DISCRIMINATIVE STIMULUS PROPERTIES OF THE STEREOISOMERS OF THE PHOSPHODIESTERASE INHIBITOR ROLIPRAM

The discriminative stimulus properties of the specific type IV phospho diesterase inhibitor, rolipram, and its two stereoisomers were assesse d using standard two-lever drug discrimination procedures in which res ponding on the appropriate lever was reinforced on a FR10 schedule. In three separate drug cues based on training rats to discriminate the r acemate (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, differ ing 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 m easure correlating with their potency in displacing [H-3]rolipram from its forebrain binding sites in vivo (r = 0.95), suggesting that the d iscriminative stimulus depends on an action of the drug upon this site . Because rolipram has been reported to possess antidepressant activit y, the ability of the tricyclic antidepressant imipramine to substitut e for rolipram was investigated; doses of 10 and 20 mg/kg did not subs titute. Amphetamine (0.156-1.25 mg/kg) also was inactive. Lisuride gav e 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 tha t the rolipram discriminative stimulus is dependent on the selective P DE inhibititory activity of the drug, and that it does not constitute a cue based on the antidepressant property of rolipram.