The adenosine receptor antagonist CGS15943 reinstates cocaine-seeking behavior and maintains self-administration in baboons.
BACKGROUND
Caffeine and the adenosine A(1) and A(2A) receptor antagonist CGS15943 produce many behavioral effects that are similar to those produced by classic stimulant drugs (e.g. cocaine and amphetamines).


OBJECTIVE
The current study evaluated whether CGS15943 would maintain self-administration and reinstate extinguished lever responding previously maintained by cocaine (i.e. cocaine-seeking) or by food (i.e. food-seeking). Reinstatement with CGS15943 was compared to cocaine, caffeine, and alprazolam.


METHODS
Up to 30 injections of 0.032 mg/kg cocaine or 30 deliveries of 1-g food pellets were available under a fixed ratio (FR10) schedule of reinforcement during daily 2-h sessions. For reinstatement tests, lever responses were extinguished by substituting saline for cocaine or by removing pellets from the mechanical feeder. After extinction of lever responding, acute "priming" doses (mg/kg, IV) of cocaine (0.1-3.2), the adenosine receptor antagonists caffeine (0.1-1.8) and CGS15943 (0.032-0.32) or the benzodiazepine receptor agonist alprazolam (0.1-1.8 mg/kg) were administered. The intravenous reinforcing effects of CGS15943 were also evaluated; each dose of CGS15943 (0.001-0.032 mg/kg) was substituted for cocaine for at least 10 days and until self-injection was relatively stable.


RESULTS
Cocaine, caffeine and CGS15943, dose-dependently increased cocaine-seeking, where as alprazolam did not. Cocaine, caffeine and CGS15943 did not increase food-seeking. CGS15943 reinstated cocaine-seeking at rates that were comparable to those produced by cocaine. Pretreatment with the adenosine A(2) agonist CGS21680 decreased CGS15943-induced reinstatement of cocaine-seeking. In self-injection testing, CGS15943 was self-administered at levels greater than vehicle. An inverted U-shaped dose-effect function was obtained with peak mean rates maintained by 0.01 mg/kg CGS15943.


CONCLUSIONS
The adenosine antagonist CGS15943 reinstated cocaine-seeking and functioned as an intravenous reinforcer. The finding that CGS21680 produced a rightward shift in the CGS15943 reinstatement dose-effect curve supports a role of adenosine mechanisms in the reinstatement of cocaine-seeking behavior.
Weerts
Elise M
EM
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Md., USA. eweerts@jhmi.edu.|Behavioral Biology Research Center, Johns Hopkins Bayview, Suite 3000, 5510 Nathan Shock Drive, Baltimore, MD 21224, USA. eweerts@jhmi.edu.
Griffiths
Roland R
RR
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Md., USA.
D000818:Animals; D016739:Behavior, Addictive / Q000139:chemically induced* / Q000523:psychology; D003042:Cocaine / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D008297:Male; D010215:Papio; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D011799:Quinazolines / Q000633:toxicity*; D018047:Receptors, Purinergic P1 / Q000502:physiology; D012646:Self Administration; D014230:Triazoles / Q000633:toxicity*
D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D011799:Quinazolines; D018047:Receptors, Purinergic P1; D014230:Triazoles; D003042:Cocaine; C052410:9-chloro-2-(2-furyl)-(1,2,4)triazolo(1,5-c)quinazolin-5-imine