Pergamon Pharmacology Biochemistry and Behavior, Vol. 50, No. 2, pp. 21 l-217, 1995 Copyright 0 1995 Elsevier Science Ltd Printed in the USA. All rights reserved 0091-3057/95 $9.50 + .OO 0091-3057(94)00296-7 Discriminative Stimulus Properties of the Stereoisomers of the Phosphodiesterase Inhibitor Rolipram HERBERT H. SCHNEIDER,*’ MOTONORI YAMAGUCHI,? JOHN S. ANDREWSt AND DAVID N. STEPHENS* zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPO *Research Laboratories, Schering AG, 13342 Berlin, Germany fhrihon Schering K.K., Osaka532, Japan *Organon International BV, 5340 BH Oss, The Netherlands Received 4 May 1994 SCHNEIDER, H. H., M. YAMAGUCHI, J. S. ANDREWS AND D. N. STEPHENS. Disrriminotive stimulus prop- erties of the stereoisomers of the phosphodiesterase inhibitor rolipram. PHARMACOL BIOCHEM BEHAV SO(2) 211- 217, 1995.-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 FRIO 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 phosphocliesterase (PDE) inhibitors were found to substitute for the racemate cue, their potencies in the behavioural measure correlating with their potency in displacing [“Hlrolipram 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 hnipramine to substi- tute 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 inhibititory activity of the drug, and that it does not constitute a cue based on the antidepressant property of rolipram. Drug discrimination Rolipram PDE inhibitors Rats In vivo binding ROLIPRAh4 is a specific inhibitor of the CAMP type IV phos- phodiesterase isoenzyme (CAMP PDE) (3). One important role of this enzyme is in terminating the signal provided by the second messenger CAMP following its triggering by G-proteins sensitive to the activation of /3-adrenergic receptors by nor- adrenaline, so that rolipram can be expected to increase the signal induced by activation of the brain’s adrenergic system (9,18). Consistent with an upregulation of adrenergic trans- mission, rolipram has been shown to be active in several ani- mal tests predictive of antidepressant activity (12,21), and an antidepressant action has been confirmed in the clinic (2,4,5). In in vitro experiments, a specific [3H]roIipram binding site has been identified in the brain (17), and in vitro autoradio- graphic studies have suggested that the highest density of roli- pram binding sites occurs in the subiculum (8). This binding site appears to be associated with rolipram’s PDE inhibitory activity (16). Subsequently, a correlation between the ability of several agents to inhibit [‘Hlrolipram binding to forebrain structures in vivo and their behavioural effects in neurophar- macological tests was reported (14). Drug discrimination procedures have been widely used to identify specific stimulus properties of drugs acting on the central nervous system. In general, antidepressants give rise to weak internal stimuli, and are difficult to establish as discrimi- native stimuli in drug discrimination procedures (1). In con- trast, rolipram forms a potent discriminative stimulus in rats ’ Requests for reprints should be addressed to Dr. H. H. Schneider, Department of Neuropsychopharmacology, Schering AG, 13342 Berlin, Germany. 211