Stimulation of dopamine release by nicotinic acetylcholine receptor ligands in rat brain slices correlates with the profile of high, but not low, sensitivity α4β2 subunit combination

alpha 4 beta 2 neuronal nicotinic receptors (nAChRs) can exist in high and low sensitivity states possibly due to distinct stoichiometries during subunit assembly: (alpha 4)(2)(beta 2)(3) pentamer (high sensitivity, HS) and (alpha 4)(3)(beta 2)(2) pentamer (low sensitivity, LS). To determine if there is a linkage between HS or LS states and receptor-mediated responses in brain, we profiled several clinically studied alpha 4 beta 2* nAChR agonists for the displacement of radioligand binding to alpha 4 beta 2 [H-3]-cytisine sites in rat brain membranes, effects on stimulation of [H-3]-dopamine release from slices of rat prefrontal cortex and striatum, and activation of HS and LS human alpha 4 beta 2 nAChRs expressed in Xenopus laevis oocytes. Binding affinities (pK(i)) and potency (pEC(50)) values for [H-3]-dopamine release closely correlated with a rank order: varenicline > (-)-nicotine > AZD3480 > dianicline congruent to ABT-089. Further, a good correlation was observed between [H-3]-dopamine release and HS alpha 4 beta 2 pEC(50) values, but not between [H-3]-dopamine release and LS alpha 4 beta 2. The relative efficacies of the agonists ranged from full to partial agonists. Varenicline behaved as a partial agonist in stimulating [H-3]-dopamine release and activating both HS and LS alpha 4 beta 2 nAChRs expressed in oocytes. Conversely, ABT-089, AZD3480 and dianicline exhibited little efficacy at US alpha 4 beta 2 (<5%), were more effective at HS alpha 4 beta 2 nAChRs, and in stimulating cortical and striatal [H-3]-dopamine release >= 30%. In the presence of alpha-conotoxin MII to block alpha 6 beta 2* nAChRs, the alpha 4 beta 2* alpha-conotoxin-insensitive [H-3]-dopamine release stimulated by these ligands correlates well with their interactions at HS, but not LS. In summary, this study provides support for HS alpha 4 beta 2* nAChR involvement in neurotransmitter release. (C) 2009 Elsevier Inc. All rights reserved.