Functional interaction between pre-synaptic α6β2-containing nicotinic and adenosine A2A receptors in the control of dopamine release in the rat striatum

Background and Purpose Pre-synaptic nicotinic ACh receptors (nAChRs) and adenosine A2A receptors (A2ARs) are involved in the control of dopamine release and are putative therapeutic targets in Parkinson's disease and addiction. Since A2ARs have been reported to interact with nAChRs, here we aimed at mapping the possible functional interaction between A2ARs and nAChRs in rat striatal dopaminergic terminals. Experimental Approach We pharmacologically characterized the release of dopamine and defined the localization of nAChR subunits in rat striatal nerve terminals in vitro and carried out locomotor behavioural sensitization in rats in vivo. Key Results In striatal nerve terminals, the selective A2AR agonist CGS21680 inhibited, while the A2AR antagonist ZM241385 potentiated the nicotine-stimulated [3H]dopamine ([3H]DA) release. Upon blockade of the α6 subunit-containing nAChRs, the remaining nicotine-stimulated [3H]DA release was no longer modulated by A2AR ligands. In the locomotor sensitization experiments, nicotine enhanced the locomotor activity on day 7 of repeated nicotine injection, an effect that no longer persisted after 1 week of drug withdrawal. Notably, ZM241385-injected rats developed locomotor sensitization to nicotine already on day 2, which remained persistent upon nicotine withdrawal. Conclusions and Implications These results provide the first evidence for a functional interaction between nicotinic and adenosine A2AR in striatal dopaminergic terminals, with likely therapeutic consequences for smoking, Parkinson's disease and other dopaminergic disorders.