CHARACTERIZATION OF THE 5-HT(2) RECEPTOR ANTAGONIST MDL 100907 AS A PUTATIVE ATYPICAL ANTIPSYCHOTIC - BEHAVIORAL, ELECTROPHYSIOLOGICAL AND NEUROCHEMICAL STUDIES

Progress toward understanding the role of the 5-hydroxytryptamine (5-H T)2 receptor in the therapy for schizophrenia has been hampered by the lack of highly selective antagonists. We now report on the effects of MDL 100,907 -[2-(4-fluorophenylethyl)]-4-piperidine-methanol], a high ly selective and potent 5-HT2 receptor antagonist, in behavioral, elec trophysiological and neurochemical models of antipsychotic activity an d extrapyramidal side-effect liability. In mice, MDL 100,907 blocked a mphetamine-stimulated locomotion at doses that did not significantly a ffect apomorphine-stimulated climbing behavior. Neither MDL 100,907 no r clozapine reduced apomorphine-induced stereotypies or produced catal epsy in rats. MDL 100,907 blocked the slowing of ventral tegmental are a (Al 0) dopaminergic neurons by amphetamine but, like clozapine, prod uced only small increases in the number of active substantia nigra zon a compacta (A9) and Al 0 dopamine neurons after acute administration. When administered chronically, MDL 100,907 and clozapine selectively r educed the number of spontaneously active Al 0 neurons, whereas halope ridol reduced activity in both the A9 and A10 regions. Consistent with their acute effect on A9 and A10 activity, neither MDL 100,907 nor cl ozapine increased dopamine metabolism in the striatum or nucleus accum bens, whereas acute haloperidol accelerated dopamine turnover in both regions. The administration of the dopamine uptake blocker amfonelic a cid with haloperidol produced a massive increase in DA metabolism char acteristic of typical antipsychotics. In contrast, MDL 100,907 and clo zapine were without effect on dopamine turnover when given in the pres ence of amfonelic acid. These data indicate that MDL 100,907 has a clo zapine-like profile of potential antipsychotic activity with low extra pyramidal side-effect liability. The receptor selectivity of MDL 100,9 07 and the proposed regulation of dopaminergic function by 5-HT2 recep tors support the conclusion that further clinical evaluation of select ive 5-HT2 antagonists as antipsychotic agents is warranted.