Bifeprunox and aripiprazole suppress in vivo VTA dopaminergic neuronal activity via D2 and not D3 dopamine autoreceptor activation

Bifeprunox and aripiprazole are two novel antipsychotics presenting partial agonistic activity for the D2 and D3 dopamine (DA) receptors. Using in vivo electrophysiological paradigms in anaesthetized rats, we have previously shown that both drugs independently inhibit the spontaneous firing and bursting activity of ventral tegmental area (VTA) dopaminergic neurons and partially reverse the suppressing effect of the full DA receptor agonist apomorphine. Moreover, we have also shown that the D2/3 receptor antagonist haloperidol prevents the inhibitory effects of these antipsychotics, confirming their partial D2-like agonistic activities [L. Dahan, H. Husum, O. Mnie-Filali, J. Arnt, P. Hertel, N. Haddjeri, Effects of bifeprunox and aripiprazole on rat serotonin and dopamine neuronal activity and anxiolytic behaviour, J. Psychopharmacol. (2009)]. In the present electrophysiological study, selective antagonists of D2 and D3 receptors were used to further characterize the inhibitory role of bifeprunox and aripiprazole on the D2 and D3 receptors in vivo. Administration of bifeprunox (250 μg/kg, i.v.) or aripiprazole (300 μg/kg, i.v.) reduced the firing activity of VTA DA neurons by 40-50%. The bursting activity was reduced by 95% and 77% by bifeprunox and aripiprazole, respectively. Systemic administration of the preferential D3 receptor antagonist GR218,231 (200 μg/kg, i.v.) did not modify the inhibitory effect of bifeprunox or aripiprazole, either on the firing or on the bursting activity. On the other hand, the preferential D2 receptor antagonist L741,626 (500 μg/kg, i.v.) completely blocked the inhibitory effect of both bifeprunox and aripiprazole on the VTA DA neuronal activity. The present study shows that bifeprunox and aripiprazole behave as partial D2, but not D3, receptor agonists in vivo, inhibiting the firing activity (preferentially the phasic activity) of VTA DA cells.