text: 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 to 5-HT1A receptors (Ki = 3.4 nM), in addition to 5-HT1D, 5-HT2, and D2 sites. While it is an antagonist at these latter receptors, ziprasidone behaves 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 in vivo using as a marker of central 5-HT1A activity the inhibition of firing of serotonin-containing neurons in the dorsal raphe nucleus. In anesthetized rats, ziprasidone dose-dependently slowed raphe unit activity (ED50 = 300 micrograms/kg i.v.) as did the atypical antipsychotics clozapine (ED50 = 250 micrograms/kg i.v.) and olanzapine (ED50 = 1000 micrograms/kg i.v.). Pretreatment with the 5-HT1A antagonist WAY-100,635 (10 micrograms/kg i.v.) prevented the ziprasidone-induced inhibition; the same dose of WAY-100,635 had little effect on the inhibition produced by clozapine and olanzapine. Because all three agents also bind to alpha 1 receptors, antagonists of which inhibit serotonin neuronal firing, 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 i.v.) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine. These profiles suggest a mechanism of action for each agent, 5-HT1A agonism for ziprasidone and alpha 1 antagonism for clozapine and olanzapine. The 5-HT1A agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions.
entities.id: T10 T11 T12 T13 T14 T15 T16 T17 T18 T19 T1 T20 T21 T22 T23 T24 T25 T26 T27 T28 T29 T2 T30 T31 T32 T33 T34 T35 T36 T37 T38 T39 T3 T40 T41 T4 T5 T6 T7 T8 T9
entities.type: CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL GENE-N CHEMICAL GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-N GENE-Y GENE-Y GENE-Y CHEMICAL GENE-Y GENE-Y CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL
entities.text: ziprasidone clozapine olanzapine ziprasidone ziprasidone adenylate ziprasidone serotonin ziprasidone clozapine Ziprasidone olanzapine WAY-100,635 ziprasidone WAY-100,635 clozapine olanzapine ziprasidone clozapine olanzapine alpha 1 receptors serotonin 5-HT1D 5-HT2 D2 5-HT1A 5-HT1A 5-HT1A adenylate cyclase 5-HT1A 5-HT1A 5-HT1A desipramine 5-HT1A receptors 5-HT1A receptor DMI NE DMI ziprasidone clozapine olanzapine