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

Autor: Koener, Beryl, Goursaud, Stéphanie, Stadt, Morgane, Calas, André-Guilhem, Jeanjean, Anne, Maloteaux, Jean-Marie, Hermans, Emmanuel
Zdroj: Naunyn-Schmiedeberg's Archives of Pharmacology; Jan2011, Vol. 383 Issue 1, p65-77, 13p
Abstrakt: 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 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-[S]thiotriphosphate ([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 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 receptors. Hence, in additional experiments, aripiprazole was found to efficiently promote [S]GTPγS binding in hippocampal membranes through the activation of 5-HT 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. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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