In vitro and in vivo characterization of F-97013-GD, a partial 5-HT1A agonist with antipsychotic- and antiparkinsonian-like properties
| Autor: | Ana Innerárity, Angel Pazos, Elena del Olmo, Luis Labeaga, Inés Artaiz, Aurelio Orjales, Arturo Zazpe, Elena Castro |
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| Rok vydání: | 2006 |
| Předmět: |
Male
Agonist Apomorphine Pyridines medicine.drug_class medicine.medical_treatment Hypothermia Motor Activity Pharmacology Catalepsy Binding Competitive Piperazines Buspirone 5-Hydroxytryptophan Antiparkinson Agents Mice Cellular and Molecular Neuroscience Dopamine Tremor Avoidance Learning medicine Animals Drug Interactions Rats Wistar Antipsychotic 5-HT receptor Clozapine Dopamine Plasma Membrane Transport Proteins Receptors Dopamine D2 Chemistry Antagonist medicine.disease Rats Serotonin Receptor Agonists Pyridazines Dopamine D2 Receptor Antagonists Jaw Guanosine 5'-O-(3-Thiotriphosphate) Head Movements Dopamine Agonists Receptor Serotonin 5-HT1A Haloperidol Serotonin Antagonists Antipsychotic Agents medicine.drug |
| Zdroj: | Neuropharmacology. 51:129-140 |
| ISSN: | 0028-3908 |
| Popis: | In order to better define the role of 5-HT(1A) receptors in the modulation of extrapyramidal motor functions, we investigated the effect of 5-HT(1A) agonists on tacrine-induced tremulous jaw movements (TJM) in rats, a putative model of parkinsonian tremor. Acute injection of 5-HT(1A) agonists 8-OH-DPAT and buspirone dose-dependently counteracted the tacrine-induced oral movements (ED(50)=0.04 and 1.0mg/kg, respectively), an effect reversed by the selective 5-HT(1A) antagonist WAY 100,635. In contrast to classical antipsychotics, the atypical antipsychotics risperidone (ED(50)=0.3mg/kg) and clozapine (ED(50)=1.5mg/kg) blocked the oral movements induced by the cholinomimetic agent at or below the doses required for suppression of conditioned avoidance response. The compound F-97013-GD (6-methyl-2-[4-(naphtylpiperazin-1-yl)butyl]-3-(2H)-pyridazinone), a putative antipsychotic drug that in functional in vitro and in vivo assays behaved as a mixed dopamine D(2)-antagonist and 5-HT(1A)-partial agonist, also displayed a potent antitremorgenic effect in this paradigm (ED(50)=0.5mg/kg). Interestingly, pretreatment with WAY 100,635 blocked the inhibitory effect of F-97013-GD but not that of clozapine. The 5-HT depleting agent para-chlorophenylalanine (PCPA) partially attenuated tacrine-induced TJM but did not block the suppressive effect of 5-HT(1A) agonists. In addition, only high doses of F-97013-GD induced catalepsy in rodents and, like 8-OH-DPAT and clozapine, the compound reversed the haloperidol-induced catalepsy in rats. These results show that 5-HT(1A) receptors play a role in the regulation of tacrine-induced TJM and suggest that their activation by novel antipsychotics may not only reduce the extrapyramidal side effects EPS liability, but also be effective in the treatment of parkinsonian tremor. |
| Databáze: | OpenAIRE |
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