Adenosine (A)2A receptor modulation of nicotine-induced locomotor sensitization. A pharmacological and transgenic approach

• A2A receptor mechanisms control nicotine sensitization.
• There is no evidence of conditioned locomotion in NSEA2A animals.
• NSEA2A animals display a reduced basal glutamate in limbic areas.
• A2A receptor agonists can help counteract the abuse actions of nicotine.

Preclinical evidence indicates an important role of adenosine (A)2A receptors in drug addiction while their therapeutic relevance is still a matter of debate. We examined the influence of the A2A receptor agonist CGS 21680 and the antagonist KW 6002 on nicotine sensitization and conditioned locomotor activity in adult (8-week old) male Sprague–Dawley rats (WT). Moreover, behavioral responses to nicotine were studied in rats overexpressing A2A receptors under the control of the neuronal specific enolase (NSE) promotor. Changes in the levels of dopamine, glutamate and γ-aminobutyric acid in wild type (WT) and NSEA2A rats were determined with using LC–MS. KW 6002 significantly enhanced expression of nicotine sensitization and conditioned locomotion, while CGS 21680 reduced all these effects in WT rats. A reduction of the expression of nicotine-evoked conditioned locomotor activity was also observed in the NSEA2A animals. The transgenic rats displayed a reduced basal tissue level of glutamate in the prefrontal cortex and hippocampus while dopamine basal levels in the nucleus accumbens were raised. Chronic nicotine treatment caused a significant reduction in the glutamate tissue level in the dorsal and ventral striatum, prefrontal cortex and cerebellum in wild type rats. In NSEA2A animals the same drug treatment instead produced a rise of glutamate levels in the hippocampus and dorsal striatum. Taken together, A2A receptor signaling in the rat brain can counteract locomotor sensitization and conditioned locomotion to nicotine which are related to nicotine reward-learning. It is suggested that treatment with A2A receptor agonists can help counteract the abuse actions of nicotine.