Pharmacological blockade of dopamine D2 receptors by aripiprazole is not associated with striatal sensitization

The partial agonist profile of novel antipsychotics such as aripiprazole has hardly been demonstrated in biochemical assays on animal tissues. As it is established that responses induced by dopamine D 2 receptor agonists are increased in models of dopaminergic sensitization, this paradigm was used i...

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Bibliographic Details
Published in:	Naunyn-Schmiedeberg's archives of pharmacology Vol. 383; no. 1; pp. 65 - 77
Main Authors:	Koener, Beryl, Goursaud, Stéphanie, Van De Stadt, Morgane, Calas, André-Guilhem, Jeanjean, Anne P., Maloteaux, Jean-Marie, Hermans, Emmanuel
Format:	Journal Article
Language:	English
Published:	Berlin/Heidelberg Springer-Verlag 2011
Subjects:	Animals Apomorphine - analogs & derivatives Apomorphine - antagonists & inhibitors Apomorphine - pharmacology Aripiprazole Biomedical and Life Sciences Biomedicine Buffers Catalepsy - chemically induced Catalepsy - diagnosis Cell Membrane - drug effects Cell Membrane - metabolism Cerebral Cortex - drug effects Cerebral Cortex - metabolism Corpus Striatum - drug effects Corpus Striatum - metabolism Domperidone - pharmacology Dopamine - pharmacology Dopamine Agonists - pharmacology Dopamine Antagonists - pharmacology Dopamine D2 Receptor Antagonists Drug Antagonism Drug Partial Agonism Guanosine 5'-O-(3-Thiotriphosphate) - metabolism Haloperidol - pharmacology Hippocampus - drug effects Hippocampus - metabolism Male Neurosciences Original Article Pharmacology/Toxicology Piperazines - pharmacology Piperidines - pharmacology Pyridines - pharmacology Quinolones - pharmacology Rats Rats, Wistar Receptors, Dopamine D2 - agonists Receptors, Dopamine D2 - metabolism Receptors, Serotonin, 5-HT1 - metabolism Serotonin - pharmacology Serotonin 5-HT1 Receptor Antagonists - pharmacology Stereotyped Behavior - drug effects Up-Regulation - drug effects Guanylyl nucleotide binding assay Partial agonist G-protein Sensitization Receptor up-regulation Functional selectivity
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Summary:	The partial agonist profile of novel antipsychotics such as aripiprazole has hardly been demonstrated in biochemical assays on animal tissues. As it is established that responses induced by dopamine D 2 receptor agonists are increased in models of dopaminergic sensitization, this paradigm was used in order to facilitate the detection of the partial agonist properties of aripiprazole. At variance with all other partial and full agonists tested, the partial agonist properties of aripiprazole were not revealed in guanosine 5′- O -(γ-[ 35 S]thiotriphosphate ([ 35 S]GTPγS) binding assays on striatal membranes from haloperidol-treated rats. Hence, aripiprazole behaved as an antagonist, efficiently inhibiting the functional response to dopamine. Similarly, in behavioural assays, aripiprazole dose-dependently inhibited the stereotypies elicited by apomorphine. However, at variance with haloperidol, repeated administrations of aripiprazole (3 weeks) at the doses of 10 and 30 mg/kg did not induce any up-regulation or hyperfunctionality of the dopamine D 2 receptors in the striatum. These data highlight the putative involvement of other pharmacological targets for aripiprazole that would support in the prevention of secondary effects commonly associated with the blockade of striatal dopamine D 2 receptors. Hence, in additional experiments, aripiprazole was found to efficiently promote [ 35 S]GTPγS binding in hippocampal membranes through the activation of 5-HT 1A receptors. Further experiments investigating the second-messenger cascades should be performed so as to establish the functional properties of aripiprazole and understand the mechanism underlying the prevention of dopamine receptor regulation in spite of the observed antagonism.
ISSN:	0028-1298 1432-1912
DOI:	10.1007/s00210-010-0577-7