Neurotensin, schizophrenia, and antipsychotic drug action

The search for the underlying pathophysiology of schizophrenia has been an active avenue of investigation since the disease was first recognized more than 100 years ago. Although a great deal of the research has been driven by the known pharmacology of effective antipsychotic drugs, i.e., overactivity of the dopamine system, recent advances in neurobiology provide evidence that reduced synaptic connectivity/neurotransmission may play a substantial role in this disorder. One neuropeptide long posited to play a role in the biology of schizophrenia is neurotensin (NT). Central nervous system administration of NT has been shown to produce a wide variety of effects. Because of its close association with the dopamine (DA) system, the role of the NT system in clinical disorders hypothesized to involve DA circuits such as schizophrenia, Parkinson's disease, and drug abuse has been closely scrutinized. In addition, NT neurotransmission has been implicated in regulation of the stress response, stress-induced gastric ulcers, temperature regulation, food consumption, and analgesia. NT also acts as a growth factor in a variety of human cancer cell lines derived from lung, colon, prostate, and pancreas. This review first provides a background of the NT system. Second, data indicating that NT may mediate the effects of antipsychotic drugs are summarized. Third, data implicating NT in the pathophysiology of schizophrenia are described. Finally, evidence suggesting the use of NTergic compounds as novel antipsychotic drugs are presented.