Comparison of Neurotensin Responses to MDL 100,907, a Selective 5HT 2A Antagonist, with Clozapine and Haloperidol

Abstract

The unique pharmacological profile of atypical antipsychotics, such as clozapine, suggests that action on nondopaminergic transmitter systems 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 peptide's putative association with psychiatric disorders. The effects of treatments by haloperidol, clozapine, and MDL 100,907 (a selective 5HT 2A antagonist thought to have antipsychotic activity) on NT pathways were determined in various extrapyramidal and limbic regions and compared. The response of neurotensin systems was determined by measuring neurotensin-like immunoreactivity after 1, 2, 4, and 5 drug administrations. It was observed that tissue content of this peptide in caudate and nucleus accumbens regions tended to be elevated after 1 or 2 drug administrations, but had either returned or was returning to control levels after 4 or 5 drug administrations. In general, the extrapyramidal and limbic neurotensin levels responded in a similar manner to clozapine and the 5HT 2A antagonist, but differently for haloperidol in most regions examined. An important exception was in the nucleus accumbens, where all three drugs had similar effects on neurotensin tissue levels. These results suggest that 5HT 2A receptors exert basal control over some extrapyramidal and limbic neurotensin systems and this interaction might contribute to the antipsychotic effects of these drugs.