Rationale: 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).

Objectives: 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.

• R01 DA013621/DA/NIDA NIH HHS/United States
• DA13621/DA/NIDA NIH HHS/United States
• R01 DA01147/DA/NIDA NIH HHS/United States