Varenicline significantly reduced immobility in both mouse strains at most doses tested (). The effect size in C57BL/6J mice (0.25–1.5 mg/kg i.p., ) was greater than in CD-1 mice (0.178 – 5.6 mg/kg i.p., ), with the response in the latter strain being comparable to that of sertraline in terms of effect size and dose-response relationship (sertraline data not shown). Strain differences could account for variations in the degree of efficacy in these forced swim test studies and are well-documented for several mouse behavioral responses (e.g. Mineur et al., 2006
). In addition, differences in monitoring times and scoring methods could also contribute to the observed effect sizes in each method. The fact that low doses of varenicline (i.e. 0.25 mg/kg in C57BL/6J mice and 0.178 mg/kg in CD-1 mice) have significant effects in both experiments is consistent with varenicline’s high in vitro
binding affinity (Ki
= 0.15 nM) and inactivating potency (IC50
= 6 nM) at α4β2 nicotinic acetylcholine receptors, as well as with its potent activity in in vivo
models, such as increasing mesolimbic dopamine release with an ED50
of 0.03 mg/kg after oral administration (Rollema et al., 2007
). Since inactive doses were not obtained in either of the studies and a clear dose-response relationship was not demonstrated, further studies will be necessary to define the responses at the low end of the dose range. A lack of dose-dependency of the forced swim test effects may suggest that once a dose of the partial agonist is administered that is sufficient to reduce endogenous ACh signaling or that achieves maximum receptor occupancy, the response will remain the same over a wide dose range, resulting in a plateauing of the effect. The forced swim test data for varenicline generated in each laboratory in different mouse strains are thus in good agreement, despite variations in the protocols. Finally, at the doses used for the forced swim test, none of the test compounds increased locomotor activity, indicating that the results are not affected by stimulant effects.
Fig. 1 Effects of varenicline and amitriptyline in the mouse forced swim test. (A): Effects of vehicle and varenicline (0.25–1.5 mg/kg i.p.) in C57BL/6J mice. Immobility time was measured in seconds for 15 min and expressed as mean ± S.E.M. (n=10, (more ...)
A comparison with the effects of the classical antidepressants amitriptyline and sertraline in CD-1 mice shows that varenicline administration results in comparable swim scores as the SSRI sertraline at doses of 5.6 mg/kg and above (). At 10 mg/kg, the tricyclic antidepressant amitriptyline, which consistently yields pronounced dose-dependency and near maximal efficacy in dose-response studies (data not shown; see e.g. Caldarone et al, 2004
), reduced immobility scores with greater efficacy than varenicline or sertraline when given alone (). Co-administration of varenicline and sertraline resulted in lower swim scores than after each sertraline dose alone. Combining 0.56 and 5.6 mg/kg of varenicline with the lowest (1.78 mg/kg) and highest (17.8 mg/kg) sertraline dose, respectively, reduced the swim score significantly more than the corresponding sertraline doses alone. Of particular interest is the finding that co-administration of the lowest varenicline dose of 0.56 mg/kg with 17.8 mg/kg sertraline had the same pronounced effect on the swim score as 10 mg/kg amitriptyline (, ).
Fig. 2 Effects of vehicle, sertraline alone (1.78, 5.6 and 17.8 mg/kg i.p.) and of co-administration of each dose of sertraline with varenicline (0.56 and 5.6 mg/kg s.c.) in the forced swim test in CD-1 mice. Immobility (score 1) and activity (score 0) were (more ...)