5-HT1A receptor activation contributes to ziprasidone-induced dopamine release in the rat prefrontal cortex

Background: Ziprasidone (Zeldox) is a novel antipsychotic with a unique combination of antagonist activities at monoaminergic receptors and transporters and potent agonist activity at serotonin 5-HT1A receptors. 5-HT1A receptor agonism may be an important feature in ziprasidone’s clinical actions because 5-HT1A agonists increase cortical dopamine release, which may underlie efficacy against negative symptoms and reduce dopamine D2 antagonist-induced extrapyramidal side effects. This study investigated the in vivo 5-HT1A agonist activity of ziprasidone by measuring the contribution of 5-HT1A receptor activation to the ziprasidone-induced cortical dopamine release in rats. Methods: Effects on dopamine release were measured by microdialysis in prefrontal cortex and striatum. The role of 5-HT1A receptor activation was estimated by assessing the sensitivity of the response to pretreatment with the 5-HT1A antagonist, WAY-100635. For comparison, the D2/5-HT2A antagonists clozapine and olanzapine, the D2 antagonist haloperidol, the 5-HT2A antagonist MDL 100,907 and the 5-HT1A agonist 8-OHDPAT were included. Results: Low doses (<3.2 mg/kg) of ziprasidone, clozapine, and olanzapine increased dopamine release to approximately the same extent in prefrontal cortex as in striatum, but higher doses (≥3.2 mg/kg) resulted in an increasingly preferential effect on cortical dopamine release. The 5-HT1A agonist 8-OHDPAT produced a robust increase in cortical dopamine (DA) release without affecting striatal DA release. In contrast, the D2 antagonist haloperidol selectively increased striatal DA release, whereas the 5-HT2A antagonist MDL 100,907 had no effect on cortical or striatal DA release. Prior administration of WAY-100635 completely blocked the cortical DA increase produced by 8-OHDPAT and significantly attenuated the ziprasidone- and clozapine-induced cortical DA increase. WAY-100635 pretreatment had no effect on the olanzapine-induced DA increase. Conclusions: The preferential increase in DA release in rat prefrontal cortex produced by ziprasidone is mediated by 5-HT1A receptor activation. This result extends and confirms other in vitro and in vivo data suggesting that ziprasidone, like clozapine, acts as a 5-HT1A receptor agonist in vivo, which may contribute to its activity as an antipsychotic with efficacy against negative symptoms and a low extrapyramidal side effect liability.