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: Arturo Zazpe, Inés Artaiz, Ana Innerárity, Elena Del Olmo, Elena Castro, Luis Labeaga, Angel Pazos, Aurelio Orjales
• Journal: Neuropharmacology (Neuropharmacology) Vol. 51 Issue 1 Pg. 129-40 (Jul 2006) ISSN: 0028-3908 [Print] England
• PMID: 16643965 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 6-methyl-2-(4-(naphthylpiperazin-1-yl)butyl)-3-(2H)-pyridazinone
• Antiparkinson Agents
• Antipsychotic Agents
• Dopamine Agonists
• Dopamine D2 Receptor Antagonists
• Dopamine Plasma Membrane Transport Proteins
• Piperazines
• Pyridazines
• Pyridines
• Receptors, Dopamine D2
• Serotonin Antagonists
• Serotonin Receptor Agonists
• Receptor, Serotonin, 5-HT1A
• Guanosine 5'-O-(3-Thiotriphosphate)
• N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
• 5-Hydroxytryptophan
• Haloperidol
• Apomorphine

Topics

• 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, physiopathology)
• Jaw (physiology)
• Male
• Mice
• Motor Activity (drug effects)
• Piperazines (metabolism, 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)