REVERSAL OF AMPHETAMINE-INDUCED BEHAVIORS BY MDL-100,907, A SELECTIVE5-HT2A ANTAGONIST

MDL 100,907 is a potent and selective antagonist of the 5-HT2A recepto r which, unlike other antagonists at this receptor, has little affinit y for the 5-HT2C receptor. We have investigated the antipsychotic pote ntial of MDL 100,907 by examining its ability to antagonise different behavioural effects of amphetamine in rats. MDL 100,907 reversed the l ocomotor stimulant effects of amphetamine in rats without itself havin g any effect on locomotor activity. It also antagonised the disruptive effects of amphetamine on the development of latent inhibition. In co ntrast, MDL 100,907 had no effect on the discriminative stimulus prope rties of amphetamine, nor did it affect the ability of amphetamine to reduce the threshold required to sustain rewarding brain stimulation i n the ventral tegmental area. This profile is different from that of t ypical and atypical neuroleptics, and also from other 5-HT2 receptor a ntagonists, which lack the selectivity of MDL 100,907. These results s uggest that MDL 100,907 may have a unique interaction with dopaminergi c systems and support the further development of selective 5-HT2 recep tor antagonists as a novel therapeutic strategy for schizophrenia.