Effect of neurotensin and immunneutralization with anti-neurotensin-serum on dopaminergic-cholinergic interaction in the striatum.

The effect of neurotensin (NT) on the release of acetylcholine (ACh) and dopamine (DA) from striatal slices of the rat brain was studied. Neurotensin, 1-150 nM, was able to release ACh from cholinergic interneurons of the striatum. Like the response to electrical stimulation, the ACh-releasing effect of NT was completely inhibited by tetrodotoxin indicating that neuronal firing is involved in its effect. Immunneutralization reduced the stimulation-evoked release of ACh, an effect that was much marked when the inhibitory dopaminergic input was suspended by sulpiride-selective antagonists of D2 receptors. Sulpiride, 0.1 mM, induced a 2-fold increase in the NT- and electrically-induced release of ACh. A quantitatively similar increase was also observed after degeneration of the nigrostriatal DA pathway with 6-hydroxydopamine (6-OHDA) (2 x 250 micrograms/animal, i.c.v.). However, the D2 receptor agonist quinpirole, 0.01 mM, significantly reduced the NT-induced release of ACh by 77%. Neurotensin enhanced the stimulation-evoked release of [3H]DA. These findings indicate that, using field stimulation when dopaminergic, cholinergic and NT-containing neurons are stimulated in concert, NT is capable of releasing both ACh and DA in the striatum, but its effect on ACh release is masked unless the D2 receptor-mediated tonic inhibitory effect of DA released from the nigro-striatal pathway is attenuated. Thus, in Parkinson's disease where the dopaminergic input is impaired, NT may be involved in producing cholinergic dominance.