Attenuation of nicotine-induced rewarding effects in A 2A knockout mice

Abstract

The non-selective A 2A antagonist caffeine has been reported to modify nicotine-induced locomotor and reinforcing effects. In the present study, we have investigated the specific role of A 2A adenosine receptors in the behavioural responses induced by nicotine by using genetically modified mice lacking A 2A adenosine receptors. Acute nicotine administration induced a similar decrease of locomotor activity in A 2A knockout mice and wild-type littermates. Acute antinociceptive responses elicited by nicotine in the tail-immersion and hot-plate tests were unaffected in these mutant mice. The rewarding properties of nicotine were then investigated using the place-conditioning paradigm. Nicotine-induced conditioned place preference was suppressed in A 2A knockout mice. Accordingly, in vivo microdialysis studies revealed that the extracellular levels of dopamine in the nucleus accumbens were not increased after nicotine administration in mutant mice. Wild-type and A 2A knockout mice were trained in conditioned taste aversion procedure in which drinking a saccharin or saline solution was paired with nicotine or saline injections. A similar reduction in the intake of nicotine-paired solution in this paradigm was obtained in both genotypes. Finally, the administration of the nicotinic antagonist mecamylamine in nicotine-dependent mice precipitated a similar withdrawal syndrome in both genotypes. Together, the present results identify A 2A adenosine receptors as an important factor that contributes to the rewarding properties of nicotine.