title: Caffeine induces differential cross tolerance to the amphetamine-like discriminative stimulus effects of dopaminergic agonists.
abstract: The purpose of this study was to determine if caffeine induces cross tolerance to the amphetamine-like discriminative stimulus effects of dopaminergic drugs that act through distinct mechanisms (e.g., release, uptake inhibition, direct activation of dopamine D(1)- or D(2)-family receptors). Rats were trained to discriminate 1.0 mg/kg d-amphetamine from saline in a two-choice discrete-trial procedure. Stimulus-generalization curves were generated by cumulative dosing for d-amphetamine (0.1-1.0 mg/kg), methylphenidate (0.3-5.6 mg/kg), SKF 81297 (0.3-3.0 mg/kg), and R-(-)-propylnorapomorphine (NPA; 0.001-1.78 mg/kg), as well as for caffeine (3.0-56 mg/kg); curves were re-determined after twice daily injections of caffeine (30 mg/kg) for 3.5 days. The rats generalized dose dependently to the four dopaminergic drugs, but only to a limited extent to caffeine. Twice daily injections of caffeine induced significant cross tolerance (i.e., increased ED(50)) to the amphetamine-like discriminative effects of methylphenidate and SKF 81297, attenuated non-significantly the effects of NPA, and did not alter the effects of amphetamine. Thus, caffeine produces differential cross tolerance to the amphetamine-like discriminative effects of dopaminergic drugs, a phenomenon in which the dopamine D(1) receptor appears to have an important role.
authors.affiliation: National Drug Dependence Treatment Centre, Department of Psychiatry, All India Institute of Medical Sciences, New Delhi-110029, India. rakajain2001@yahoo.com
authors.forename: Raka
authors.initials: R
authors.lastname: Jain
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Holtzman
mesh_terms: D000661:Amphetamine / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001058:Apomorphine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001552:Benzazepines / Q000494:pharmacology; D002110:Caffeine / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D002755:Choice Behavior / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects*; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance / Q000502:physiology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C425777:10,11-dihydroxy-N-n-propylnorapomorphine; D001552:Benzazepines; D000697:Central Nervous System Stimulants; D018491:Dopamine Agonists; D002110:Caffeine; C067113:SK&F 81297; D000661:Amphetamine; D001058:Apomorphine