title: In vitro and in vivo characterization of F-97013-GD, a partial 5-HT1A agonist with antipsychotic- and antiparkinsonian-like properties.
abstract: 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.
authors.affiliation: Department of Research, FAES FARMA, S.A., Máximo Aguirre 14, 48940 Leioa, Vizcaya, Spain.
authors.forename: Arturo
authors.initials: A
authors.lastname: Zazpe
authors.forename: Inés
authors.initials: I
authors.lastname: Artaiz
authors.forename: Ana
authors.initials: A
authors.lastname: Innerárity
authors.forename: Elena
authors.initials: E
authors.lastname: Del Olmo
authors.forename: Elena
authors.initials: E
authors.lastname: Castro
authors.forename: Luis
authors.initials: L
authors.lastname: Labeaga
authors.forename: Angel
authors.initials: A
authors.lastname: Pazos
authors.forename: Aurelio
authors.initials: A
authors.lastname: Orjales
mesh_terms: D006916:5-Hydroxytryptophan / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001058:Apomorphine / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced; D018491:Dopamine Agonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004347:Drug Interactions; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006220:Haloperidol / Q000037:antagonists & inhibitors; D019416:Head Movements / Q000187:drug effects; D007035:Hypothermia / Q000139:chemically induced / Q000503:physiopathology; D007568:Jaw / Q000502:physiology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*; D011725:Pyridines / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects*; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D012702:Serotonin Antagonists / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D014202:Tremor / Q000503:physiopathology
chemical_list: C513228:6-methyl-2-(4-(naphthylpiperazin-1-yl)butyl)-3-(2H)-pyridazinone; D000978:Antiparkinson Agents; D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D065127:Dopamine D2 Receptor Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins; D010879:Piperazines; D011724:Pyridazines; D011725:Pyridines; D017448:Receptors, Dopamine D2; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D006916:5-Hydroxytryptophan; D006220:Haloperidol; D001058:Apomorphine