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

In order to better define the role of 5-HT1A receptors in the modulation of extrapyramidal motor functions, we investigated the effect of 5-HT1A agonists on tacrine-induced tremulous jaw movements (TJM) in rats, a putative model of parkinsonian tremor. Acute injection of 5-HT1A agonists 8-OH-DPAT and buspirone dose-dependently counteracted the tacrine-induced oral movements (ED50 = 0.04 and 1.0 mg/kg, respectively), an effect reversed by the selective 5-HT1A antagonist WAY 100,635. In contrast to classical antipsychotics, the atypical antipsychotics risperidone (ED50 = 0.3 mg/kg) and clozapine (ED50 = 1.5 mg/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 D2-antagonist and 5-HT1A-partial agonist, also displayed a potent antitremorgenic effect in this paradigm (ED50 = 0.5 mg/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-HT1A 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-HT1A 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.