Effectiveness of nicotinic agonists as desensitizers at presynaptic α4β2- and α4α5β2-nicotinic acetylcholine receptors.

Introduction: Nicotine interacts with nicotinic acetylcholine receptors (nAChRs) and modifies neuronal functions. The net result of nicotine exposure is difficult to assess because multiple nAChR subtypes exist and are expressed on multiple classes of neurons. Nicotine, unlike the natural agonist acetylcholine, remains in tissues for hours, and during this extended exposure nAChRs desensitize. Therefore, agonists can block the natural functions of nAChRs. Higher nicotine concentrations are required to desensitize 42-nAChRs containing the 5 subunit. The aim of these experiments was to determine if this property holds true for compounds other than nicotine. [H-3]-dopamine release from crude mouse striatal synaptosomal preparations was used to measure activation and desensitization of the [(42)(2)2] and [(42)(2)5] nAChR subtypes. Affinity was measured by competition with [I-125]-epibatidine. Nine compounds of varying affinity and efficacy were tested. All compounds partially desensitized both subtypes; concentration necessary for desensitization correlated with binding site affinity but not efficacy. All compounds showed a similar, significant shift in concentration necessary for a 50% effect when the 5 subunit was included (averaging 8-fold higher). The extent of desensitization produced by a 10-min exposure did not correlate with affinity or efficacy of compound. Full or partial nicotinic agonists used as medications may effectively desensitize 42-nAChRs. However, significantly higher concentrations of all compounds tested were required to elicit desensitization of 452-nAChRs than 42-nAChRs. If desensitization is the important property for a smoking cessation drug, basic screening at both subtypes may provide a mechanistic foundation for effectiveness.