Neurotensin

Neurotensin (NT) is a 13-amino acid neuropeptide (Glu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu) originally isolated from bovine hypothalamus by Carraway and Leeman in 1973. It is distributed throughout the central nervous system (hypothalamus, limbic system, striatum, spinal cord) and the gastrointestinal tract (ileum L-cells, submucous neurons).

**Dopamine system interaction — the "endogenous antipsychotic" concept:** Neurotensin co-localizes and co-released with dopamine in mesolimbic neurons. NTS1 activation on dopaminergic neurons reduces their firing rate and dopamine release. This led to the hypothesis that NT is an endogenous modulator of psychotic symptoms — lower NT activity in CSF has been reported in schizophrenia, particularly in dopamine-hyperactive states.

Non-peptide NTS1 agonists have been shown to produce antipsychotic-like effects (reduced amphetamine-induced locomotion, conditioned avoidance responding) in rodent models WITHOUT the extrapyramidal motor side effects of D2 blockers, making NTS1 an attractive target for next-generation antipsychotic development.

**Pain modulation:** Intrathecal NT activates descending pain inhibitory pathways via NTS1 on dorsal horn neurons, producing analgesia comparable to low-dose morphine in some models. Synergy with opioid analgesia has been demonstrated.

**GI and metabolic effects:** NT is secreted by ileal L-cells after fat ingestion (particularly long-chain fatty acids). It slows intestinal transit, modulates gastric acid secretion, and stimulates colonic motility — coordinating the GI response to nutrient absorption. NT also reduces food intake via hypothalamic NTS1, contributing to the satiety response.