Does neurotensin mediate the effects of antipsychotic drugs?

The possibility that the neuropeptide neurotensin (NT) may function as an e ndogenous antipsychotic compound was first hypothesized almost two decades ago. Since that time, considerable effort has been directed towards determi ning whether NT neurons mediate the effects of antipsychotic drugs (APDs). The anatomic, biochemical, behavioral, and clinical relevance of this hypot hesis is reviewed. Although the majority of the available evidence is indir ect the availability of several NT receptor (NTR) antagonists have now made possible the direct examination of the involvement of the NT system in the mechanism of action of APDs. Preliminary studies in our laboratory demonst rate the ability of a selective NTR antagonist to block the effects of APDs in two models of sensory motor gating deficits characteristic of schizophr enia. These data, taken together with a compelling series of studies demons trating that increases of NT/neuromedin N mRNA expression and NT content in the nucleus accumbens and striatum after chronic administration of APDs ar e predictive of clinical efficacy and extrapyramidal side effects, respecti vely, provide direct preclinical evidence for a role of the NT system in th e clinical efficacy of APDs. Although effects of selective NTR antagonists in normal volunteers or schizophrenic patients have not been studied, and n onpeptidergic NTR agonists have not yet been identified, these cumulative r esults provide the groundwork for the use of NT-ergic compounds in the trea tment of schizophrenia. Biol Psychiatry 1999;46:340-351 (C) 1999 Society of Biological Psychiatry.