Chronic Blockade of Neurotensin Receptors Strongly Reduces Sensitized, but Not Acute, Behavioral Response to D-amphetamine

Abstract

This study investigated the effect of a chronic blockade of neurotensin (NT) receptors on the sensitized behavioral response to amphetamine using a nonpeptide NT receptor antagonist, SR 48692. Rats received four injections of D-amphetamine (0.5 or 1 mg/kg, IP) every other day (day 1, 3, 5 and 7) and were then challenged with the same dose of amphetamine after a 6-day withdrawal (day 14) to establish the presence of locomotor sensitization. Daily administration of SR 48692 (1 mg/kg, IP) throughout the amphetamine regimen (day 1 to day 14) almost completely blocked the sensitized locomotor response to amphetamine without affecting stereotyped behaviors (experiment 1). The decreased amphetamine-induced sensitization in chronically SR 48692-treated rats did not appear to result from an influence on basal locomotor activity, as chronic SR 48692 treatment did not modify the spontaneous locomotor activity developed in response to mild stresses (experiment 2). Moreover, we showed that chronic pretreatment with SR 48692 (1 mg/kg, 14 daily IP injections) had no effect on the locomotor activation induced by a single IP administration of amphetamine (experiment 3). These data suggest that a sustained blockade of NT receptors considerably reduces the sensitized behavioral response to amphetamine without altering the acute effect of this psychostimulant or the locomotor activation induced by a mild stress. This ability of SR 48692 to specifically reduce the behavioral sensitization to amphetamine suggests that NT receptor antagonists could have potential clinical utility in the treatment of some psychiatric disorders.