Selective tolerance to the hypothermic and anticataleptic effects of a neurotensin analog that crosses the blood–brain barrier

Abstract

NT69L, a neurotensin analog that crosses the blood–brain barrier, reduces body temperature, reverses apomorphine-induced climbing, haloperidol-induced catalepsy, and d-amphetamine- and cocaine-induced locomotor activity in rats. In this study we tested the development of tolerance to these effects of NT69L in rats. The blockade of apomorphine-induced climbing behavior and d-amphetamine- and cocaine-induced hyperactivity seen after a single acute injection did not show significant change with repeated daily injections of NT69L. Thus, for example, NT69L after five daily injections at a fixed dosage was as effective at reversing cocaine-induced hyperactivity as after the first injection. On the other hand, repeated daily injections of NT69L resulted in a diminished hypothermic response and a diminished anticataleptic effect against haloperidol. The effect of NT69L on blood glucose, cortisol, and thyroxine (T 4) were all back to control levels after five daily injections. Thus, tolerance developed to NT69L after the first injection, when it was tested for causing hypothermia, blockade of haloperidol-induced catalepsy, and change in blood glucose, cortisol and T 4 levels. Since tolerance did not develop to the effects of drugs acting as direct (apomorphine) or indirect ( d-amphetamine and cocaine) agonists at dopamine receptors over the course of 5 days, these findings suggest a selective role of neurotensin in the modulation of dopamine neurotransmission. Furthermore, due to the lack of development of tolerance, NT69L or similar analogs might be useful in modulating certain behavioral effects of psychostimulants or have potential use as an antipsychotic drug in humans.