340, USA. judith.siuciak@bms.com
Judith A
JA
Siuciak
Sheryl A
SA
McCarthy
Douglas S
DS
Chapin
Ashley N
AN
Martin
D000818:Animals; D001143:Arousal / Q000187:drug effects / Q000502:physiology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000503:physiopathology*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics*; D003913:Dextroamphetamine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009042:Motivation; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology; D012701:Serotonin / Q000378:metabolism*
D012701:Serotonin; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003913:Dextroamphetamine; D004298:Dopamine