Vol. 290, Issue 2, 535-542, August 1999

Caffeine, Acting on Adenosine A₁ Receptors, Prevents the Extinction of Cocaine-Seeking Behavior in Mice¹

A. Kuzmin , B. Johansson, E. E. Zvartau and B. B. Fredholm

Department of Pharmacology, Pavlov Medical University, St. Petersburg, Russia (A.K., E.Z.); and Section of Molecular Neuropharmacology, Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden (A.K., B.J., B.B.F.)

Drug-naive DBA/2 mice were trained to self-administer cocaine (40 µg/kg/infusion) 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 injections. Twenty-four hours after the training session (cocaine or saline self-administration), mice were injected i.p. with saline, cocaine, caffeine, 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-triazolo[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 operant boxes as during the training session but without response-contingent i.v. infusions. Saline injection elicited similar responding in animals from the 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 responding in the active group than in the yoked control group during a single extinction trial. The adenosine A₁-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-dependent 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 pharmacological class (adenosine-receptor antagonist) can induce behavior changes similar to the effects of the original self-administered drug (indirect dopamine-receptor agonist). The data also suggest that the effects of caffeine on cocaine-seeking behavior might be related to interaction with adenosine A₁ receptors, but not A_2A receptors.