5-HT(1A) receptor activation contributes to ziprasidone-induced dopamine release in the rat prefrontal cortex

• Published in: Biological psychiatry (1969) 2000-08, Vol.48 (3), p.229-237
• Main Authors: Rollema, H, Lu, Y, Schmidt, A W, Sprouse, J S, Zorn, S H
• Format: Article
• Language: English
• Subjects: Animals; Antipsychotic Agents - pharmacology; Benzodiazepines; Chromatography, High Pressure Liquid - methods; Clozapine - pharmacology; Corpus Striatum - drug effects; Dopamine - metabolism; Haloperidol - pharmacology; Male; Microdialysis - methods; Olanzapine; Piperazines - pharmacology; Pirenzepine - analogs & derivatives; Pirenzepine - pharmacology; Prefrontal Cortex - drug effects; Rats; Rats, Sprague-Dawley; Receptors, Serotonin - drug effects; Sensitivity and Specificity; Synaptic Transmission - drug effects; Thiazoles - pharmacology; Time Factors
• ISSN: 0006-3223
• DOI: 10.1016/S0006-3223(00)00850-7

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. 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. Low 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. 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.