5-HT 1A Agonist Properties Contribute to a Robust Response to Vilazodone in the Novelty Suppressed Feeding Paradigm

Abstract

Background: Differences in 5-HT 1A receptor function have been implicated in vulnerability to depression and in response to treatment. Adding 5-HT 1A partial agonists to selective serotonin reuptake inhibitors has been touted as a strategy to increase their efficacy. Here we use the novelty suppressed feeding paradigm to compare the effects of vilazodone, a high-potency selective serotonin reuptake inhibitor, with high affinity for 5-HT 1A receptors to the reference selective serotonin reuptake inhibitor fluoxetine across several mouse strains that differ in their response to selective serotonin reuptake inhibitors.

Methods: To confirm 5-HT 1A agonist activity, body temperature was measured after acute administration of vilazodone or fluoxetine, as administration of 5-HT 1A agonists induces hypothermia. We next used 3 strains of mice to examine the effects of the drugs on latency in the novelty suppressed feeding, a paradigm generally sensitive to chronic but not acute effects of antidepressants.

Results: Vilazodone induces robust hypothermia and blocks stress-induced hyperthermia in a 5-HT 1A -dependent manner, consistent with agonist effects at 5-HT 1A autoreceptors. In 129SvEv mice, vilazodone (10mg/kg/d) reduces the latency to eat in the novelty suppressed feeding test within 8 days, while no effect of fluoxetine (20mg/kg/d) was detected at that time. In contrast, both vilazodone and fluoxetine are effective at decreasing latency to eat in the novelty suppressed feeding paradigm in a strain with low autoreceptor levels. In mice with higher autoreceptor levels, no significant difference was detected between fluoxetine and vehicle ( P=. 8) or vilazodone and vehicle ( P =.06).

Conclusion: In mice, vilazodone may offer advantages in time of onset and efficacy over a reference selective serotonin reuptake inhibitor in the novelty suppressed feeding test.

Keywords: 5-HT 1A; fluoxetine; novelty suppressed feeding; vilazodone.

Figure 1.

5-HT_1A receptor agonist-induced hypothermia in mice: reversal by 5-HT_1A receptor antagonists. (A) The 5-HT_1A receptor agonist 8-OH-DPAT produced a hypothermic response in mice, and this effect was significantly reversed/antagonized by the 5-HT_1A receptor antagonist WAY 100635 (n = 7–8 mice/group). (B) Mice injected with vilazodone [VIL] 1, 3, and 10mg/kg showed dose-dependent decreases in body temperature (n = 5–8 mice/group). (C) The hypothermic response to vilazodone was significantly attenuated by co-administration with the 5-HT_1A receptor antagonist WAY 100635, indicating that the hypothermic response to vilazodone is due its effects at 5-HT_1A receptors (n = 7 mice/group). (D) Effect of conventional selective serotonin reuptake inhibitors (SSRIs) (fluoxetine [FLX] and citalopram [CIT]) (n = 5–8 mice/group; *P<.05, **P<.01).

Figure 2.

Attenuation of stress-induced hyperthermia by 5-HT_1A receptor agonists in mice. (A) Stress-induced hyperthermia was attenuated by the 5-HT_1A agonist 8-OH-DPAT; this effect of 8-OH-DPAT was antagonized by WAY 100,635 (n = 4–5 mice/group). (B) Vilazodone 1, 3, and 10mg/kg significantly attenuated stress-induced hyperthermia to a novel cage (n = 5 mice/group). (C) Co-administration with WAY 100,635 diminishes the effects of vilazodone (n = 5 mice/group). Mean hyperthermic response to vehicle=1.9±06^oC, vil 10mg/kg = .62±04^oC, and vil+WAY = 1.33±.11^oC. (*P<.05; **P<.01).

Figure 3.

129SvEv Mice: subchronic and chronic treatment effect on feeding latency in novelty suppressed feeding (NSF). (A-B) Following a subchronic, 8-day treatment, a response was observed in mice treated with vilazodone 10mg/kg as evidenced by lower latency to feed relative to vehicle-treated controls in the NSF test. Fluoxetine did not significantly affect latency to feed in this test (n = 15 mice/group). (C-D) A robust response was also observed in mice following chronic, 28-day treatments with vilazodone 3 and 10mg/kg relative to vehicle-treated controls in the NSF test. The difference in latency elicited by chronic fluoxetine administration at 20mg/kg was not significant (n = 15 mice/group). (A-D) Kaplan-Meier cumulative survival curve. (B-D) Scatter graph depicting individual animal latencies with mean and SEM (*P<.05 vs vehicle; **P<.01 vs vehicle).

Figure 4.

tetO-1A+/+/Pet-tTS+ mice on DOX continuously (Hi) and off DOX at P50 (Low): subchronic and chronic treatment effect on feeding latency in novelty suppressed feeding. At 8 days, no difference in mean latency was detected between vehicle and either fluoxetine (20mg/kg) or vilazodone (10mg/kg) in 5-HT_1A Hi mice. (A-B) At 28 days of treatment, vehicle and fluoxetine groups have similar latencies. The vilazodone group has a lower latency that is not statistically different from the vehicle group (C,D) (8 days: n = 14–15 mice/group; 28 days: n = 12–15 mice/group). (E-F) The 5-HT_1A Low mice responded robustly to both fluoxetine (20mg/kg) and vilazodone (10mg/kg) after only 8 days of treatment (n = 13–14 mice/group). (G-H) In 5-HT_1A Low mice, chronic (28-d) treatment with either fluoxetine or vilazodone significantly reduced feeding latency in the novelty suppressed feeding (NSF) arena (n = 12–13 mice/group). (A,C,E,G) Kaplan-Meier cumulative survival curve. (B,D,F,H) Scatter graph depicting individual animal latencies with mean and SEM (*P<.05 vs vehicle, **P<.01 vs vehicle).