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The novel antipsychotic aripiprazole is a partial agonist at short and long isoforms of the D2 receptor regulating prolactin release and cAMP



The novel antipsychotic aripiprazole is a partial agonist at short and long isoforms of the D2 receptor regulating prolactin release and cAMP



Society for Neuroscience Abstracts 27(2): 1766



Aripiprazole is a novel antipsychotic with a unique mechanism of action, which differs from currently marketed typical and atypical antipsychotics. Aripiprazole has been shown to be a partial agonist at the D2 family of dopamine receptors in biochemical and pharmacological studies. To demonstrate aripiprazole as a partial D2 agonist in pituitary cells at the molecular level, we retrovirally transduced the short (D2S) and the long (D2L) form of the human dopamine D2 receptor gene into a rat pituitary cell line, GH4C1. (3H)-raclopride saturation binding analyses revealed a Bmax value that was 4-fold higher at D2S-expressing cells than at D2L-expressing cells, while a Kd value was similar. Aripiprazole inhibited forskolin-stimulated release of prolactin in both D2S- and D2L-expressing cells, although the maximal inhibition of prolactin release was less than that of dopamine. Similarly, aripiprazole partially inhibited forskolin-induced cAMP accumulation in D2S- and D2L-expressing cells. Aripiprazole antagonized the suppression attained by dopamine (10-7M) in both cells and, at the maximal blockade of cAMP, yielded residual cAMP level equal to those produced by aripiprazole alone. These results indicate that aripiprazole acts a partial agonist at both D2S and D2L receptors expressed on GH4C1 cells. Our data may explain, at least in part, the observations that aripiprazole shows a novel antipsychotic activity with weak adverse events including no significant increase of serum prolactin levels in clinical studies.

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