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.

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ABSTRACT-We examined the effects of two noradrenergic tricyclic antidepressants and two selective serotonin re-uptake inhibitors in the tail suspension test, with a suspension period of 30 min instead of the usual 10 min. Within the first 10 min, desipramine, nortriptyline and fluvoxamine significantly reduced the duration of immobility. Whereas desipramine and nortriptyline were also efficacious in the rest of the test period, fluvoxamine was not. Fluoxetine showed no significant effect throughout the study period. These results suggest that a prolonged tail suspension test results in functional changes in the noradrenergic and serotonergic systems and alters the sensitivity to antidepressants.

ABSTRACT-A selective inhibitor of cyclic nucleotide phosphodiesterase (PDE) 4, rolipram, markedly enhanced the forskolin-induced increase of intracellular dopamine and dihydroxyphenylacetate (DOPAC, a metabolite of dopamine) levels in primary cultured rat mesencephalic neurons and the forskolin-induced increase of dopamine and DOPAC in extracellular medium. Selective inhibitors of PDE2, PDE3, PDE5 and PDE6 did not have such a promoting effect, and the PDE1 inhibitor vinpocetine and W-7 caused dopa mine depletion in the neurons. These findings suggested that PDE4 plays a major role in regulating the intracellular cAMP level to control the dopamine biosynthesis in mesencephalic neurons, whereas PDE 1 regulates dopamine release instead.