title: The effect of phosphodiesterase inhibitors on the extinction of cocaine-induced conditioned place preference in mice.
abstract: Several phosphodiesterase inhibitors (PDEis) improve cognition, suggesting that an increase in brain cAMP and cGMP facilitates learning and memory. Since extinction of drug-seeking behavior requires associative learning, consolidation and formation of new memory, the present study investigated the efficacy of three different PDEis in the extinction of cocaine-induced conditioned place preference (CPP) in B6129S mice. Mice were conditioned by escalating doses of cocaine which was resistant to extinction by free exploration. Immediately following each extinction session mice received (a) saline/vehicle, (b) rolipram (PDE4 inhibitor), (c) BAY-73-6691 (PDE9 inhibitor) or (d) papaverine (PDE10A inhibitor). Mice that received saline/vehicle during extinction training showed no reduction in CPP for >10 days. BAY-73-6691 (a) dose-dependently increased cGMP in hippocampus and amygdala, (b) significantly facilitated extinction and (c) diminished the reinstatement of cocaine CPP. Rolipram, which selectively increased brain cAMP levels, and papaverine which caused increases in both cAMP and cGMP levels, had no significant effect on the extinction of cocaine CPP. The results suggest that increase in hippocampal and amygdalar cGMP levels via blockade of PDE9 has a prominent role in the consolidation of extinction learning.
authors.affiliation: Division of Neuroscience, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Shervin
authors.initials: S
authors.lastname: Liddie
authors.forename: Karen L
authors.initials: KL
authors.lastname: Anderson
authors.forename: Andres
authors.initials: A
authors.lastname: Paz
authors.forename: Yossef
authors.initials: Y
authors.lastname: Itzhak
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000679:Amygdala / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001245:Association Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D003042:Cocaine / Q000633:toxicity; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005108:Extinction, Psychological / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007859:Learning Disabilities / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D057567:Memory, Long-Term / Q000187:drug effects; D051379:Mice; D057507:Mice, 129 Strain; D058990:Molecular Targeted Therapy; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000188:drug therapy* / Q000503:physiopathology; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D011720:Pyrazoles / Q000008:administration & dosage / Q000627:therapeutic use; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use; D013037:Spatial Behavior / Q000187:drug effects
chemical_list: C507056:BAY 73-6691; D009419:Nerve Tissue Proteins; D010726:Phosphodiesterase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C507055:Pde9a protein, mouse; D006152:Cyclic GMP; D003042:Cocaine