The antidepressant-like effect of the melatonin receptor ligand luzindole in mice during forced swimming requires expression of MT₂ but not MT₁ melatonin receptors

We previously reported an antidepressant-like effect in C3H/HeN mice during the forced swimming test (FST) following treatment with the MT ₁/MT₂ melatonin receptor ligand, luzindole. This study investigated the role melatonin receptors (MT₁ and/or MT₂) may play in the effect of luzindole in the FST using C3H/HeN mice with a genetic deletion of either MT₁ (MT₁KO) or MT₂ (MT₂KO) melatonin receptors. In the light phase (ZT 9-11), luzindole (30 mg/kg, i.p.) significantly decreased immobility during swimming in both wild type (WT) (135.6 ± 25.3 s, n = 7) and MT₁KO (132.6 ± 13.3 s, n = 8) as compared with vehicle-treated mice (WT: 207.1 ± 6.0 s, n = 7; MT₁KO: 209.5 ± 6.2 s, n = 8) (P < 0.001). In the dark phase (ZT 20-22), luzindole also decreased time of immobility in both WT (89.5 ± 13.9 s, n = 8) and MT₁KO (66.5 ± 6.4 s, n = 8) mice as compared with the vehicle treated (WT: 193.8 ± 3.5, n = 6; MT₁KO: 176.6 ± 6.2 s, n = 8) (P < 0.001). Genetic disruption of the MT₁ gene did not alter the diurnal rhythm of serum melatonin in MT₁KO mice (ZT 9-11: 1.3 ± 0.6 pg/mL, n = 7; ZT 20-22: 10.3 ± 1.1 pg/mL, n = 8) as compared with WT (ZT 9-11: 1.4 ± 0.7 pg/mL; ZT 20-22: 10.6 pg/mL). Swimming did not alter the serum melatonin diurnal rhythm in WT and MT1KO mice. Decreases in immobility of WT and MT₁KO mice by luzindole treatment were not affected by gender or age (3 months versus 8 months). In contrast, luzindole did not decrease immobility during the FST in MT₂KO mice. We conclude that the antidepressant-like effect of luzindole may be mediated through blockade of MT₂ rather than MT₁ melatonin receptors.