, Volume 203, Issue 2, pp 355-367
Date: 08 Aug 2008

Effects of chronic caffeine exposure on adenosinergic modulation of the discriminative-stimulus effects of nicotine, methamphetamine, and cocaine in rats



Adenosine receptors are involved in cocaine and methamphetamine discrimination and exposure to caffeine can affect behavioral effects of nicotine in rats.


Here we investigated the relative involvement of adenosine A1 and A2A receptors in nicotine, cocaine, and methamphetamine discrimination, before and/or during chronic caffeine exposure.

Materials and methods

The nonselective adenosine receptor antagonist caffeine, the A1-receptor antagonist cyclopentyltheophylline (CPT), and the A2A-receptor antagonist MSX-3 were evaluated in rats trained to discriminate 0.4 mg/kg nicotine from saline under a fixed-ratio schedule of food delivery. Effects of adenosine receptor antagonists were then compared in rats discriminating nicotine, methamphetamine, or cocaine from saline during chronic caffeine exposure in their drinking water.


Caffeine, CPT, and MSX-3 partially generalized to nicotine and shifted nicotine dose–response curves leftwards. During chronic caffeine exposure, however, all three ligands failed to generalize to nicotine and failed to shift nicotine dose–response curves. In previous experiments, CPT and MSX-3 partially generalized to methamphetamine and cocaine and shifted dose–response curves leftwards. In the present experiments, CPT neither generalized nor shifted dose–response curves for methamphetamine or cocaine during chronic caffeine exposure. However, MSX-3 partially generalized to both psychostimulants and shifted their dose–response curves leftwards. Caffeine partially generalized to cocaine, but not methamphetamine, and shifted both dose–response curves leftwards.


Both adenosine A1 and A2A receptors are capable of modulating the discriminative-stimulus effects of nicotine. Chronic caffeine exposure produces complete tolerance to both A1- and A2A-mediated effects in nicotine-trained rats. In contrast, chronic caffeine exposure produces tolerance to adenosine A1-mediated, but not A2A-mediated, effects in methamphetamine- and cocaine-trained rats.