European Journal of Pharmacology, 107 (1985) 169-181 169 Elsevier LORAZEPAM AND PENTOBARBITAL DISCRIMINATION: INTERACTIONS WITH CGS 8216 AND CAFFEINE NANCY A. ATOR 1,, and ROLAND R. GRIFFITHS 1,2 The Johns Hopkins University School of Medicine, 1 Department of Psychiatry and Behavioral Sciences, 2 Department of Neuroscience, 720 Rutland Avenue, Rm. 623, Baltimore, MD 21205, U.S.A. Received 10 July 1984, accepted 20 September 1984 N.A. ATOR and R.R. GRIFFITHS, Lorazepam and pentobarbital discrimination: interactions with CGS 8216 and caffeine, European J. Pharmacol. 107 (1985) 169-181 Baboons and rats were trained under a two-lever, food-reinforced drug discrimination procedure. The training drug was either lorazepam (1.0 mg/kg) or pentobarbital (5.6 mg/kg in baboons, 10.0 mg/kg in rats). Under test conditions, a range of training drug doses occasioned 100% drug lever responding. CGS 8216 (3.2-10.0 mg/kg) combined with lorazepam produced a complete shift to the no-drug lever in both species; this shift was surmountable with higher doses of lorazepam. CGS 8216 (32.0 mg/kg) combined with pentobarbital produced a statistically significant decrease in drug-lever responding in rats, and in baboons CGS 8216 initially, but not subsequently, produced a complete shift to the no-drug lever. Caffeine (0.32-10.0 mg/kg) combined with lorazepam inconsistently decreased drug-lever responding across multiple determinations in baboons and significantly decreased drug lever responding in rats. Caffeine combined with pentobarbital also yielded an inconsistent decrease in drug lever responding in baboons but there was no effect in rats. Thus the most reliable and complete antagonism across species was obtained with the CGS 8216/lorazepam combinations. Drug discrimination CGS 8216 Caffeine Lorazepam Pentobarbital 1. Introduction That the discriminative stimulus function of certain drugs may be mediated by specific popula- tions of receptors has been suggested by studies in which discriminative stimulus effects were antago- nized by compounds known to be competitive antagonists in a variety of other preparations (e.g. morphine, Shannon and Holtzman, 1976; nicotine, Meltzer et al., 1980). Benzodiazepines have been used successfully as discriminative stimuli, and it recently was shown that the discriminative stimu- lus effects of diazepam and lorazepam, but not pentobarbital, were antagonized by the specific benzodiazepine antagonist Ro 15-1788 in baboons * To whom all correspondence should be addressed: The Johns Hopkins University School of Medicine, Division of Behav- ioral Biology, 720 Rutland Avenue, Baltimore, MD 21205. and rats (Ator and Griffiths, 1983; Herling and Shannon, 1982). The present study was under- taken to extend our understanding of sedative- hypnotic discriminative stimuli by examining the effects of another benzodiazepine antagonist, CGS 8216, and an adenosine antagonist, caffeine, in combination with lorazepam and pentobarbital. CGS 8216 is a pyrazoloquinolone with a high affinity for benzodiazepine binding sites (Czernik et al., 1982; Yokoyama et al., 1982) and has shown antagonist activity in blocking the anticonvulsant, antipunishment, and discriminative stimulus ef- fects of diazepam in rats (Bernard et al., 1981; Shannon and Herling, 1983; Yokoyama et al., 1982). Caffeine is a potent inhibitor of adenosine binding but also has inhibited specific [3H]di- azepam binding (Boulenger et al., 1982; Marangos et al., 1979). In studies with both humans and 0014-2999/85/$03.30 © 1985 ElsevierScience Publishers B.V.