Effects of rolipram, a selective inhibitor of phosphodiesterase 4, on hyperlocomotion induced by several abused drugs in mice.
The effects of rolipram, a selective inhibitor of phosphodiesterase 4, on the hyperlocomotion induced by several abused drugs (methamphetamine, morphine and phencyclidine) and a dopamine D1-receptor agonist (SKF81297; (+/-)-6-chloro-7,8-dihydroxy-1-phenyl-2,3 ,4,5-tetrahydro-1H-3-benzazepin hydrobromide) in mice were investigated. Methamphetamine (0.5-2.0 mg/kg), morphine (5.0-20 mg/kg), phencyclidine (1.25-5.0 mg/kg) and SKF81297 (2.5-10 mg/kg) each induced dose-dependent hyperlocomotion. A low dose (1.0 mg/kg) or moderate dose (3.2 mg/kg) of rolipram suppressed methamphetamine (2.0 mg/kg)- and morphine (20 mg/kg)-induced hyperlocomotion, but not phencyclidine (5.0 mg/kg)-induced hyperlocomotion. These results suggest that cAMP in the brain is involved in methamphetamine- and morphine-induced hyperlocomotion, while the underlying mechanism(s) of phencyclidine-induced hyperlocomotion may be different from those of methamphetamine- and morphine-induced hyperlocomotion. It is well known that methamphetamine- and morphine-induced hyperlocomotion are mediated by the dopaminergic system and that interaction between postsynaptic D1- and D2-receptors may play an important role in the expression of various dopamine-mediated behaviors. In the present study, SKF81297 (10 mg/kg)-induced hyperlocomotion was significantly but not completely suppressed by the highest dose of rolipram (10 mg/kg). Therefore it is unlikely that postsynaptic D1-receptor-mediated functions are involved in the suppressive effects of rolipram on methamphetamine- and morphine-induced hyperlocomotion. These results suggest that rolipram may inhibit methamphetamine- and morphine-induced hyperlocomotion via increase cAMP levels at D2-receptors.
Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., Yokohama, Japan.
T
T
Mori
J
J
Baba
Y
Y
Ichimaru
T
T
Suzuki
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D015259:Dopamine Agents / Q000494:pharmacology; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D010622:Phencyclidine / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D020889:Rolipram / Q000494:pharmacology*
D001552:Benzazepines; D015259:Dopamine Agents; D010726:Phosphodiesterase Inhibitors; D008694:Methamphetamine; C067113:SK&F 81297; D009020:Morphine; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D010622:Phencyclidine; D020889:Rolipram