期刊
JOURNAL OF PSYCHOPHARMACOLOGY
卷 23, 期 2, 页码 177-189出版社
SAGE PUBLICATIONS LTD
DOI: 10.1177/0269881108089586
关键词
antipsychotics; aripiprazole; bifeprunox; dopamine receptors; dorsal raphe; schizophrenia; serotonin receptors; ventral tegmental area
资金
- Lundbeck A/S (Valby, Denmark)
- Solvay Pharmaceuticals Research (Weesp, Holland)
- Wyeth Research (Princeton, USA)
- University of Claude Bernard Lyon 1
The atypical antipsychotic bifeprunox is a partial dopamine D-2 and 5-HT1A 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 D-2 receptor antagonist haloperidol prevented these inhibitory effects, confirming partial D-2-like agonistic properties. On 5-HT neurons, bifeprunox was more potent than aripiprazole to suppress firing activity. The 5-HT1A 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 D-2-like and 5-HT1A 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.
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