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TITLE:

Electrophysiological Assessment of Accelerated 5-HT_1A Autoreceptor Desensitization in Rats Produced by Vilazodone, a Novel Serotonin Reuptake Inhibitor and 5-HT_1A Receptor Partial Agonist

Charles R. Ashby, Jr., Ph.D.¹, John H. Kehne, Ph.D.², Gerd D. Bartoszyk, Ph.D.³, Kerri A. Pierz, Ph.D.⁴, Matthew J. Renda, Ph.D.⁴, Maria C. Athanasiou, Ph.D.⁴

 

¹St. John’s University, Jamaica, NY; ² Translational Neuropharmacology Consulting, LLC, Rockville, MD; ³Merck KGaA, Darmstadt, Germany; ⁴PGxHealth, LLC, a Division of Clinical Data, New Haven, CT

ABSTRACT: (Current abstract word count = 250 words; maximum allowed, 250)

PRIMARY CATEGORY: pharmacology pre-clinical

SECONDARY CATEGORY: mood disorder

Background: Vilazodone HCl is a novel serotonin reuptake inhibitor (SRI) and 5-HT_1A receptor partial agonist in Phase 3 trials for the treatment of depression. Vilazodone was assessed relative to SSRIs in electrophysiological studies for SRI-mediated and for direct 5-HT_1A agonism-mediated desensitization of dorsal raphe (DR) 5-HT_1A autoreceptors.

Methods: Using standard extracellular recording in anesthetized male Sprague-Dawley rats, DR 5-HT neuronal activity was measured 4 or 24 hours after subcutaneous administration with saline, vilazodone (0.3, 1 mg/kg), paroxetine (5 mg/kg), or fluoxetine (10 mg/kg), either acutely (single injection) or subchronically (1 injection/day for 3 days). Treatment effects were assessed

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by determining the number of spontaneously active DR 5-HT neurons and quantitating the dose of the intravenous 5-HT_1A receptor agonist, 8-OH-DPAT, required to inhibit firing of DR 5-HT neurons by 50% (ID₅₀, 5-HT_1A agonism-mediated).

Results: The number of spontaneously active DR 5-HT neurons was significantly reduced 4 hours after both acute and subchronic administration of vilazodone or either SSRI and remained lower after 24 hours only with fluoxetine-treated animals. Vilazodone, not SSRIs, elevated ID₅₀ values 2—3-fold for 8-OH-DPAT reduction of DR 5-HT neuronal firing 4 hours after acute and 4 and 24 hours after subchronic administration.

Conclusions: Vilazodone and SSRIs significantly decreased DR neuron firing by 5-HT reuptake inhibition. Vilazodone, but not SSRIs, significantly reduced DR neuron firing by 5-HT_1A agonism after subchronic dosing, including at 24 hours. These results are consistent with vilazodone-mediated acceleration of 5-HT_1A autoreceptor desensitization relative to SSRIs and the potential for improved antidepressant effect in humans.