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In vivo actions of aripiprazole on serotonergic and dopaminergic systems in rodent brain

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Abstract

Rationale

Aripiprazole is an atypical antipsychotic drug with high in vitro affinity for 5-HT1A, 5-HT2A and dopamine (DA) D2 receptors. However, its in vivo actions in the brain are still poorly characterized.

Objective

The aim was to study the in vivo actions of aripiprazole in the rat and mouse brain.

Methods

Brain microdialysis and single-unit extracellular recordings were performed.

Results

The systemic administration of aripiprazole reduced 5-HT output in the medial prefrontal cortex (mPFC) and dorsal raphe nucleus of the rat. Aripiprazole also reduced extracellular 5-HT in the mPFC of wild-type (WT) but not of 5-HT1A (−/−) knockout (KO) mice. Aripiprazole reversed the elevation in extracellular 5-HT output produced by the local application of the 5-HT2A/2C receptor agonist DOI in mPFC. Aripiprazole also increased the DA output in mPFC of WT but not of 5-HT1A KO mice, as observed for atypical antipsychotic drugs, in contrast to haloperidol. Contrary to haloperidol, which increases the firing rate of DA neurons in the ventral tegmental area (VTA), aripiprazole induced a very moderate reduction in dopaminergic activity. Haloperidol fully reversed the inhibition in dopaminergic firing rate induced by apomorphine, whereas aripiprazole evoked a partial reversal that was significantly different from that evoked by haloperidol and from the spontaneous reversal of dopaminergic activity in rats treated with apomorphine.

Conclusions

These results indicate that aripiprazole modulates the in vivo 5-HT and DA release in mPFC through the activation of 5-HT1A receptors. Moreover, aripiprazole behaves as a partial agonist at DA D2 autoreceptors in vivo, an action which clearly distinguishes it from haloperidol.

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Abbreviations

5-HT:

5-hydroxytryptamine or serotonin

APO:

apomorphine

ARI:

aripiprazole

BAY:

BAYx3702

DA:

dopamine

DPAT:

8-OH-DPAT

DR:

dorsal raphe nucleus

HAL:

haloperidol

KO:

knockout

mPFC:

medial prefrontal cortex

VTA:

ventral tegmental area

WT:

wild type

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Acknowledgment

This work was supported by grants from the Spanish Ministry of Education and Science (SAF 2004-05525) and Bristol Myers Squibb. PC and AB are recipients of a Ramón y Cajal contract from the Ministry of Science and Technology. LDM is recipient of a predoctoral fellowship from IDIBAPS. Support from the Spanish Ministry of Health, Instituto de Salud Carlos III, Red de Enfermedades Mentales (REM-TAP Network) is also acknowledged. We thank Leticia Campa and Judith Ballart for skilful technical assistance.

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Authors and Affiliations

  1. Department of Neurochemistry, Institut d’ Investigacions Biomèdiques de Barcelona (CSIC), IDIBAPS, Rosselló, 161, 6th floor, 08036, Barcelona, Spain

    A. Bortolozzi, L. Díaz-Mataix, P. Celada & F. Artigas

  2. Department of Pharmacology, Weill Medical College, Cornell University, New York, NY, USA

    M. Toth

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  1. A. Bortolozzi
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  2. L. Díaz-Mataix
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  3. M. Toth
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Correspondence to F. Artigas.

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A. Bortolozzi and L. Díaz-Mataix have contributed equally to this study.

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Bortolozzi, A., Díaz-Mataix, L., Toth, M. et al. In vivo actions of aripiprazole on serotonergic and dopaminergic systems in rodent brain. Psychopharmacology 191, 745–758 (2007). https://doi.org/10.1007/s00213-007-0698-y

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