Electrophysiological evidence for rapid 5-HT1A autoreceptor inhibition by vilazodone, a 5-HT1A receptor partial agonist and 5-HT reuptake inhibitor

Abstract

This study examined the effect of vilazodone, a combined serotonin (5-HT) reuptake inhibitor and 5-HT(1A) receptor partial agonist, paroxetine and fluoxetine on the sensitivity of 5-HT(1A) autoreceptors of serotonergic dorsal raphe nucleus neurons in rats. These effects were assessed by determining the intravenous dose of (±)-8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) required to suppress the basal firing rate of these neurons by 50% (ID₅₀) in anesthetized rats using in vivo electrophysiology. 5-HT uptake inhibition was determined by the ability of the compounds to reverse (±)-p-chloroamphetamine (PCA)-induced rat hypothalamic 5-HT depletion ex vivo. Acute vilazodone administration (0.63 and 2.1 µmol/kg, s.c.), compared with vehicle, significantly increased (2-3-fold) the ID₅₀ of 8-OH-DPAT at 4 h, but not 24h after administration. Subchronic administration (3 days) significantly increased the ID₅₀ value at 4 h (3-4-fold) and at 24 h (~2-fold). In contrast, paroxetine and fluoxetine at doses that were supramaximal for 5-HT uptake inhibition did not significantly alter the ID₅₀ value of 8-OH-DPAT after acute or subchronic administration. Vilazodone antagonized the action of PCA 3.5 h and 5 h after a single dose (ID₅₀ 1.49 and 0.46 µmol/kg, s.c., respectively), but was inactive 18 h post-administration, corroborating the electrophysiological results at 24 h following acute administration. The results are consistent with the concept of rapid and, following repeated treatment, prolonged inhibition of 5-HT(1A) autoreceptors by vilazodone. This effect could occur by either direct interaction with, or desensitization of, these receptors, an effect which cannot be ascribed to vilazodone's 5-HT reuptake inhibiting properties.

Association of 5-HT1A Receptors with Affective Disorders

“…This effect is due to the action mechanism of this SSRI, which is a partial agonist of postsynaptic 5-HT 1A receptors. In addition, it desensitizes 5-HT 1A auto-receptors in the raphe more quickly than fluoxetine or paroxetine [79], is 30 times more powerful than serotonin transporter (SERT), and causes a larger increase of extracellular 5-HT in the ventral hippocampus and frontal cortex [80]. These facts justify the short latency to the appearance of therapeutic effects.…”

A Review of Vilazodone, Serotonin, and Major Depressive Disorder

“…Studies in animal models support this hypothesis, as vilazodone appears to desensitize 5-HT 1A autoreceptors more rapidly than conventional SSRIs 65. Additionally, vilazodone has also been shown to increase serotonin levels in rat cortex and hippocampus to an extent greater than other SSRIs, as measured by in vivo microdialysis 66,67…”

Neuroadaptations of the 5-HT System Induced by Antidepressant Treatments: Old and New Strategies

“…While paroxetine or fluoxetine did not affect the ID50 value of 8-OH-DPAT, acute and subchronic administrations of vilazodone significantly increased this value, even after 24 hours in the case of a subchronic treatment [91]. This result suggests that this antidepressant induces a rapid but also prolonged inhibition of 5-HT1A autoreceptors, which can occur by either direct interaction with these receptors or their desensitization [91]. Undoubtedly, further studies are needed to determine other effects of this new antidepressant on the 5-HT system.…”

“…It has been shown that vilazodone induces an elevation of 5-HT amounts in the medial and the lateral cortex that is six-fold higher than those induced by SSRIs paroxetine, citalopram or fluoxetine [86]. Using in vivo electrophysiology in the DRN of anesthetized rats, the sensitivity of 5-HT1A autoreceptors of 5-HT neurons was tested by determining the intravenous dose of the agonist 8-OH-DPAT required to suppress the basal firing rate of these neurons by 50% (ID50) after acute or subchronic (3 days) treatment with vilazodone [91]. While paroxetine or fluoxetine did not affect the ID50 value of 8-OH-DPAT, acute and subchronic administrations of vilazodone significantly increased this value, even after 24 hours in the case of a subchronic treatment [91].…”

“…Using in vivo electrophysiology in the DRN of anesthetized rats, the sensitivity of 5-HT1A autoreceptors of 5-HT neurons was tested by determining the intravenous dose of the agonist 8-OH-DPAT required to suppress the basal firing rate of these neurons by 50% (ID50) after acute or subchronic (3 days) treatment with vilazodone [91]. While paroxetine or fluoxetine did not affect the ID50 value of 8-OH-DPAT, acute and subchronic administrations of vilazodone significantly increased this value, even after 24 hours in the case of a subchronic treatment [91]. This result suggests that this antidepressant induces a rapid but also prolonged inhibition of 5-HT1A autoreceptors, which can occur by either direct interaction with these receptors or their desensitization [91].…”