Neurochemical evaluation of the novel 5-HT1A receptor partial agonist/serotonin reuptake inhibitor, vilazodone

doi:10.1016/j.ejphar.2005.01.018

European Journal of Pharmacology

Volume 510, Issues 1–2, 7 March 2005, Pages 49-57

https://doi.org/10.1016/j.ejphar.2005.01.018 Get rights and content

Abstract

Vilazodone has been reported to be an inhibitor of 5-hydoxytryptamine (5-HT) reuptake and a partial agonist at 5-HT_1A receptors. Using [³⁵S]GTPγS binding in rat hippocampal tissue, vilazodone was demonstrated to have an intrinsic activity comparable to the 5-HT_1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Vilazodone (1–10 mg/kg p.o.) dose-dependently displaced in vivo [³H]DASB (N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine) binding from rat cortex and hippocampus, indicating that vilazodone occupies 5-HT transporters in vivo. Using in vivo microdialysis, vilazodone (10 mg/kg p.o.) was demonstrated to cause a 2-fold increase in extracellular 5-HT but no change in noradrenaline or dopamine levels in frontal cortex of freely moving rats. In contrast, administration of 8-OH-DPAT (0.3 mg/kg s.c.), either alone or in combination with a serotonin specific reuptake inhibitor (SSRI; paroxetine, 3 mg/kg p.o.), produced no increase in cortical 5-HT whilst increasing noradrenaline and dopamine 2 and 4 fold, respectively. A 2-fold increase in extracellular 5-HT levels (but no change in noradrenaline or dopamine levels) was observed after combination of the 5-HT_1A receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(pyridinyl)cyclohexanecarboxamide) (WAY-100635; 0.3 mg/kg s.c.) and paroxetine (3 mg/kg p.o.). In summary, vilazodone behaved as a high efficacy partial agonist at the rat hippocampal 5-HT_1A receptors in vitro and occupied 5-HT transporters in vivo. In vivo vilazodone induced a selective increase in extracellular levels of 5-HT in the rat frontal cortex. This profile was similar to that seen with a 5-HT_1A receptor antagonist plus an SSRI but in contrast to 8-OH-DPAT either alone or in combination with paroxetine.

Introduction

Vilazodone is a combined serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor (SSRI) and 5-HT_1A receptor partial agonist (Sorbera et al., 2001) which exhibits anxiolytic-like behaviour in well established rodent models of anxiety, such as the rat ultrasonic vocalisation test (Bartoszyk et al., 1997) and antidepressant-like effects in the forced swim test (Page et al., 2002). Furthermore, vilazodone has been shown to increase extracellular 5-HT in the medial prefrontal cortex and ventral hippocampus of rats (Page et al., 2002).

It is widely accepted that acute increases in forebrain 5-HT levels, induced by administration of SSRIs, are restrained (Invernizzi et al., 1992, Malagie et al., 1995, Romero and Artigas, 1997) by an SSRI-induced reduction in serotonergic neurotransmission mediated by presynaptic 5-HT_1A autoreceptors (Blier and De Montigny, 1987, Gartside et al., 1995). Hence the effects of SSRIs can be augmented by co-administration of 5-HT_1A receptor antagonists such as WAY-100635 (Gartside et al., 1995, Hjorth et al., 1997, Sharp et al., 1997). However, partial agonists such as buspirone (Dawson and Nguyen, 1998) or agonists such as tandospirone (Yoshino et al., 2002) are not able to produce this augmentation. Pindolol is a partial 5-HT_1A receptor agonist with low intrinsic activity, yet its ability to augment SSRI-induced increases in 5-HT is equivocal. Some groups demonstrate a potentiation of fluoxetine or citalopram induced increases in 5-HT (Hjorth, 1996, Dawson and Nguyen, 2000), whereas others show no effect (Hughes and Sharp, 1998, Gartside et al., 1999). It has been suggested that the level of intrinsic activity of 5-HT_1A receptor partial agonists is critical in determining whether or not a drug of this class can potentiate the effect of an SSRI (Dawson and Nguyen, 1998).

As well as having no effect on 5-HT, 5-HT_1A receptor antagonists such as WAY-100635 also do not affect extracellular noradrenaline or dopamine levels (Hajos-Korcsok and Sharp, 1996, Gobert et al., 1997b). In contrast, 5-HT_1A receptor agonists and partial agonists such as (±)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), buspirone and MKC-242, have been shown to increase extracellular dopamine and noradrenaline in a number of brain regions in the rat (Done and Sharp, 1994, Suzuki et al., 1995, Chen and Reith, 1995, Gobert et al., 1998).

