Caffeine, acting on adenosine A(1) receptors, prevents the extinction of cocaine-seeking behavior in mice

Drug-naive DBA/2 mice were trained to self-administer cocaine (40 mu g/kg/i nfusion) i.v. by nose poking. The number of nose-poke responses was higher in mice receiving response-contingent injections of cocaine (active group) than in yoked controls or in animals receiving response-contingent saline i njections. Twenty-four hours after the training session (cocaine or saline self-administration), mice were injected i.p. with saline, cocaine, caffein e, 1,3-dipropyl-8-cyclopentyl xanthine (DPCPX), 8-cyclopentyl theophylline (8-CPT), 5-amino-7-(2-phenylethyl)2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazo lo[1,5-c]pyrimidine (SCH 58261), or 9-chloro-2(2-furyl)[1,2,4]triazolo[1,5- c]quinazolin-5-amine (CGS 15943) and placed again in exactly the same opera nt boxes as during the training session but without response-contingent i.v . infusions. Saline injection elicited similar responding in animals from t he active group and from the yoked control group. A low dose of cocaine (5 mg/kg) or caffeine (3 mg/kg), but not higher doses, produced greater respon ding in the active group than in the yoked control group during a single ex tinction trial. The adenosine A(1)-receptor antagonists DPCPX and 8-CPT and the nonselective antagonist CGS 15943 partially reproduced the effect of a low dose of caffeine on the cocaine-associated behavior in a dose-dependen t manner and did not alter the nose-poke activity of yoked control mice in the extinction experiment. In contrast, the adenosine A(2A) antagonist SCH 58261, in doses above 1 mg/kg, reduced nose-poke activity equally in active and yoked control animals. This confirms that a drug from a different phar macological class (adenosine-receptor antagonist) can induce behavior chang es similar to the effects of the original self-administered drug (indirect dopamine-receptor agonist). The data also suggest that the effects of caffe ine on cocaine-seeking behavior might be related to interaction with adenos ine A, receptors, but not A(2A) receptors.