Neurotensin

NEUROTENSIN

Neurotensin (NT) is a tridecapeptide that was first isolated from the central nervous system but subsequently was found to be present in the gastrointestinal tract and in the circulation. It is synthe-sized as part of a larger precursor that also contains neuromedinN, a six-amino-acid NT-like peptide.

In the brain, processing of the precursor leads primarily to the formation of NT and neuromedin N; these are released together from nerve endings. In the gut, processing leads mainly to the formation of NT and a larger peptide that contains the neurome-din N sequence at the carboxyl terminal. Both peptides are secreted into the circulation after ingestion of food. Most of the activity of NT is mediated by the last six amino acids, NT(8-13).

Like many other neuropeptides, NT serves a dual function as a neurotransmitter or neuromodulator in the central nervous sys-tem and as a local hormone in the periphery. When administered centrally, NT exerts potent effects including hypothermia, anti-nociception, and modulation of dopamine and glutamate neu-rotransmission. When administered into the peripheral circulation, it causes vasodilation, hypotension, increased vascular permeabil-ity, increased secretion of several anterior pituitary hormones, hyperglycemia, inhibition of gastric acid and pepsin secretion, and inhibition of gastric motility. It also exerts effects on the immune system.

In the central nervous system, there are close associations between NT and dopamine systems, and NT may be involved in clinical disorders involving dopamine pathways such as schizophre-nia, Parkinson’s disease, and drug abuse. Consistent with this, it has been shown that central administration of NT produces effects in rodents similar to those produced by antipsychotic drugs. the NTR₃ receptor is a single transmembrane domain protein that belongs to a family of sorting proteins.

NT receptor agonists that cross the blood-brain barrier, all peptide analogs of NT(8-13), have been developed. Conversely, NT receptors can be blocked with the nonpeptide antagonists SR142948A and meclinertant (SR48692). SR142948A is a potent antagonist of the hypothermia and analgesia produced by centrally administered NT. It also blocks the cardiovascular effects of sys-temic NT. The development of drugs that selectively target or block NT receptors has resulted in potential therapeutic agents for the treatment of schizophrenia and Parkinson’s disease, as well as drug abuse.