Discriminative stimulus effects of the type-4 phosphodiesterase inhibitor rolipram in rats

Rationale: Rolipram, an inhibitor of cyclic AMP phosphodiesterase (PDE4) pr oduces discriminative stimulus effects in rats. These effects may be relate d to a wide range of central nervous system effects described previously. O bjective: The purposes of the present study were to: (i) assess the specifi city of the discriminative stimulus effects of rolipram; (ii) examine the r ole of beta adrenergic receptors; (iii) assess the effects of imipramine an d nisoxetine; and (iv) determine whether SKF 38393, a compound which also i ncreases cAMP levels, substitutes for rolipram. Methods: Rats were trained to discriminate 0.1 mg/kg rolipram from its vehicle in a two-lever task. Fo llowing discrimination training, substitution and antagonism tests were car ried out. Results: In generalization tests, the PDE4 inhibitors ICI 63,197 and Ro 20-1724 substituted for rolipram in a dose-dependent manner (substit ution at 0.3 mg/kg and 3 mg/kg, respectively). The selective inhibitors of PDE1, PDE2, and PDE5/6 did not substitute for rolipram; however, a dose of 10 mg/kg of the PDE3 inhibitor milrinone did substitute. The beta adrenergi c agonists clenbuterol and dobutamine at least partially substituted for ro lipram (0.1 mg/kg and 18 mg/kg, respectively). By contrast, the DI dopamine rgic agonist SKF 38393 and the monoamine uptake inhibitors imipramine and n isoxetine were ineffective (at doses up to 3, 10, and 10 mg/kg, respectivel y). Conclusions: The present results indicate that the discriminative stimu lus effects of rolipram are related to the inhibition of the hydrolytic act ivity of PDE4. Generalized increases in cyclic nucleotides do not appear to be sufficient for producing rolipram-like effects. It appears that a mecha nism involving beta adrenergic receptors may contribute to the effects of r olipram.. consistent with previous neuropharmacological data. Finally, the discriminative stimulus effects of rolipram appear to be unrelated to its a ntidepressant-like effect, but may provide a,surrogate marker for central n ervous system-related side effects of PDE4 inhibitors.