In vivo actions of aripiprazole on serotonergic and dopaminergic systems in rodent brain.
BACKGROUND
Aripiprazole is an atypical antipsychotic drug with high in vitro affinity for 5-HT(1A), 5-HT(2A) 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-HT(1A) (-/-) knockout (KO) mice. Aripiprazole reversed the elevation in extracellular 5-HT output produced by the local application of the 5-HT(2A/2C) receptor agonist DOI in mPFC. Aripiprazole also increased the DA output in mPFC of WT but not of 5-HT(1A) 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-HT(1A) receptors. Moreover, aripiprazole behaves as a partial agonist at DA D2 autoreceptors in vivo, an action which clearly distinguishes it from haloperidol.
Bortolozzi
A
A
Department of Neurochemistry, Institut d' Investigacions Biomèdiques de Barcelona (CSIC), IDIBAPS, Rosselló, 161, 6th floor, 08036, Barcelona, Spain.
Díaz-Mataix
L
L
Toth
M
M
Celada
P
P
Artigas
F
F
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D000068180:Aripiprazole; D017660:Autoreceptors / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis; D010879:Piperazines / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology*; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism
D014150:Antipsychotic Agents; D017660:Autoreceptors; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D010879:Piperazines; D015363:Quinolones; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D017448:Receptors, Dopamine D2; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D000068180:Aripiprazole; D006220:Haloperidol; D004298:Dopamine