Inhibition of dopaminergic agonist-induced gnawing behavior by neuroleptic drugs in mice

Several neuroleptic drugs cause the Parkinsonian syndrome (PS) in humans; however, this effect is not detectable in rodents. PS-inducing drugs inhibit gnawing or biting behavior induced by apomorphine, amphetamine, DOPA, and thozalinone. The effects of five narcoleptic drugs (chlorpromazine, haloperidol, perphenazine, thioridazine, and trifluoperazine) on this behavior were tested in ICR male mice (10 per dose level). The drugs were given ip 30 min before each of the following inducing agents: DL-DOPA (500 mg/kg, iv), apomorphine (100 mg/kg, ip), amphetamine (12.5 mg/kg, ip), and thozalinone (100 mg/kg, ip). The criterion for blocking effectiveness was the prevention of the biting or gnawing behavior. Prevention indexes (PI) were calculated from the LD50/ED50. Data are consistent with the PS-inducing potencies of these five drugs. Another selective index (SI) of each drug was established by the ED50/ND50 ratio. There is some correlation between PI values and clinical symptoms, but it is not as well defined as that between SI values and clinical symptoms. Data from the thozalinone test (SI) appear to provide the best prediction for the PS-inducing potencies of the drugs tested. Thus, this technique appears to be suitable for use as an animal model in preclinical toxicity studies.