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

Abstract

RATIONALE Nicotinic acetylcholine receptor (nAChR) agonists, partial agonists and antagonists have antidepressant-like effects in rodent models and reduce symptoms of depression in humans. OBJECTIVE The aim of this study was to determine if the β2* partial agonist sazetidine-A (sazetidine) showed an antidepressant-like effect in the forced swim test that was mediated by β2* nAChRs activation or desensitization. RESULTS Sazetidine, the less selective β2* partial agonist varenicline and the full β2* agonist 5-I-A8350, exhibited acute antidepressant-like effects in the forced swim test. The role of β2* 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-β-erythroidine (DHβE); 2) no effect of sazetidine in mice lacking the β2 subunit of the nAChR; and 3) a high correspondence between behaviorally active doses of sazetidine and β2* receptor occupancy. β2* receptor occupancy following acute sazetidine, varenicline, and 5-I-A8350 extended beyond the duration of action in the forced swim test. The long lasting receptor occupancy of sazetidine did not diminish behavioral efficacy in the forced swim test following repeated dosing. CONCLUSIONS These results demonstrate that activation of β2* nAChRs mediate sazetidine’s antidepressant-like actions and suggest that ligands that activate β2* nAChRs would be promising targets for the development of a new class of antidepressant.

Chronic Sazetidine-A at Behaviorally Active Doses Does Not Increase Nicotinic Cholinergic Receptors in Rodent Brain

“…These studies indicated that during chronic infusion of saz-A for 2 weeks its steady-state concentration in brain was less than 10% of that in blood. Likewise, after 2 weeks of twice-daily injections of saz-A, its brain concentration 10 min after the last injection was also approximately only 10% that of blood, which agrees with a recent study that measured brain and blood concentrations of saz-A in mice after a single intraperitoneal injection (Caldarone et al, 2011). This is in marked contrast to both nicotine and varenicline, which were highly concentrated in brain during both methods of chronic administration; moreover, both the concentrations and the brain-to-blood ratios of nicotine and varenicline were similar to previously reported values (Ghosheh et al, 1999;Doura et al, 2008;Rollema et al, 2010).…”

“…3) and increase performance on tasks of attention . Furthermore, in preclinical tests these doses of saz-A produce behaviors that are consistent with potential antidepressant and/or antianxiety effects (Kozikowski et al, 2009;Turner et al, 2010Turner et al, , 2011Caldarone et al, 2011). Thus it seems that saz-A acts in the brain; yet even at doses two to six times these behaviorally active doses saz-A did not increase nAChR density.…”

“…The doses of saz-A used here reduce self-administration of nicotine (Levin et al, 2010b;Rezvani et al, 2011;Johnson et al, 2012) and alcohol and improve performance in tasks of attention in rats with only modest effects on food intake (Levin et al, 2010b;Rezvani et al, 2010) Moreover, similar doses of saz-A exert positive effects in preclinical tests of anxiolytic (Turner et al, 2010(Turner et al, , 2011 and antidepressant activity in mice (Kozikowski et al, 2009;Caldarone et al, 2011). Turner et al (2010) found in addition that these doses of saz-A did not significantly affect the latency of mice to feed or the average amount of food consumed in home environments.…”

“…Saz-A produces several potentially important behavioral effects in rodents: it decreases nicotine self-administration (Levin et al, 2010b;Rezvani et al, 2010;Johnson et al, 2012), reduces alcohol consumption (Rezvani et al, 2010), and increases performance on tasks of attention, even after attention is disrupted by pretreatment with scopolamine or dizocilpine [(5S,10R)-(ϩ)-5-methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine] (MK801) . In addition, in preclinical tests saz-A produces behavior indicative of potential antidepressant and/or antianxiety effects (Kozikowski et al, 2009;Turner et al, 2010Turner et al, , 2011Caldarone et al, 2011).…”

Discovery and pharmacological evaluation of a novel series of adamantyl cyanoguanidines as P2X7 receptor antagonists

“…Despite the far from ideal pharmacokinetic properties of 35, compounds with short half-lives are still able to display activity through the forced-swim test (FST) as a result of the short duration of the procedure (6 min). [28,29] While the pharmacokinetic profile of 35 would make it unsuitable for clinical development, and is by no means a viable lead candidate itself, we believe it is sufficient for proof-of-concept studies in the FST. To examine whether these compounds could penetrate the BBB, act on centrally expressed P2X 7 Rs and induce a behavioural response in vivo, the 3-pyridyl analogue 35 (highest LiPE value; Table 2) was tested in the FST.…”