TREBALL 6 In vivo actions of aripiprazole on serotonergic and dopaminergic systems in rodent brain

The atypical antipsychotic drug aripiprazole (ARI) shows high in vitro affinity for 5-HT1A, 5-HT2A and dopamine (DA) D2 receptors. In the present study we examined the in vivo actions of ARI in he rat and mouse brain using single unit recordings and microdialysis. The systemic administration of ARI reduced 5-HT release in the medial prefrontal cortex (mPFC) and dorsal raphe nucleus of the rat. Aripiprazole also reduced 5-HT release in the mPFC of wild-type (WT) but not 5-HT1A (-/-) knockout (KO) mice. As previously observed for other antipsychotic drugs, ARI reversed the elevation in 5-HT output produced by the local application of the 5-HT2A/2C receptor agonist DOI. Likewise, ARI increased the DA output in mPFC of WT but not 5-HT1A KO mice. Contrary to haloperidol, which markedly increases the firing rate of DA neurons in the ventral tegmental area (VTA), ARI did not evoke consistent changes of dopaminergic activity. When administered after apomorphine, haloperidol fully reversed the inhibition in firing rate, whereas ARI evoked a moderate reversal which was significantly different from that evoked by haloperidol and from the spontaneous reversal of dopaminergic activity in rats treated with apomorphine and saline. Overall, the present results indicate that ARI modulates the in vivo 5-HT and DA release in mPFC through the activation of 5-HT1A receptors. Likewise, ARI behaves as a partial agonist at DA D2 receptors in vivo, an action which clearly distinguishes it from conventional antipsychotics.