Discriminative effects of CGS 15943, a competitive adenosine receptor antagonist, in monkeys: comparison to methylxanthines.
Caffeine and related methylxanthines are competitive antagonists at A1- and A2-adenosine receptors, but have other actions at the cellular level that contribute to their effects on behavior. As an approach toward determining the role of adenosine receptors in the behavioural effects of drugs, four squirrel monkeys were trained to discriminate between injections of CGS 15943 (1.0 mg/kg i.m.), a nonxanthine adenosine receptor antagonist that does not inhibit phosphodiesterase, and its vehicle. All monkeys generalized dose-dependently and completely to six of seven methylxanthines: 3-isobutyl-1-methylxanthine (0.1-1.75 mg/kg), theophylline (0.03-3.0 mg/kg), paraxanthine (0.3-30 mg/kg), 8-cyclopentyltheophylline (0.3-30 mg/kg), theobromine (0.3-30 mg/kg) and caffeine (1.0-30 mg/kg). Three of four monkeys did not generalize to 8-p-sulfophenyl-theophylline (1.0-30 mg/kg), which does not cross the blood-brain barrier. When the training dose of CGS 15943 was administered concurrently with adenosine-receptor agonists, its effects were blocked dose-dependently and completely by CGS 21680 (A2 selective), only partially by cyclohexyladenosine (A1 selective), but were not blocked by 5'-N-ethylcarboxamidoadenosine (nonselective). CGS 21680 did not block responding on the CGS 15943-appropriate lever occasioned by 30 mg/kg of caffeine or 3.0 mg/kg of theophylline. These results suggest that stimulus control of behavior by CGS 15943 derives, in part, from blockade of A2-adenosine receptors located in the central nervous system. However, the potency order of methylxanthines as CGS 15943-like discriminative stimuli did not correlate with their relative affinities at either A2- or A1-adenosine receptors or their potencies for other known effects at the cellular level. Therefore, a novel mechanism of action might account for the CGS 15943-like discriminative effects of some or all of these drugs.
Holtzman
S G
SG
Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia, USA.
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D004193:Discrimination Learning / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D008297:Male; D058915:Purinergic P1 Receptor Antagonists; D011799:Quinazolines / Q000494:pharmacology*; D012453:Saimiri; D013806:Theophylline / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology*; D014970:Xanthines / Q000494:pharmacology*
D058915:Purinergic P1 Receptor Antagonists; D011799:Quinazolines; D014230:Triazoles; D014970:Xanthines; C008514:methylxanthine; D013806:Theophylline; D015056:1-Methyl-3-isobutylxanthine; C052410:9-chloro-2-(2-furyl)-(1,2,4)triazolo(1,5-c)quinazolin-5-imine