COMPARISON OF NEUROTENSIN RESPONSES TO MDL-100,907, A SELECTIVE 5HT(2A) ANTAGONIST, WITH CLOZAPINE AND HALOPERIDOL

The unique pharmacological profile of atypical antipsychotics, such as clozapine, suggests that action on nondopaminergic transmitter system s might contribute to the unique therapeutic benefits of these drugs. In order to test this possibility, the response of neurotensin systems to drugs with antipsychotic potential was examined because of this pe ptide's putative association with psychiatric disorders. The effects o f treatments by haloperidol, clozapine, and MDL 100,907 (a selective 5 HT(2A) antagonist thought to have antipsychotic activity) on NT pathwa ys were determined in various extrapyramidal and limbic regions and co mpared. The response of neurotensin systems was determined by measurin g neurotensin-like immunoreactivity after 1, 2, 4, and 5 drug administ rations, it was observed that tissue content of this peptide in caudat e and nucleus accumbens regions tended to be elevated after 1 or 2 dru g administrations, but had either returned or was returning to control levels after 4 or 5 drug administrations. In general, the extrapyrami dal and limbic neurotensin levels responded in a similar manner to clo zapine and the 5HT, antagonist, but differently for halaperidol in mos t regions examined. An important exception was in the nucleus accumben s, where all three drugs had similar effects on neurotensin tissue lev els, These results suggest that 5HT, receptors exert basal control ove r some extrapyramidal and limbic neurotensin systems and this interact ion might contribute to the antipsychotic effects of these drugs. Copy right (C) 1997 Elsevier Science Inc.