Enhancement of antidepressant-like response by intranasally-administered GALR2 and Y1R agonists in the forced swimming test
We performed the forced swimming test (FST) to achieve the functional outcome related to the findings on the ventral hippocampus after the intranasal coadministration of GALR2 and Y1R agonists. Rats were pre-exposed to water for 15 minutes in the FST and twenty-four hours after the intranasal (i.n.) administration the immobility and swimming parameters were measured during the 5 min test phase to assess signs of depression-like behavior.
The dose response curve showed that the GALR2 agonist lacked effects at 68 µg and 132 µg in the FST. Regarding the Y1R agonist, the 68 µg dose was ineffective while the 132 µg induced a significant decrease in the immobility time (one-way ANOVA, F4,25 = 3.79 , p<0.05, Supplementary Figure 1a) compared to the rest of the groups (Newman-Keuls post-hoc test: p<0,05; Supplementary Figure 1a). Moreover, an increase in the swimming behavior (one-way ANOVA, F4,25 = 3.57, p<0,05; Supplementary Figure 1b) was observed compared to the rest of the groups (Newman-Keuls post-hoc test: p<0,05; Supplementary Figure 1b).
Upon the M1145 and the Y1R i.n. coadministration a significant decrease in the immobility time (one-way ANOVA, F5,30 = 8.96, p<0.001, Figure 5a) was observed compared with control animals (Newman-Keuls post-hoc test: p<0,001; Figure 5b), M1145 (Newman-Keuls post-hoc test: p<0,001; Figure 5b) and Y1R agonist alone (Newman-Keuls post-hoc test: p<0,01; Figure 5b). Moreover, an increase in the swimming behavior (one-way ANOVA, F5,30 = 10.58, p<0,001; Figure 5b) was observed after the combined treatment compared to the control animals (Newman-Keuls post-hoc test: p<0,001; Figure 5b), M1145 (Newman-Keuls post-hoc test: p<0,001; Figure 5b) and Y1R agonist alone (Newman-Keuls post-hoc test: p<0,05; Figure 1 b). GALR2 contribution in this result was confirmed since the addition of the GALR2 antagonist M871 counteracted the synergistic effects on immobility (Newman-Keuls post-hoc test: p<0,01; Figure 5b) and swimming (Newman-Keuls post-hoc test: p<0,05; Figure 5b) induced by the coadministration of M1145 and the Y1R agonist in the FST. Importantly, we confirmed the BDNF influence in this action since the addition of the TrkB antagonist ANA-12 blocked the synergistic on immobility (Newman-Keuls post-hoc test: p<0,01; Figure 5b) and swimming (Newman-Keuls post-hoc test: p<0,05; Figure 5b) induced by the coadministration of M1145 and the Y1R agonist in the FST.
The i.n. administration of the Y1R agonist decreased the time of immobility compared to the control (Newman-Keuls post-hoc test: p<0,05; Figure 5b) and the M1145 (Newman-Keuls post-hoc test: p<0,05; Figure 5b) animals; while induced an increase in the swimming behavior compared to the control (Newman-Keuls post-hoc test: p<0,05; Figure 5b) and the M1145 (Newman-Keuls post-hoc test: p<0,05; Figure 5b) groups. However, the administration of the GalR2 agonist M1145 alone lacked effects on the FST (Figure 5b) compared with the control group.