In vitro and in vivo characterization of F-97013-GD, a partial 5-HT1A agonist with antipsychotic- and antiparkinsonian-like properties

• Published in: Neuropharmacology 2006-07, Vol.51 (1), p.129-140
• Main Authors: Zazpe, Arturo, Artaiz, Inés, Innerárity, Ana, Del Olmo, Elena, Castro, Elena, Labeaga, Luis, Pazos, Angel, Orjales, Aurelio
• Format: Article
• Language: English
• Subjects: 5-Hydroxytryptophan - pharmacology; Animals; Antiparkinson Agents - pharmacology; Antipsychotic Agents - pharmacology; Apomorphine - pharmacology; Avoidance Learning - drug effects; Binding, Competitive - drug effects; Catalepsy - chemically induced; Dopamine Agonists - pharmacology; Dopamine D2 Receptor Antagonists; Dopamine Plasma Membrane Transport Proteins - metabolism; Drug Interactions; Guanosine 5'-O-(3-Thiotriphosphate) - metabolism; Haloperidol - antagonists & inhibitors; Head Movements - drug effects; Hypothermia - chemically induced; Hypothermia - physiopathology; Jaw - physiology; Male; Mice; Motor Activity - drug effects; Piperazines - metabolism; Piperazines - pharmacology; Pyridazines - pharmacology; Pyridines - metabolism; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT1A - drug effects; Receptors, Dopamine D2 - metabolism; Serotonin Antagonists - metabolism; Serotonin Receptor Agonists - pharmacology; Tremor - physiopathology
• ISSN: 0028-3908
• DOI: 10.1016/j.neuropharm.2006.03.008

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.