Electrophysiological Perspectives on the Therapeutic Use of Nicotinic Acetylcholine Receptor Partial Agonists

Abstract

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 ␣4␤2* [(␣4) 2 (␤2) 3 , (␣4) 3 (␤2) 2 , and (␣4) 2 (␤2) 2 ␣5)] receptor subtypes that was not seen with other test compounds. Partial agonists produced no detectable steady-state activation of ␣7 nAChR, but seemed to show small potentiation of ACh-evoked responses; however, "run-up" of ␣7 ACh responses was also sometimes observed under control conditions. Potential off-target effects of the partial agonists therefore included the modulation of ␣7 responses by ␣4␤2 partial agonists and decreases in ␣4␤2* responses by ␣7-selective agonists. These data indicate the dual effects expected for ␣4␤2* partial agonists and provide models and insights for utility of partial agonists in therapeutic development.

Varenicline and Cytisine Diminish the Dysphoric-Like State Associated with Spontaneous Nicotine Withdrawal in Rats

“…There were, however, no significant differences between the nicotine-withdrawing rats treated with saline or 3-pyr-Cyt. It has been reported that 3-pyr-Cyt is a very weak partial agonist at a4b2* nAChRs (Mineur et al, 2009;Papke et al, 2011). The present data suggest that a very weak partial agonist at a4b2* nAChRs does not attenuate the elevations in ICSS thresholds associated with nicotine withdrawal and might therefore not diminish the negative mood state associated with smoking cessation.…”

“…The maximal efficacy of varenicline for the a4b2 nAChR receptor is only 24% of that of nicotine (Coe et al, 2005). More importantly, a recent study showed that the efficacy of nicotine for the a4b2a5 nAChR was 35% that of acetylcholine, whereas the efficacy of varenicline was only 9% of that of acetylcholine (Papke et al, 2011). The activation of a5* nAChRs in the medial habenula has an important role in the aversive effects of nicotine (Fowler et al, 2011).…”

“…Thus, 0.6 mg/kg of nicotine base has aversive effects and the same dose of varenicline has rewarding effects. This difference between nicotine and varenicline might be due to the fact that varenicline has a lower efficacy for a variety of nAChRs (Papke et al, 2011). The maximal efficacy of varenicline for the a4b2 nAChR receptor is only 24% of that of nicotine (Coe et al, 2005).…”

Nicotinic Acetylcholine Receptor Alterations in Autism Spectrum Disorders – Biomarkers and Therapeutic Targets

“…Interestingly, much like nicotine, varenicline can upregulate 42 nAChRs in vitro. Finally, as a partial agonist, it has the additional benefit of providing chronic low-level activation of 42 nAChRs (Papke et al, 2011) and possibly associated downstream intracellular signaling pathways. Varenicline has been shown to change behaviors in some smokers, and a public health advisory from the FDA includes warnings of increased suicidal thoughts and actions.…”

Nicotine Dependence and Depression, What is the Future for Therapeutics?

“…Additionally, it seems likely that the future of anti-nicotinic therapies, both as smoking cessation aids and as potential therapies for depression, will come from the development of new, truly selective, partial agonists that will produce a down-regulation of α4β2* receptor function with little or no activity for other nAChR subtypes. Recent publications indicate that such drugs are likely to become available [26,27], and the tools are available to confirm that agents that are active in animal models will be likely to have similar activity profiles for human receptors with therapeutically relevant experimental protocols [28]. However, the challenges for the development of therapeutics in these areas are great.…”