Discriminative stimulus properties of the stereoisomers of the phosphodiesterase inhibitor rolipram.

The discriminative stimulus properties of the specific type IV phosphodiesterase inhibitor, rolipram, and its two stereoisomers were assessed using standard two-lever drug discrimination procedures in which responding on the appropriate lever was reinforced on a FR10 schedule. In three separate drug cues based on training rats to discriminate the racemate (0.2 mg/kg, IP), the (-)-isomer (0.1 mg/kg), or the (+)-isomer (2 mg/kg) from vehicle, all forms substituted for one another, differing only in potency. In keeping with published reports, the (-)-isomer was the more potent form, the (+)-isomer being approximately 10 times less potent. Several phosphodiesterase (PDE) inhibitors were found to substitute for the racemate cue, their potencies in the behavioural measure correlating with their potency in displacing [3H]rolipram from its forebrain binding sites in vivo (r = 0.95), suggesting that the discriminative stimulus depends on an action of the drug upon this site. Because rolipram has been reported to possess antidepressant activity, the ability of the tricyclic antidepressant imipramine to substitute for rolipram was investigated; doses of 10 and 20 mg/kg did not substitute. Amphetamine (0.156-1.25 mg/kg) also was inactive. Lisuride gave rise to drug-appropriate responding in 50% of rats only at a dose of 0.078 mg/kg, which severely disrupted responding. It is concluded that the rolipram discriminative stimulus is dependent on the selective PDE inhibitory activity of the drug, and that it does not constitute a cue based on the antidepressant property of rolipram.