Stimulation by neurotensin of dopamine and 5-hydroxytryptamine (5-HT) release from rat prefrontal cortex: possible role of NTR1 receptors in neuropsychiatric disorders.

The modulation of cortical dopaminergic and serotonergic neurotransmissions by neurotensin (NT) was studied by measuring the release of dopamine (DA) and 5-hydroxytryptamine (5-HT) from the prefrontal cortex (PFC) of freely moving rats. The samples were collected via transversal microdialysis. Dopamine and 5-HT levels in the dialysate were measured using high-performance liquid chromatography (HPLC) with an electrochemical detector. Local administration of neurotensin (1microM or 0.1microM) in the PFC via the dialysis probe produced significant, long-lasting, and concentration-dependent increase in the extracellular release of DA and 5-HT. The increase produced by 1microM neurotensin reached a maximum of about 210% for DA and 340% for 5-HT. A high-affinity selective neurotensin receptor (NTR1) antagonist {2-[(1-(7-chloro-4-quinolinyl)-5-(2,6-dimethoxyphenyl)pyrazol-3yl)carbonylamino tricyclo (3.3.1.1.(3.7)) decan-2-carboxylic acid} (SR 48692), perfused locally at a concentration of 0.1microM and 0.5microM in the PFC antagonized the effects of 1microM neurotensin. Our in vivo neurochemical results indicate, for the first time, that neurotensin is able to regulate cortical dopaminergic and serotonergic neuronal activity in freely moving rats. These effects are possibly mediated by interactions of neurotensin with neurons releasing DA or 5-HT, projecting to the PFC from the ventrotegmental area (VTA) and from the dorsal raphe nuclei (DRN), respectively. The potentiating effects of neurotensin on DA and 5-HT release in the PFC are regulated by NTR1 receptors, probably located on dopaminergic and serotonergic nerve terminals or axons.

Neurotensin modulation of acetylcholine, GABA, and aspartate release from rat prefrontal cortex studied in vivo with microdialysis.

The effects of the peptide transmitter neurotensin (NT) on the release of acetylcholine (ACh), gamma-aminobutyric acid (GABA), glutamate (Glu), aspartate (Asp), and taurine from the prefrontal cortex (PFC) of freely moving rats were studied by transversal microdialysis. Neurotensin (0.2 and 1 microM) administered locally in the PFC produced a concentration-dependent increase in the extracellular levels of ACh, GABA, and Asp, but not of Glu or taurine. The increase produced by 1 microM NT reached a maximum of about 240% for ACh, 370% for GABA, and 380% for Asp. Lower doses of NT (0.05 microM) did not cause a significant change in ACh, GABA, or Asp output in the PFC. Higher concentrations of NT (2 microM) did not induce further increases in the level of neurotransmitters. A high-affinity selective neurotensin receptor (NTR1) antagonist SR 48692 (0.5 microM) perfused locally blocked neurotensin (1 microM)-evoked ACh, GABA, and Asp release. Local infusion of the sodium channel blocker tetrodotoxin (TTX) (1 microM) decreased the release of ACh, had no significant effect on GABA or Asp release, and prevented the 1 microM neurotensin-induced increase in ACh, GABA, and Asp output. Removal of calcium from the Ringer's solution prevented the peptide from having any effects on the neurotransmitters. Thus, in vivo NT plays a modulatory role in the PFC by interacting with cortical neurons releasing GABA and Asp and with ACh-containing neurons projecting to the PFC. The NT effects are of neural origin, as they are TTX-sensitive, and mediated by the NTR1 receptor, as they are antagonized by SR 48692.