Comparison of the Novel Antipsychotic Ziprasidone with Clozapine and Olanzapine Inhibition of Dorsal Raphe Cell Firing and the Role of 5-HT1A Receptor Activation
| Autor: | Stevin H. Zorn, Linda Reynolds, Hans Rollema, Jeffrey Sprouse, John Braselton |
|---|---|
| Rok vydání: | 1999 |
| Předmět: |
Male
Agonist Pyridines medicine.drug_class Action Potentials Pharmacology Piperazines Rats Sprague-Dawley Benzodiazepines Dorsal raphe nucleus medicine Animals Ziprasidone Clozapine 5-HT receptor Neurons Adrenergic Uptake Inhibitors Dose-Response Relationship Drug Raphe Chemistry Desipramine Pirenzepine Rats Serotonin Receptor Agonists Thiazoles Psychiatry and Mental health nervous system Olanzapine Receptors Serotonin Raphe Nuclei 5-HT1A receptor Serotonin Antagonists Raphe nuclei Receptors Serotonin 5-HT1 Selective Serotonin Reuptake Inhibitors medicine.drug |
| Zdroj: | Neuropsychopharmacology. 21:622-631 |
| ISSN: | 0893-133X |
| DOI: | 10.1016/s0893-133x(99)00057-3 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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