Neurotensin-induced dopamine release in vivo and in vitro from substantia nigra and nucleus caudate

We compared the dopamine (DA) releasing effect of neurotensin (NT) from cell bodies (substantia nigra) and nerve terminals (nucleus caudate). In rats implanted with push-pull cannula, NT induced DA release from substantia nigra and nucleus caudate. NT was more potent in releasing DA from the substantia nigra than from the nucleus caudate (EC50%, 1.1 μM in substantia nigra and 9.8 μM in nucleus caudate). In vitro, in superfused rabbit brain slices, NT enhanced the depolarization-evoked release of DA and exerted a direct releasing effect. The latter was greater in the substantia nigra, and the former in the nucleus caudate. The direct releasing effect of NT was not inhibited, but enhanced by nomifensine (3 μM). Sulpiride, a D2 DA receptor antagonist, failed to modify NT-induced DA release; in addition, NT did not affect the inhibition of DA and acetylcholine release produced by LY-171555, a D2 DA agonist. In both the substantia nigra and the nucleus caudate, desensitization to the releasing effect of NT was observed, either after 2.5, 5, or 10 min of exposure to the peptide. A synergistic interaction on DA release was observed between NT and potassium (K+), and between NT and electrical stimulation. Greater synergism was observed with high extracellular K+. Pretreatment of striatal slices with 15 mM K+ produced a 9-fold enhancement of NT-induced DA release. When K+ (25 mM, 2 min) was given together with NT there was a 2- to 3-fold increase in DA release compared to the release evoked by K+ in the absence of NT. These results suggest that the modulatory effects of NT on DA neurons would be highly dependent on the concentrations of extracellular K+ in the microenvironment of the NT receptors. In addition, NT-induced DA release may be mediated by changes in K+ fluxes. It also appears that synergistic interactions would occur when depolarizing agents and drugs that mobilize intracellular calcium are administered. NT-induced increases in DA release are not due to an action on D2 DA presynaptic receptors or on the DA transporter, and NT does not interfere with the action of D2 DA agonists. Finally, desensitization to NT develops in both dopaminergic cell bodies and axon terminals.