Evidence for a role of endogenous neurotensin in the initiation of amphetamine sensitization

This study was aimed at testing the hypothesis that endogenous neurotensin plays a role in the initiation of sensitization to the locomotor activating effect of amphetamine. During an initial training phase, different groups of male rats were injected on four occasions (every second day: Days 1, 3, 5 and 7) with one of three doses (40, 80 or 160 mu g/kg, ip) of the neurote nsin antagonist, SR-48692, or its vehicle, followed 30 min later by ampheta mine (1.5 mg/kg,, ip), or saline. Ambulatory, non-ambulatory, and vertical movements were measured for 2 h in photocell cages immediately following th e second injection. One week after the training phase, sensitivity to amphe tamine (0.75 mg/kg, ip) was tested in all the rats (sensitization test). Th e results show that SR-48692, when given alone, produced levels of locomoto r activity that were not statistically different from control. At the low d ose, it potentiated amphetamine-induced ambulatory and non-ambulatory movem ents, an effect observed on Day 7 but not on Day 1. On the day of the sensi tization test, rats pre-exposed to amphetamine alone displayed stronger amb ulatory and non-ambulatory movements than vehicle pre-exposed rats, a sensi tization effect that was attenuated and prevented by SR-48692 at 80 and 160 mu g/kg, respectively. The present results demonstrate that activation of neurotensin receptors by endogenous neurotensin is required for the initiat ion of amphetamine sensitization. They provide additional evidence that an increase in central neurotensinergic neurotransmission may lead to a lastin g increased sensitivity to psychostimulant drugs. (C) 2000 Elsevier Science Ltd. All rights reserved.