Suitability of amfonelic acid-induced locomotor stimulation in mice as a model for the evaluation of classical and atypical antipsychotics.
The potential usefulness of amfonelic acid ( AFA ), a selective dopamine (DA)-releasing agent, in quantitatively assessing the antidopaminergic and antipsychotic potencies of drugs, was evaluated. The procedure consisted of determining the ED50S of a number of neuroleptics in inhibiting the locomotor-stimulant effect of amfonelic acid in mice. These results were compared with the published data on the relative potencies of the neuroleptics to induce catalepsy in rats, to block drug-induced stereotypy and to alleviate psychotic symptoms clinically. It was observed that the amfonelic acid model was as good as, but not superior to, the other three procedures in identifying the potencies of classical antipsychotics. This model, however, was able to predict the clinical effectiveness of two atypical antipsychotics, thioridazine and clozapine, much more accurately than could be achieved by the other methods. Certain other atypical antipsychotics such as, mezilamine , RMI 81, 582, sulpiride and sultopride also produced a dose-related blockade of the amfonelic acid induced locomotor stimulation in mice. The antagonism to amfonelic acid exhibited by mezilamine was weaker, and that of RMI 81,582 was stronger than that of chlorpromazine. Only large doses of the two benzamides were effective in blocking the effect of amfonelic acid, sultopride being about 3 times more effective than sulpiride in this regard. Another analogue of benzamide, YM-09151-2, known to have the profile of a classical antipsychotic, was more effective than haloperidol in blocking the stimulant effect of amfonelic acid. Trebenzomine , which is considered to have the properties of an atypical antipsychotic, although this was proved otherwise when tested clinically, actually potentiated the response of mice to amfonelic acid. Apomorphine antagonized the stimulant effect of amfonelic acid, which could be attributed to its agonist activity at presynaptic DA receptors. Apomorphine has been reported to have clinical antipsychotic effects. Certain non-antipsychotic drugs such as prazosin (but not phenoxybenzamine), promethazine, methysergide, diazepam, as well as the gamm -aminobutyric acid agonists, muscimol and THIP, also inhibited the amfonelic acid-induced locomotor stimulation. In spite of this drawback, the present procedure should prove to be a useful animal model for the evaluation of the antipsychotic potencies of drugs. Its ability to identify the potential usefulness of atypical antipsychotics is noteworthy.
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008954:Models, Biological; D009043:Motor Activity / Q000187:drug effects*; D009268:Nalidixic Acid / Q000031:analogs & derivatives; D009287:Naphthyridines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011224:Prazosin / Q000494:pharmacology
D014150:Antipsychotic Agents; D001549:Benzamides; D009287:Naphthyridines; D009268:Nalidixic Acid; C030265:nemonapride; C006486:amfonelic acid; D011224:Prazosin