Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Pharmacol Exp Ther
2011 May 01;3372:367-79. doi: 10.1124/jpet.110.177485.
Show Gene links
Show Anatomy links
Electrophysiological perspectives on the therapeutic use of nicotinic acetylcholine receptor partial agonists.
Papke RL
,
Trocmé-Thibierge C
,
Guendisch D
,
Al Rubaiy SA
,
Bloom SA
.
???displayArticle.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 α4β2* [(α4)(2)(β2)(3), (α4)(3)(β2)(2), and (α4)(2)(β2)(2)α5)] 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.
Benowitz,
Pharmacology of nicotine: addiction, smoking-induced disease, and therapeutics.
2009, Pubmed
Benowitz,
Pharmacology of nicotine: addiction, smoking-induced disease, and therapeutics.
2009,
Pubmed
Bullock,
Neurosteroids modulate nicotinic receptor function in mouse striatal and thalamic synaptosomes.
1997,
Pubmed
Champtiaux,
Subunit composition of functional nicotinic receptors in dopaminergic neurons investigated with knock-out mice.
2003,
Pubmed
de Fiebre,
Characterization of a series of anabaseine-derived compounds reveals that the 3-(4)-dimethylaminocinnamylidine derivative is a selective agonist at neuronal nicotinic alpha 7/125I-alpha-bungarotoxin receptor subtypes.
1995,
Pubmed
,
Xenbase
de Jonge,
The alpha7 nicotinic acetylcholine receptor as a pharmacological target for inflammation.
2007,
Pubmed
Grady,
Mouse striatal dopamine nerve terminals express alpha4alpha5beta2 and two stoichiometric forms of alpha4beta2*-nicotinic acetylcholine receptors.
2010,
Pubmed
Horenstein,
Multiple pharmacophores for the selective activation of nicotinic alpha7-type acetylcholine receptors.
2008,
Pubmed
,
Xenbase
Hurt,
A comparison of sustained-release bupropion and placebo for smoking cessation.
1997,
Pubmed
Kem,
The brain alpha7 nicotinic receptor may be an important therapeutic target for the treatment of Alzheimer's disease: studies with DMXBA (GTS-21).
2000,
Pubmed
Kuryatov,
Roles of accessory subunits in alpha4beta2(*) nicotinic receptors.
2008,
Pubmed
Lai,
Association study of nicotinic-receptor variants and major depressive disorder.
2001,
Pubmed
Leonard,
Smoking and schizophrenia: abnormal nicotinic receptor expression.
2000,
Pubmed
Leonard,
Smoking, Genetics and Schizophrenia: Evidence for Self Medication.
2007,
Pubmed
Lester,
Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery.
2009,
Pubmed
Lester,
Activation and desensitization of heteromeric neuronal nicotinic receptors: implications for non-synaptic transmission.
2004,
Pubmed
Lopez-Hernandez,
Partial agonist and neuromodulatory activity of S 24795 for alpha7 nAChR responses of hippocampal interneurons.
2007,
Pubmed
,
Xenbase
Luetje,
Both alpha- and beta-subunits contribute to the agonist sensitivity of neuronal nicotinic acetylcholine receptors.
1991,
Pubmed
,
Xenbase
Mansvelder,
Synaptic mechanisms underlie nicotine-induced excitability of brain reward areas.
2002,
Pubmed
Marks,
86Rb+ efflux mediated by alpha4beta2*-nicotinic acetylcholine receptors with high and low-sensitivity to stimulation by acetylcholine display similar agonist-induced desensitization.
2010,
Pubmed
Martin,
Schizophrenia and the alpha7 nicotinic acetylcholine receptor.
2007,
Pubmed
McClure,
Mood, side-effects and smoking outcomes among persons with and without probable lifetime depression taking varenicline.
2009,
Pubmed
Miller,
Bupropion inhibits nicotine-evoked [(3)H]overflow from rat striatal slices preloaded with [(3)H]dopamine and from rat hippocampal slices preloaded with [(3)H]norepinephrine.
2002,
Pubmed
,
Xenbase
Mineur,
Biological basis for the co-morbidity between smoking and mood disorders.
2009,
Pubmed
Mineur,
Cytisine-based nicotinic partial agonists as novel antidepressant compounds.
2009,
Pubmed
,
Xenbase
Nelson,
Alternate stoichiometries of alpha4beta2 nicotinic acetylcholine receptors.
2003,
Pubmed
,
Xenbase
Olincy,
Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia.
2006,
Pubmed
Olincy,
Treating schizophrenia symptoms with an alpha7 nicotinic agonist, from mice to men.
2007,
Pubmed
Papke,
Working with OpusXpress: methods for high volume oocyte experiments.
2010,
Pubmed
,
Xenbase
Papke,
Comparative pharmacology of rat and human alpha7 nAChR conducted with net charge analysis.
2002,
Pubmed
,
Xenbase
Papke,
Activation and desensitization of nicotinic alpha7-type acetylcholine receptors by benzylidene anabaseines and nicotine.
2009,
Pubmed
,
Xenbase
Papke,
alpha7 receptor-selective agonists and modes of alpha7 receptor activation.
2000,
Pubmed
Papke,
Tricks of perspective: insights and limitations to the study of macroscopic currents for the analysis of nAChR activation and desensitization.
2010,
Pubmed
,
Xenbase
Papke,
Partial agonist properties of cytisine on neuronal nicotinic receptors containing the beta 2 subunit.
1994,
Pubmed
,
Xenbase
Picciotto,
Acetylcholine receptors containing the beta2 subunit are involved in the reinforcing properties of nicotine.
1998,
Pubmed
Picciotto,
It is not "either/or": activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood.
2008,
Pubmed
Pittenger,
Stress, depression, and neuroplasticity: a convergence of mechanisms.
2008,
Pubmed
Saccone,
Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs.
2007,
Pubmed
Slemmer,
Bupropion is a nicotinic antagonist.
2000,
Pubmed
Walsh,
Up-regulation of nicotinic receptors by nicotine varies with receptor subtype.
2008,
Pubmed
Zhou,
Human alpha4beta2 acetylcholine receptors formed from linked subunits.
2003,
Pubmed
,
Xenbase
