Further investigations of the interactions of antipsychotics with the (-)2,5-dimethoxy-4-methylamphetamine (DOM) discriminative stimulus.
David Fiorella, Scott Helsley, R A Rabin, Jerrold C Winter
Neuropharmacology October 1997 DOI: 10.1016/s0028-3908(97)00121-4 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study (drug discrimination) Peer reviewed |
|---|---|
| Population | Rats trained to discriminate (-)-DOM or clozapine |
| Interventions | (-)-2 5-dimethoxy-4-methylamphetamine (DOM) SCH 23390 sulpiride amperozide melperone octoclothepin tiospirone ritanserin clozapine risperidone |
| Key points | Complete or partial antagonism of (-)-DOM-induced stimulus control appears to identify antipsychotics with significant 5-HT2A antagonist properties: tiospirone and ritanserin produced complete antagonism, amperozide, melperone, and octoclothepin produced intermediate antagonism, and SCH 23390 and sulpiride produced none. Risperidone did not substitute for clozapine in clozapine-trained rats, which the authors argue indicates that clozapine and risperidone differ in their stimulus effects despite shared 5-HT2A antagonism. |
Abstract
Stimulus control induced by (-)-2,5-dimethoxy-4-methylamphetamine (DOM) is believed to be mediated by agonism at 5-HT2A receptors. We hypothesized that blockade of (-) DOM-induced stimulus control may thus prove useful in the pre-clinical characterization of novel antipsychotic agents by providing an in vivo index of antagonism at that receptor. A previous study (Fiorella et al., 1995a) observed no antagonism by typical agents such as haloperidol and thioridazine, partial antagonism by the atypical agent, clozapine, and full antagonism by risperidone, a second atypical antipsychotic. The present investigation extends these observations to include seven additional drugs: SCH 23390, sulpiride, amperozide, melperone, octoclothepin, tiospirone and ritanserin. Of the drugs tested in rats in which (-) DOM-induced stimulus control had reliably been established, only tiospirone and ritanserin produced complete antagonism of the (-) DOM stimulus. Intermediate levels of antagonism were observed following treatment with amperozide, melperone, and octoclothepin. Finally, SCH 23390 and sulpiride yielded no evidence of antagonistic activity in (-) DOM-trained animals. Because clozapine and risperidone are both classified as atypical antipsychotics yet yield different degrees of antagonism of (-) DOM-induced stimulus control, we tested the substitution of risperidone for clozapine in rats trained with clozapine as a discriminative stimulus. No significant substitution was observed. In conclusion it appears that complete or partial antagonism of the (-) DOM stimulus serves as an effective pre-clinical means of identifying antipsychotics with significant 5-HT2A antagonist properties. However, the failure of risperidone to substitute for clozapine in pigeons (Hoenicke et al., 1992) and in rats (present study) suggests that despite their shared 5-HT2A antagonist properties, clozapine and risperidone differ with respect to their stimulus effects.