Dissociation between duration of action in the forced swim test in mice and nicotinic acetylcholine receptor occupancy with sazetidine, varenicline, and 5-I-A85380.

摘要

RATIONALE: Nicotinic acetylcholine receptor (nAChR) agonists, partial agonists, and antagonists have antidepressant-like effects in rodents and reduce symptoms of depression in humans. OBJECTIVES: The study determined whether the antidepressant-like effect of the nAChR beta2* partial agonist sazetidine-A (sazetidine) in the forced swim test was due to activation or desensitization of beta2* nAChRs. The study also determined if sazetidine's behavioral responses in the forced swim test corresponded to beta2* nAChRs receptor occupancy and drug bioavailability. RESULTS: Acute antidepressant-like effects in the forced swim test were seen with sazetidine and the full beta2* agonist 5-I-A8350 (BALB/cJ mice) and the less selective beta2* partial agonist varenicline in C57BL/6J but not BALB/cJ mice. The role of beta2* nAChRs was confirmed by results showing: (1) reversal of sazetidine's antidepressant-like effects in the forced swim test by nAChR antagonists mecamylamine and dihydro-beta-erythroidine; (2) absence of sazetidine's effect in mice lacking the beta2 subunit of the nAChR; and (3) a high correspondence between behaviorally active doses of sazetidine and beta2* receptor occupancy. beta2* receptor occupancy following acute sazetidine, varenicline, and 5-I-A8350 lasted beyond the duration of action in the forced swim test. Sazetidine's long lasting receptor occupancy did not diminish behavioral efficacy in the forced swim test following repeated dosing. CONCLUSIONS: Results demonstrate that activation of a small population of beta2* nAChRs (10-40%) is sufficient to elicit sazetidine's antidepressant-like actions without producing tolerance and suggest that ligands that activate beta2* nAChRs would be promising targets for the development of a new class of antidepressant.