Effects of bifeprunox and aripiprazole on rat serotonin and dopamine neuronal activity and anxiolytic behaviour

Abstract

The atypical antipsychotic bifeprunox is a partial dopamine D₂ and 5-HT_1A receptor agonist. Using in-vivo electrophysiological and behavioural paradigms in the rat, the effects of bifeprunox and aripiprazole were assessed on ventral tegmental area (VTA) dopamine and dorsal raphe serotonin (5-HT) cell activity and on foot shock–induced ultrasonic vocalisation (USV). In VTA, bifeprunox and aripiprazole decreased (by 20–50%) firing of dopamine neurons. Interestingly, bursting activity was markedly reduced (by 70–100%), bursting being associated with a larger synaptic dopamine release than single spike firing. Both ligands reduced inhibition of firing rate induced by the full dopamine receptor agonist apomorphine, whereas the D₂ receptor antagonist haloperidol prevented these inhibitory effects, confirming partial D₂-like agonistic properties. On 5-HT neurons, bifeprunox was more potent than aripiprazole to suppress firing activity. The 5-HT_1A receptor antagonist WAY-100,635 prevented their effects. In the USV test of anxiolytic-like activity, bifeprunox had higher potency than aripiprazole to reduce vocalisations. Both WAY-100,635 and haloperidol reversed the effects of both agonists. The present in-vivo study shows that bifeprunox is a potent partial D₂-like and 5-HT_1A receptor agonist reducing preferentially the phasic activity of dopamine neurons. Thus, bifeprunox would be expected to be an effective compound against positive and negative symptoms of schizophrenia.