Behavioral and neurochemical characterization of mice deficient in the phosphodiesterase-1B (PDE1B) enzyme.
PDE1B is a calcium-dependent cyclic nucleotide phosphodiesterase that is highly expressed in the striatum. In order to investigate the physiological role of PDE1B in the central nervous system, PDE1B knockout mice (C57BL/6N background) were assessed in behavioral tests and their brains were assayed for monoamine content. In a variety of well-characterized behavioral tasks, including the elevated plus maze (anxiety-like behavior), forced swim test (depression-like behavior), hot plate (nociception) and two cognition models (passive avoidance and acquisition of conditioned avoidance responding), PDE1B knockout mice performed similarly to wild-type mice. PDE1B knockout mice showed increased baseline exploratory activity when compared to wild-type mice. When challenged with amphetamine (AMPH) and methamphetamine (METH), male and female PDE1B knockout mice showed an exaggerated locomotor response. Male PDE1B knockout mice also showed increased locomotor responses to higher doses of phencyclidine (PCP) and MK-801; however, this effect was not consistently observed in female knockout mice. In the striatum, increased dopamine turnover (DOPAC/DA and HVA/DA ratios) was found in both male and female PDE1B knockout mice. Striatal serotonin (5-HT) levels were also decreased in PDE1B knockout mice, although levels of the metabolite, 5HIAA, were unchanged. The present studies demonstrate increased striatal dopamine turnover in PDE1B knockout mice associated with increased baseline motor activity and an exaggerated locomotor response to dopaminergic stimulants such as methamphetamine and amphetamine. These data further support a role for PDE1B in striatal function.
Siuciak
J A
JA
CNS Discovery Research, Pfizer Global Research & Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA. judith.a.siuciak@pfizer.com
McCarthy
S A
SA
Chapin
D S
DS
Reed
T M
TM
Vorhees
C V
CV
Repaske
D R
DR
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D015306:Biogenic Monoamines / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects / Q000235:genetics*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D010622:Phencyclidine / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000172:deficiency*; D012737:Sex Factors; D013550:Swimming
D015306:Biogenic Monoamines; D000697:Central Nervous System Stimulants; D018691:Excitatory Amino Acid Antagonists; D016291:Dizocilpine Maleate; D010727:Phosphoric Diester Hydrolases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; C517267:Pde1b protein, mouse; D010622:Phencyclidine