Structure-activity studies of neurotensin on muscular rigidity and tremors induced by 6-hydroxydopamine lesions in the posterolateral hypothalamus of the rat.

It has previously been reported that intracerebroventricular administration of neurotensin (30 micrograms) reduced muscular rigidity and tremors, induced by a neurochemical lesion with 6-hydroxydopamine in the posterolateral hypothalamus of rats. In the present study, the effects of two fragments (NT1-10 and NT8-13) and two analogues ([D-Tyr11]-NT and [Ala11]-NT) of neurotensin on the grasping time (index of muscle rigidity) and tremors in 6-hydroxydopamine-lesioned rats are reported. Intracerebroventricular administration with 120 micrograms of NT1-10 and [Ala11]-NT had no effect on the muscle rigidity and tremors induced by the neurochemical lesion. The administration of NT8-13 60 micrograms) significantly attenuated both behavioural responses. The analogue [D-Tyr11]-NT produced a much greater attenuation of the muscle rigidity and tremors. The dose of 1.8 micrograms of [D-Tyr11]-NT significantly reduced the grasping time, while the number of tremors was attenuated with the threshold dose of 0.9 micrograms. Together, these results suggest that the effects of neurotensin on muscle rigidity and tremors, induced by pretreatment with 6-hydroxydopamine injected into the posterolateral hypothalamus, were not caused by non-specific effects but largely depended on the carboxy terminal of the peptide. The tyrosine residue in position 11 of the molecule plays a critical role in the action of neurotensin, as shown with the high potency and duration of action of the analogue [D-Tyr11]-NT. As previously suggested, the greater effect with [D-Tyr11]-NT may be due to greater resistance of the analogue to enzymatic degradation because of the incorporation of the D-Tyr amino acid, in position 11 of neurotensin.