Neurotensin: perchance an endogenous neuroleptic?
Nemeroff, C.B.
Biological Psychiatry 15(2): 283-302
1980
ISSN/ISBN: 0006-3223 PMID: 6106513 Document Number: 155671
Neurotensin (NT), an endogenous tridecapeptide, is distributed heterogeneously in rat brain, localized preferentially in the synaptosomal fraction after density gradient centrifugation and binds to brain membranes reversibly, saturably and with high affinity. These characteristics along with the demonstration of a Ca2+-dependent release of this neuropeptide from brain slices suggest that this substance is a neuromodulator. Properties of NT were compared with neuroleptic agents since preliminary studies suggested similarities between the peptide and antipsychotic drugs, and NT is localized in high concentration in the nucleus accumbens, a major site of termination of the mesolimbic dopamine (DA) system, a circuit implicated in the pathogenesis of schizophrenia. Like neuroleptics, NT injected intracisternally (IC) or intracerebroventricularly (but not peripherally) produces: potentiation of barbiturate sedation; hypothermia; diminished locomotor activity; and muscle relaxation. Treatments which reduce the functional activity of DA circuits (6-hydroxydopamine-induced DA depletion or haloperidol pretreatment) augment NT-induced hypothermia. Bilateral nucleus accumbens injections of NT, like haloperidol, significantly antagonized increased locomotor activity and rearing induced by d-amphetamine (2 mg/kg i.p.). The hypothermia and muscle relaxation induced by NT and neuroleptics is antagonized by IC injection of thyrotropin-releasing hormone, the endogenous tripeptide. Unlike neuroleptic drugs, NT did not inhibit the binding of 3H-spiroperidol to the DA receptors in either the nucleus caudatus or the nucleus accumbens. NT was a potent antinociceptive agent. It was more potent on a molar basis than met-enkephalin, leu-enkephalin and morphine but less potent than .beta.-endorphin. The hypothesis that NT is a neuromodulator was supported. It is a neuropeptide which shares many but not all properties with neuroleptic agents. Its role in normal and abnormal behavioral and neurological disease states remains undetermined.