Partial agonists for α4β2 nicotinic receptors stimulate dopaminergic neuron firing with relatively enhanced maximal effects

BACKGROUND AND PURPOSE Partial agonists selective for alpha 4 beta 2 nicotinic ACh receptors have been developed for smoking cessation as they induce weak activation of native alpha 4 beta 2* receptors and inhibit effect of nicotine. However, it is unclear whether at brain functions there is an existence of receptor reserve that allows weak receptor activation to induce maximum physiological effects. We assessed the extent of alpha 4 beta 2 partial agonist-induced increase of firing rate in dopaminergic neurons and evaluated the influence of receptor reserve. EXPERIMENTAL APPROACH The relative maximal effects and potencies of six nicotinic agonists were assessed on recombinant human alpha 4 beta 2 and alpha 7 receptors expressed in mammalian cell lines by measuring calcium influx. Agonist-induced increase of the spontaneous firing rate of dopaminergic neurons was recorded using microelectrodes in the ventral tegmental area of rat brain slices. KEY RESULTS All alpha 4 beta 2 partial and full agonists increased the firing rate concentration-dependently. Their sensitivity to subtype-selective antagonists showed predominant activation of native alpha 4 beta 2* receptors. However, partial agonists with relative maximal effects as low as 33% on alpha 4 beta 2 receptors maximally increased the firing rate and induced additional depolarization block of firing, demonstrating that partial activation of receptors caused the maximum increase in firing rate in the presence of a receptor reserve. CONCLUSIONS AND IMPLICATIONS Partial alpha 4 beta 2 agonists induced relatively enhanced effects on the firing rate of dopaminergic neurons, and the effect was mainly attributed to the existence of native alpha 4 beta 2* receptor reserve. The results have implications in the understanding of physiological effects and therapeutic efficacies of alpha 4 beta 2 partial agonists.