The neurotensin receptor antagonist, SR48692, attenuates the expression of amphetamine-induced behavioural sensitisation in mice

Abstract

The effects of acute administration of the neurotensin receptor antagonist, SR48692 (2-[[1-(7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)-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 amphetamine (2.0 mg/kg, 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 mg/kg SR48692 15 min before a challenge i.p. injection of 2.0 mg/kg 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-induced 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.