Ž . European Journal of Pharmacology 428 2001 97–103 www.elsevier.comrlocaterejphar The neurotensin receptor antagonist, SR48692, attenuates the expression of amphetamine-induced behavioural sensitisation in mice Fabiana G. Costa a , Roberto Frussa-Filho b , Luciano F. Felicio a, ) a Departamento de Patologia, Faculdade de Medicina Veterinaria e Zootecnia, UniÕersidade de Sao Paulo, 05508-970 Sao Paulo, Brazil ´ ˜ ˜ b Departamento de Farmacologia, Escola Paulista de Medicina, UniÕersidade Federal de Sao Paulo, Sao Paulo, Brazil ˜ ˜ Received 4 January 2001; received in revised form 30 July 2001; accepted 1 August 2001 Abstract Ž w Ž . Ž The effects of acute administration of the neurotensin receptor antagonist, SR48692 2- 1- 7-chloroquinolin-4-yl -5- 2,6-dimetho- . x 4 . xyphenyl -1H-pyrazol-3-carbonyl amino adamantane-2-carboxylic acid , on amphetamine-induced behavioural sensitisation were studied with the locomotor activity of mice in an open-field as an experimental parameter. The animals were repeatedly pretreated with saline or Ž . amphetamine 2.0 mgrkg, i.p. once a day, every other day for 13 days and 2, 9 and 16 days after the last injection they received an acute i.p. administration of saline or 0.3 mgrkg SR48692 15 min before a challenge i.p. injection of 2.0 mgrkg amphetamine. Locomotor activity of the amphetamine-challenged mice was significantly higher in amphetamine-pretreated animals than in saline-pretreated mice on days 9 and 16 after withdrawal. SR48692 prevented the expression of this behavioural sensitisation. In addition, in saline-pretreated mice, the first two challenge injections of amphetamine sufficed to induce a sensitized locomotor response to the third challenge injection of the drug. SR48692 administration before amphetamine challenge injections prevented the development of this challenge injection-in- duced sensitisation in saline-pretreated mice but not in amphetamine-pretreated animals. In order to determine the effects of SR48692 on the expression of amphetamine-induced behavioural sensitisation in the absence of this challenge injection-induced sensitisation, the experiment was redone with a single challenge test 9 days after pretreatment. Once again, SR48692 prevented the expression of amphetamine-induced behavioural sensitisation. These results suggest that neurotensinergic transmission has a critical role in both the initiation and expression of locomotor sensitisation to amphetamine. q 2001 Published by Elsevier Science B.V. Keywords: Neurotensin; Dopamine; Motivation; Locomotor activity; Open-field 1. Introduction Chronic intermittent administration of amphetamine to animals produces a progressive and enduring increase in Ž hyperactivity and stereotyped behaviour Bellot et al., 1996; . Kalivas and Stewart, 1991; Nelson and Ellison, 1978 . This phenomenon, called behavioural sensitisation, has been widely recognized as an animal model of lasting susceptibility to exacerbation of psychostimulant-induced Ž . psychosis Robinson and Becker, 1986 . As regards sensi- tisation to the locomotor stimulatory effects of am- phetamine, this model has also been suggested to be useful for studying mechanisms underlying drug craving in hu- Ž . mans Robinson and Berridge, 1993 . Indeed, whereas substantial evidence links the locomotor-stimulating ef- fects of addictive drugs to their positive reinforcing pro- Ž . perties Wise and Bozarth, 1982 , most drugs of abuse ) Corresponding author. Tel.: q 55-11-3818-7934; fax: q 55-11-3818- 7829. Ž . E-mail address: lfelicio@usp.br L.F. Felicio . stimulate locomotion in rodents and induce sensitisation Ž . Kalivas and Stewart, 1991 . It has been hypothesized that activation of mesolimbic dopaminergic pathways—from the ventral tegmental area to the nucleus accumbens—is related to both the reinforc- ing and locomotor-stimulating properties of drugs of abuse Ž . Wise and Bozarth, 1987 . Sensitisation to the locomotor- stimulating effects of amphetamine also appears to require alterations within the mesoaccumbens dopamine system. Indeed, a variety of data shows that the initiation of behavioural sensitisation to psychostimulants occurs in the ventral tegmental area, whereas the neuronal events associ- ated with the expression of the phenomenon are centered in a collection of interconnected limbic nuclei, among which dopamine transmission in the nucleus accumbens Ž . seems to play a critical role Pierce and Kalivas, 1997 . Neurotensin is an endogenous tridecapeptide which is mainly localized in regions containing either cell bodies or terminals of dopamine neurons, including the mesolimbic Ž . dopamine system Kasckow and Nemeroff, 1991 . Mi- croinjection of neurotensin into the ventral tegmental area 0014-2999r01r$ - see front matter q 2001 Published by Elsevier Science B.V. Ž . PII: S0014-2999 01 01271-7