Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine: Inhibition of dorsal raphe cell firing and the role of 5-HT1A receptor activation

Ziprasidone is a novel antipsychotic agent which binds with high affinity t o 5-HT1A receptors (K-i = 3.4 nM), in addition to 5-HT1D, 5-HT2, and D-2 si tes. While it is an antagonist at these latter receptors, ziprasidone behav es as a 5-HT1A agonist in vitro in adenylate cyclase measurements. The goal of the present study was to examine the 5-HT1A properties of ziprasidone i n vivo using as a marker of central 5-HT1A activity the inhibition of firin g of serotonin-containing neurons in the dorsal raphe nucleus. In anestheti zed rats, ziprasidone dose-dependently slowed raphe unit activity (ED50 = 3 00 mu g/kg IV) as did the atypical antipsychotics clozapine (ED50 = 250 mu g/kg IV) and olanzapine (ED50 = 1000 mu g/kg IV). Pretreatment with the 5-H T1A antagonist WAY-100,635 (10 mu g/kg IV) prevented the ziprasidone-induce d inhibition; the same dose of WAY-100,635 had little effect on the inhibit ion produced by clozapine and olanzapine. Because all three agents also bin d to alpha(1) receptors, antagonists of which inhibit serotonin neuronal fi ring, this aspect of their pharmacology was assessed with desipramine (DMI) , a NE re-uptake blocker previously shown to reverse the effects of alpha(1 ) antagonists on raphe unit activity. DMI (5 mg/kg IV) failed to reverse th e inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine. These profiles suggest a mechanism of ac tion for each agent, 5-HT1A agonism for ziprasidone and alpha(1) antagonism for clozapine and olanzapine. The 5-HT1A agonist activity reported here cl early distinguishes ziprasidone from currently available antipsychotic agen ts and suggests that this property may play a significant role in its pharm acologic actions. [Neuropsychopharmacology 21:622-631, 1999] (C) 1999 Ameri can College of Neuropsychopharmacology. Published by Elsevier Science Inc.