Neurotensin is a tridecapeptide with anatomic and functional relationships to dopaminergic neurons. Previously we showed that one of our brain-penetrating neurotensin analogs, NT69L (N-met-L-Arg, L-Lys, L-Pro, L-neo-Trp, L-tert-Leu, L-Leu), blocks cocaine- and D-amphetamine-induced hyperactivity in rats. We have now performed a similar study in rats sensitized to nicotine over 15 days of administration. Male Sprague-Dawley rats were randomly assigned to receive daily injections for 15 days with one of the following combinations: saline/nicotine (0.35 mg/kg), NT69L (1 mg/kg)/nicotine, saline/saline, or NT69L/saline with a 30-min period between injections. On day 15 each group was given saline/nicotine or NT69L/nicotine and tested in an activity chamber. One-time administration of NT69L attenuated nicotine-induced activity with an ED50 of 1.6 μg/kg. Rats injected with nicotine over the 15 days had a significant increase in locomotor activity, consistent with nicotine-induced locomotor sensitization. A single injection of NT69L on day 15 prior to nicotine markedly decreased nicotine-induced hyperactivity. Although daily injections of NT69L lessened its effect, statistically significant reductions in hyperactivity to nicotine persisted throughout the study. There was no significant difference in activity between rats injected with NT69L/saline and saline/saline. Thus, the activity reduction was not due to sedation. Acute and chronic nicotine injection caused an increase in cytisine binding in prefrontal cortex. NT69L significantly reduced the increase caused by acute but not chronic injection of nicotine. Nicotine injection resulted in an increase in dopamine levels in the striatum and dopamine and norepinephrine levels in the prefrontal cortex. NT69L lowered the norepinephrine and dopamine levels in the prefrontal cortex but did not affect striatal dopamine. The present study is the first report, to our knowledge, of a possible role for neurotensin in the development of nicotine dependence, and suggests that neurotensin analogs such as NT69L may be explored as treatment for nicotine and other psychostimulant abuse.
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