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

Abstract：

BACKGROUND AND PURPOSE:Partial agonists selective for α4β2 nicotinic ACh receptors have been developed for smoking cessation as they induce weak activation of native α4β2* 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 α4β2 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 α4β2 and α7 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 α4β2 partial and full agonists increased the firing rate concentration-dependently. Their sensitivity to subtype-selective antagonists showed predominant activation of native α4β2* receptors. However, partial agonists with relative maximal effects as low as 33% on α4β2 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 α4β2 agonists induced relatively enhanced effects on the firing rate of dopaminergic neurons, and the effect was mainly attributed to the existence of native α4β2* receptor reserve. The results have implications in the understanding of physiological effects and therapeutic efficacies of α4β2 partial agonists.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

Chen Y,Broad LM,Phillips KG,Zwart R

doi

10.1111/j.1476-5381.2011.01628.x

subject

Has Abstract

pub_date

2012-02-01 00:00:00

pages

1006-16

issue

eissn

0007-1188

issn

1476-5381

journal_volume

165

pub_type

杂志文章

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