Actions of neurotensin: a review of the electrophysiological studies

Three effects of NT were observed on midbrain DA cells. The modulatory effect of NT, that is, the attenuation of DA-induced inhibition, has been most extensively examined. Studies indicate that this effect of NT was not simply due to a nonspecific excitation. NT selectively attenuated DA-induced inhibition without affecting either GABA-induced inhibition or glutamate-induced excitation of the same cells, and the attenuation of DA-induced inhibition could be observed at the doses at which the basal activity of DA cells was not changed by NT. The attenuation of DA-induced inhibition by NT is also unlikely to result from the formation of a DA-NT complex, since neuromedin N, which competes with NT for the same receptor but does not bind to DA, mimicked the effects, and neurotensin(1-11), which forms a complex with DA but is inactive in competing for NT receptors, did not. The similarities between the effects of NT and those of 8-bromo-cAMP and forskolin suggest that intracellular cAMP and protein kinase A may be involved. This suggestion was supported by the findings that IBMX (an inhibitor of phosphodiesterases) potentiated the effect of NT; and SQ22536 (an inhibitor of adenylate cyclase) and H8 (an inhibitor of protein kinase A) antagonized it. Phorbal-12,13-dibutyrate (an activator of protein kinase C) did not mimic the effect of neurotensin, and H7 (an inhibitor of protein kinase C) did not reduce the effect, suggesting that protein kinase C is unlikely to be involved in the modulatory effect of neurotensin. Experiments in vitro indicated that the excitatory effect of NT on DA cells occurred at higher concentrations (> 10 nM) than those needed for producing the modulatory effect. Its persistence during DA receptor blockade by sulpiride suggests that this effect was not entirely mediated by an attenuation of the inhibition induced by endogenously released DA. At even higher concentrations (> 100 nM), a sudden cessation of cell activity preceded by an increase in firing rate was observed. Whether this effect of NT was due to depolarization inactivation or a toxic effect of the peptide at high concentrations remains to be determined. In most other areas studied, the excitatory effect of NT was most commonly observed. In many areas, this excitatory effect was apparently a direct postsynaptic effect of NT. However, different mechanisms may be involved (see Table 1). For example, in some areas NT acted through a decrease in membrane conductance, while in others no change or an increase in the membrane conductance was observed.(ABSTRACT TRUNCATED AT 400 WORDS)