5-HT(1A) 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-HT(1A) receptors. 5-HT(1A) receptor agonism may be an important feature in ziprasidone's clinical actions because 5-HT(1A) agonists increase cortical dopamine release, which may underlie efficacy against negative symptoms and reduce dopamine D(2) antagonist-induced extrapyramidal side effects. This study investigated the in vivo 5-HT(1A) agonist activity of ziprasidone by measuring the contribution of 5-HT(1A) 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-HT(1A) receptor activation was estimated by assessing the sensitivity of the response to pretreatment with the 5-HT(1A) antagonist, WAY-100635. For comparison, the D(2)/5-HT(2A) antagonists clozapine and olanzapine, the D(2) antagonist haloperidol, the 5-HT(2A) antagonist MDL 100,907 and the 5-HT(1A) 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 (> or =3.2 mg/kg) resulted in an increasingly preferential effect on cortical dopamine release. The 5-HT(1A) agonist 8-OHDPAT produced a robust increase in cortical dopamine (DA) release without affecting striatal DA release. In contrast, the D(2) antagonist haloperidol selectively increased striatal DA release, whereas the 5-HT(2A) 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-HT(1A) receptor activation. This result extends and confirms other in vitro and in vivo data suggesting that ziprasidone, like clozapine, acts as a 5-HT(1A) 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.
Rollema
H
H
Department of Neuroscience, Central Research Division, Pfizer Inc., Groton, CT 06340, USA.
Lu
Y
Y
Schmidt
A W
AW
Sprouse
J S
JS
Zorn
S H
SH
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001569:Benzodiazepines; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003024:Clozapine / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D017551:Microdialysis / Q000379:methods; D000077152:Olanzapine; D010879:Piperazines / Q000494:pharmacology*; D010890:Pirenzepine / Q000031:analogs & derivatives / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects*; D012680:Sensitivity and Specificity; D009435:Synaptic Transmission / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology*; D013997:Time Factors
D014150:Antipsychotic Agents; D010879:Piperazines; D011985:Receptors, Serotonin; D013844:Thiazoles; D001569:Benzodiazepines; D010890:Pirenzepine; C092292:ziprasidone; D003024:Clozapine; D006220:Haloperidol; D000077152:Olanzapine; D004298:Dopamine