PT  - JOURNAL ARTICLE
AU  - Roger L. Papke
AU  - Caryn Trocmé-Thibierge
AU  - Daniela Guendisch
AU  - Shehd Abdullah Abbas Al Rubaiy
AU  - Stephen A. Bloom
TI  - Electrophysiological Perspectives on the Therapeutic Use of Nicotinic Acetylcholine Receptor Partial Agonists
AID  - 10.1124/jpet.110.177485
DP  - 2011 May 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 367--379
VI  - 337
IP  - 2
4099  - http://jpet.aspetjournals.org/content/337/2/367.short
4100  - http://jpet.aspetjournals.org/content/337/2/367.full
SO  - J Pharmacol Exp Ther2011 May 01; 337
AB  - Partial agonist therapies rely variously on two hypotheses: the partial agonists have their effects through chronic low-level receptor activation or the partial agonists work by decreasing the effects of endogenous or exogenous full agonists. The relative significance of these activities probably depends on whether acute or chronic effects are considered. We studied nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus laevis oocytes to test a model for the acute interactions between acetylcholine (ACh) and weak partial agonists. Data were best-fit to a basic competition model that included an additional factor for noncompetitive inhibition. Partial agonist effects were compared with the nAChR antagonist bupropion in prolonged bath application experiments that were designed to mimic prolonged drug exposure typical of therapeutic drug delivery. A primary effect of prolonged application of nicotine was to decrease the response of all nAChR subtypes to acute applications of ACh. In addition, nicotine, cytisine, and varenicline produced detectable steady-state activation of α4β2* [(α4)2(β2)3, (α4)3(β2)2, and (α4)2(β2)2α5)] receptor subtypes that was not seen with other test compounds. Partial agonists produced no detectable steady-state activation of α7 nAChR, but seemed to show small potentiation of ACh-evoked responses; however, “run-up” of α7 ACh responses was also sometimes observed under control conditions. Potential off-target effects of the partial agonists therefore included the modulation of α7 responses by α4β2 partial agonists and decreases in α4β2* responses by α7-selective agonists. These data indicate the dual effects expected for α4β2* partial agonists and provide models and insights for utility of partial agonists in therapeutic development.