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

Laboratory of Neuropharmacology, Faculty of Pharmacy, University of Claude Bernard Lyon I, Lyon, France

H Husum

H. Lundbeck A/S, Valby, Copenhagen, Denmark

O Mnie-Filali

Laboratory of Neuropharmacology, Faculty of Pharmacy, University of Claude Bernard Lyon I, Lyon, France

J Arnt

H. Lundbeck A/S, Valby, Copenhagen, Denmark ja{at}lundbeck.com

P Hertel

H. Lundbeck A/S, Valby, Copenhagen, Denmark

N Haddjeri

Laboratory of Neuropharmacology, Faculty of Pharmacy, University of Claude Bernard Lyon I, Lyon, France

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.

Key Words: antipsychotics • aripiprazole • bifeprunox • dopamine receptors • dorsal raphe • schizophrenia • serotonin receptors • ventral tegmental area

This version was published on March 1, 2009

Journal of Psychopharmacology, Vol. 23, No. 2, 177-189 (2009)
DOI: 10.1177/0269881108089586


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