Dopamine D2 and serotonin 5-HT1A receptors mediate the actions of aripiprazole in mesocortical and mesoaccumbens transmission

The antipsychotic agent aripiprazole acts as a partial agonist of dopamine D2 and serotonin 5-HT1A receptors. However, the detailed actions of aripiprazole in mesolimbic and mesocortical transmission remain to be clarified. To address this, we examined the effects of systemic and local administrations of aripiprazole on extracellular levels of dopamine and GABA in medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and anterior (aVTA) and posterior (pVTA) ventral tegmental areas. Intraperitoneal injection of aripiprazole (0.5 mg/kg) increased dopamine release in mPFC without affecting those in aVTA, pVTA, or NAc, whereas 10 mg/kg decreased the release in all four regions. Local sulpiride administration in aVTA increased concentration-dependently dopamine release in both aVTA and NAc without affecting that in mPFC, whereas local aripiprazole administration in aVTA concentration-dependently decreased dopamine release in aVTA and mPFC without affecting that in NAc. Blockade of 5-HT1A receptor in aVTA produced aripiprazole-induced dopamine release in aVTA and prevented the aripiprazole-induced reduction of dopamine release in mPFC. Local administration of aripiprazole in mPFC increased dopamine and decreased GABA releases, whereas local administration of sulpiride had no effect on dopamine or GABA. In mPFC, blockade of 5-HT1A receptor prevented the aripiprazole-induced dopamine elevation and GABA reduction; however, under the activation of GABA A receptor, local perfusion with aripiprazole in mPFC decreased GABA release without affecting dopamine release. The results suggested that the combination of 5-HT1A and D2 partial agonistic actions of aripiprazole against mesocortical and mesoaccumbens transmission, explains, at least in part, the atypical antipsychotic properties of aripiprazole. This article is part of a Special Issue entitled ‘Post-Traumatic Stress Disorder’. ► Aripiprazole enhanced mesocortical but not mesolimbic dopaminergic transmissions. ► High dose aripiprazole reduced mesocortical and mesolimbic dopaminergic transmission. ► D2 partial agonistic action of aripiprazole enhanced dopamine release. ► 5-HT1A partial agonistic action of aripiprazole reduced dopamine release. ► 5-HT1A and D2 partial agonistic actions explain atypical antipsychotic properties.