Thus in the present study, the neurochemical effects of vilazodone were compared to selective 5-HT_1A receptor ligands alone and in combination with the SSRI, paroxetine. The actions of vilazodone on 5-HT, dopamine and noradrenaline were compared to combinations of 5-HT_1A receptor agonist (8-OH-DPAT) plus paroxetine or 5-HT_1A receptor antagonist (WAY-100635) plus paroxetine. Extracellular levels of 5-HT, noradrenaline and dopamine in frontal cortex were measured using in vivo microdialysis in freely moving rats. In addition, vilazodone was assessed for its ability to occupy rat 5-HT transporter sites in vivo using displacement of [³H]DASB (N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine) binding (Wilson et al., 2000, Wilson et al., 2002, Meyer et al., 2001). Furthermore, vilazodone was assessed in a native tissue GTPγS binding preparation as a functional measure of intrinsic agonist activity at postsynaptic 5-HT_1A receptors.

Section snippets

Materials

WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(pyridinyl)cyclohexanecarboxamide) and paroxetine hydrochloride hemihydrate (3S-trans)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine hydrochloride hydrate (2:1)) were all synthesised by Medicinal Chemistry, GlaxoSmithKline (Harlow, UK). Vilazodone (EMD 68843; 5-{4-[4-(5-cyano-3-indolyl)-butyl]-1-piperazinyl}-benzofuran-2-carboxamide hydrochloride) was synthesised by Medicinal Chemistry, Merck KGaA (Darmstadt,

[³⁵S]-GTPγS binding to rat hippocampal membranes

The selective antagonists, WAY-100635 and SB-224289, were used to define the components of the 5-HT-induced stimulation of [³⁵S]-GTPγS binding mediated via 5-HT_1A and 5-HT_1B receptors, respectively (Fig. 1A). In the presence of SB-224289 (3 μM) the response to 5-HT was assumed to be solely due to the activation of 5-HT_1A receptors and this concentration of SB-224289 was included routinely in subsequent experiments to block the 5-HT_1B receptor-mediated component of the 5-HT response. Under these

Discussion

Vilazodone (EMD-68843) is reputed to be a combined 5-HT reuptake inhibitor and 5-HT_1A receptor partial agonist (Bartoszyk et al., 1997, Sorbera et al., 2001). Previous data (Wilson et al., 2000, Wilson et al., 2002) has demonstrated that the radiotracer, [¹¹C]DASB, binds selectively to the 5-HT transporter across a range of brain regions in the rat. Thus demonstrating the utility of this radioligand for the evaluation of occupancy of transporter sites within the rodent brain. The results of the

Acknowledgements

The authors would like to thank members of the Laboratory Animal Science Department and Dr. Claire Shilliam for their assistance with surgical procedures, and Alan Atkins for his analytical expertise.

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¹: Current address: Department of Neuroscience, Wyeth Research, CN8000, Princteon, NJ 08543, USA.

²: Merck KgaA, Darmstadt, Germany.

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Neurochemical evaluation of the novel 5-HT1A receptor partial agonist/serotonin reuptake inhibitor, vilazodone

Abstract

Introduction

Section snippets

Materials

[35S]-GTPγS binding to rat hippocampal membranes

Discussion

Acknowledgements

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Neuropharmacology

Neuropharmacology

Neuroscience

Neuroscience

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Neuropharmacology

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Neuropsychopharmacology

Neuropsychopharmacology

Nucl. Med. Biol.

Neurochem. Int.

Modification of 5-HT neuron properties by sustained administration of the 5-HT1A agonist gepirone: electrophysiological studies in the rat brain

Synapse

Role of somatodendritic 5-HT autoreceptors in modulating 5-HT neurotransmission

Ann. N.Y. Acad. Sci.

Postsynaptic 5-HT1A receptors control 5-HT release in the rat medial prefrontal cortex

NeuroReport

Monoamine interactions measured by microdialysis in the ventral tegmental area of rats treated systemically with (+/−)-8-hydroxy-2-(di-n-propylamino)tetralin

J. Neurochem.

Neurochemical evaluation of the novel 5-HT_1A receptor partial agonist/serotonin reuptake inhibitor, vilazodone

[³⁵S]-GTPγS binding to rat hippocampal membranes

Modification of 5-HT neuron properties by sustained administration of the 5-HT_1A agonist gepirone: electrophysiological studies in the rat brain

Postsynaptic 5-HT_1A receptors control 5-HT release in the rat medial prefrontal cortex