Effects of neurotensin on midbrain dopamine neurons: are they mediated by formation of a neurotensin-dopamine complex?

The effects of neurotensin on midbrain dopamine neuron activity were studied in brain slices using single-unit recording techniques. At low concentrations (0.2-10 nM), neurotensin attenuated dopamine-induced inhibition without a significant effect on the basal firing rate. At higher concentrations (greater than 10 nM), however, it consistently caused an increase in cell activity. At even higher concentrations (greater than 100 nM), a sudden cessation of cell activity preceded by an increase in firing rate was observed. Whether this effect of neurotensin was due to depolarization inactivation or to a toxic effect of the peptide at high concentrations remains to be determined. To determine whether the effects of neurotensin were mediated by formation of a neurotensin-dopamine complex, several neurotensin analogues were studied. Neurotensin (8-13), which binds to both neurotensin receptors and dopamine, mimicked the effects of native neurotensin. Neuromedin N, which competes with neurotensin for the same receptor but does not bind to dopamine, also mimicked the effects. However, neurotensin (1-11), which forms a complex with dopamine but is inactive in competing for neurotensin receptors, was ineffective. In addition, the excitatory effect of neurotensin was not attenuated in the presence of dopamine receptor blockade by sulpiride. These results suggest that formation of a neurotensin-dopamine complex may not account for the action of neurotensin on dopamine cells. When combined with the fact that there is a high density of neurotensin receptors on dopamine cells, our results support the suggestion that the observed effects of neurotensin on dopamine neurons are most likely mediated by an activation of neurotensin receptors.