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

Abstract

Background and purpose.  Partial agonists selective for α4β2 nicotinic acetylcholine receptors have been developed for smoking cessation based on the hypothesis that they induce weak activation of native α4β2* receptors and inhibit effect of nicotine. However, the relative physiological effects of partial agonists are largely unknown. For instance, on neuronal functions where partial activation of a receptor pool is sufficient for the maximum response, i.e. where there is receptor reserve, partial agonists may become maximally effective. We assessed effects of α4β2 partial agonists on the firing of dopamine neurons and evaluated the influence by receptor reserve. Experimental approach.  Six agonists with different relative maximal effects on recombinant human α4β2 receptors were examined on the spontaneous firing rate of dopamine neurons in the ventral tegmental area. Key Results.  Agonists induced concentration-dependent increase in firing rate in a mecamylamine and DHßE, but not α-conotoxin MII or methyllycaconitine-sensitive, manner, indicating predominant activation of native α4β2* receptors. α4β2 partial agonists, cytisine (21%) and TC-2559 (33%), increased the firing rate to 43 and 100% of the maximum, respectively, showing enhanced effects relative to full agonists. However, full agonists induced an additional depolarisation block of firing at high concentrations, revealing the presence of surplus receptors for the maximum increase of firing rate. Conclusions and implications.  Partial activation of all the receptors was sufficient for the maximum increase of firing rate in dopamine neurons, creating a receptor reserve and relatively enhanced effects of partial α4β2 agonists by activating all receptors. The availability of native α4β2* receptors may thus modulate physiological effects and therapeutic efficacies of α4β2 partial agonists.

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